Document DD9NrQVKZ03VEmBoL7gyVezp4

A Case Study: Polychlorinated Biphenyls Edward J. Burger, Jr., M.D., Sc.D. Office of the President's Science Adviser, Science and Technolog)' Policy Office, Washington, D.C. ABSTRACT The Government "decisions" on polychlorinated biphenyls (PCBs) constituted an unusual regulatory exercise compared to much ol the experience of the past few years.1 PCBs had been developed in the late 1926s to serve in instances where high physical and chemical stability were advantageous. In part, precise ly because of these peculiar properties, they became recognized as particular environmental hazards. The processes of analysis and study by the Government for decision were fuller and more deliberate than is often the case. A number of scientific reviews were foined in the process. Benefits as well as hazards were explicitly considered. Regulatory type action was not taken until suitable information was marshalled and recent scientific evidence was given the benefit of interpretation. Finally, the process of deliberation was an unusually open one with the results of analy sis fully displayed. Wtitten for the itudy on Decision Making for Regulating Chemicals in the Environment, Environmental Studies Board, National Research Council, National Academy of Sciences, and undertaken at the request of the U.S. Environmental Protection Agency. Contract No. 66-01-2262, this natter was completed in December 1974. 1 In February 197$, the National Academy of Sciences or ganised a working conference to explore the process of Government decicion-making to regulate chemicals in the en vironment. To assist this conference, a series of case studies of past regulatory decisions waa solicited from persons who had reasonably detailed knowledge of them. What follows is the case study of polychlorinated biphenyls a* one of the aeries used in the NAS study. The maturity of the Govern ment pronouncements and decisions in this instance derived from a series of studies and analytic uxerciacs convened by the Office of the President's Science Adviser. /This study is eiso to appear as a uarl of a book hv the author on rcctilmlon and human health, to he lv I--iinpt.ni Hooka. Inr > INTRODUCTION - NATURE OF THE DECISION The process of Federal Governmcnl deliberation and decision on polychlorinated biphenyls (PCBs) was relatively circumscribed and straightforward. The Government actually possessed little in the way of legal, regulatory authority. Hence, the "decisions" leaned heavily on persuasion and on para regulatory moves. Nevertheless, the Government's decisions in this case did lead to the intended and recommended actions (reduction and restriction in certain uses of PCBs) and a tightening of the procedures governing the manufacture, importation and continued use of these chemicals. Most important, perhaps, was the fact that the de cisions and actions assumed by the Government (and by parts of the private sector) were taken deliberately and on the basis of unusually good analysis and infor mation. the PCB decisions, in hrie^ were unnstnlly well informed decisions when compared to others of this tvne, and the analyses used to arrive at the Jc^~ cisions were probably fuller and of a higher quality than is the case with mosi regulatory actions. The several agencies ol the federal Government concerned with the PCB question contributed to the deliberations and to the analyses. At the same time, an outside group of scientific experts was engaged by the Office of Science and Teclmology to consider PCBs from a broad perspective as a case study of a hazardous substance existing in the environment in trace quantities. The Government's major deliberative body for its decisions was an inierngcncy, PCB Task Force - run jointly by the OST and the CEQ. The case study of the outside advisers lo the OST was time ly and useful to the Government's own analyses. Journal ofthe International Society for Technology Assessment. Spring 1 y 76 otSTA international Society for Technology Assessment, Washington, D.C. HONS 081284 THE ENVIRONMENT - OFTEN DISTANT FROM APPARENT SOURCES PCDs were among (he materials found, but when analysed they were often confused with other sub stances. PCBs were first distinguislved from the "unknown interfering compounds" found in nature in 1966 by Jensen1 and the next year by Widmark.3 On the basis of tliis latter report, the Food and Drug Administration was moved to develop analytic methods to distinguish between PCBs and chlorinated organic pesticides encountered in monitoring for regulation. in February 1969, Dr. Robert Rjsebrough gath ered attention by warning, in an article in the San Francisco Chronicle, of the dangers of PCBs In the cco-systcm. Over the next 6-7 months, the FDA in creased its surveillance of foodstuffs for evidence of PCB residues. Notable positive findings were in fish. Monitoring of foodstuffs, raw agricultural products, fish, and feeds for PCBs was augmented throughout 1970. PCBs were found in fish and in marine animals in high concentrations close to plants which manufac tured the chemical. ACCIDENTAL SPILLS OR LEAKAGES OF LARGE QUANTITIES OF POLYCHLORINATED BIPHENYLS WITH CONSEQUENT CONTAMINA TION OF FOODSTUFFS AND ANIMAL FEEDS. In 1968, PCBs, used as a heat-exchange fluid in a pastcuiizcr, leaked into rice oil being manufactured for hente cooking use in a plant in Japan. More than I ,000 persons were affected by the contaminated rice oil, many of whom cxliibited persistent skin lesions as well as systemic disease (Yusho disease). In July 1971, leakage of heat exchange fluid caused con tamination of pasteurized fish meal which was used as a feed ration for chickens and catfish. In addition to these two major areas of concern, PCBs began to be reported with increasing frequency in poultry and in eggs, and in packaging material for food. PCBs appeared with increasing frequency in 1970 and 1971 in the professional scientific literature deal ing with wildlife and the environment.4'* In Sep tember 1970, the National Swedish Environment Pro tection Board held a conference on PCBs.6 One of * lemen, S.: A new chemical hazard, New Sciential, 32: 612 (1966). * Widmark. (j.: Possible interference by chlorinated biphenyls, J. Assoc. Offic. Anal. Chum.. 50: 1069 (1967). * Pcaknll, D.H.. ami J.C. Lincer: Polychlorinated biplu'nyh. Another longlife widespread chemical in the environment, lllosciencf. 20: 95*- 964(1970). * PvtlmnUn, PC Ns; Leaks of toxic substance raises issues of effects, regulation. Science, 1 7): 899-902 (1971). * PCII Conference, National Swedish Environment Pio- the sessions of this conference highlighted the "en vironmental problem". This conference, perhaps for the first time, brought together the extent of under standing on the manufacture, use, and biological effects of, the extenl of environmental contamination by, and the analytic methods for, PCBs.6 In August 1971, an Environmental Quality Work shop was convened in Durham, New Hampshire, by the National Academy of Sciences, to consider Marine Environmental Quality and Ocean Pollu tants.7 PCB contamination was highlighted. In addition, provoked by both the accidental spills and by the widespread finding of trace quanti ties of PCBs in the environment, there emerged in the lay press a series of stories and articles dealing with PCB contamination. Most of them occurred in late 1971 and reflected especially the contamination of foodstuffs,*14 The FDA, aware that PCBs were to be found as a contaminant in the environment, and alert to the occasionally reported cases of accidental spillages, elected to engage in watchful surveillance of food. It did this in part in cooperation with the Depaitment of Agriculture. As a result of the findings of PCBs specifically in fish and milk, the FDA established, between December 1969 and February 1970, "Action Levels" for PCBs in milk, poultry and fish. Action levels are temporary jhresholds for regulatory decision pending the establishment of a more per manent regulatofy policy and procedure. In August 1970, the FDA established a similar action level for eggs. During 1970 and 1971, the FDA used these guideline values in various seizures of foods found contaminated with PCBs. The number of reported contaminations of foods, recreational fish, packaging maietials and animal feeds increased toward the latter half of 1971. Accompanying the announcements in the public press (and, undoubtedly, reflective of them), there also occurred toward the end of 1971 a senes of inquiries from Congressmen and other elected officials over PCB contamination of food and the environment. On taction Hoard, Research Secretarial, Wcnnertiren Centet. Stockholm, Sweden. 29 September 1970. ' Marine environmental i|ualily, A special study held under the auspices of the National Scientific Committee on Oceano graplty of the National Academy of Science' Ocean Affairs Board, Durham, New Huntpsliire, 9- 13 August 197 i. Monsanto limits food plants' use of chemical I'CU. The Washington Post, JO September 1971. * Some dried foods found (itinied by perilous chemical, The Wathineton Post, 28 September |97|. 10 Tainted turkeys. The Washiuftou Post, 24 September 1971. ' Turkeys, salmon tainted by I'CBs, The livening Star, 23 September 1971. n A contaminant Is found in cardboard. The New York Times, 28 September 1971. l* If you think DDT'* a problem, meet I'CM. The New York Times, 30 September 1971. 14 FDA studying chance of contamination in containers for food, The Wall Street Journal, 28 SL-pteiniH'r 1071. TO Journal of the International Society for Technology Assessment, Spring UK) HONS 001285 16 August 1971, Senator McGovern addressed a let ter to the Commissioner of the FDA, reflecting this concern. In September, Governor Miliken of Michigan sent a telegram to Elliott Richardson, Secretary of HEW, in which he announced a restriction of com mercial salmon fishing because of the finding of PCBs In fish. By August 1971, the FDA (and to some extent, the USDA) found itself rapidly propelled into a posi tion where it would be "required" by public pressure and advocacy to take a stronger and more forthright position against PCBs. The scientific issues were still not dear and there were glaring gaps in information. What really were the biological effects of the complex known as PCBs? How did the various PCBs vary in human toxicity and which members of the PCB fami ly were found as contaminants? Was observed tox icity due to PCBs proper or to contaminants pro duced during their manufacture? How widespread was the contamination, and how good was the moni toring system in picking up accidental spills? Further more, it was clear that (he twin issues of widespread environmental contamination, by trace quantities of PCBs, and the selective, higher level contamination of foods and feed, had to be joined at some point in Government decision-making. On 5 August, 1971, the FDA, on its own initiative, called a meeting of spokesmen from each of several Government agencies and Federal research labora tories to review the state of scientific understanding of PCBs. Die text for the meeting was the reported series of accidental spills and leakages.1' Shortly fol lowing that meeting, the Department of Agriculture and the Commissioner of the FDA asked the Office of the President's Science Adviser to provide assis tance and act as a focus for the Government's actions and decisions concerning PCBs. This request was made because: (1) the issue cut across several Federal agencies and also involved outside scientists, (2) the issue was rapidly becoming uncomfortable for the FDA to handle alone, and (3) the Office of Science and Technology already had under way a scientific review of polychlorinated biphenyls and had quietly begun to gather information several months back. In April 1970, spokesmen for (he Monsanto Com pany agreed to meet with the staff of the President's Science Adviser in the OST to discuss a number of issues concerning PCBs, including a series of animal toxicology studies which Monsanto had undertaken. During this meeting, Monsanto was asked for infor mation concerning the amounts of PCB it manu factured and distributed. The company, being the sole producer in the U.S., was reluctant to make pub lic this information, although it reported that it might 11 Transcript or proceedings of the interagency meetinf on polychlorinated biphenyls (PCIk), Food and Diuf Adminis tration, Department or iU-ulili, Kducatum, nd Welfare, Washington, D C.. S August 1971. be able to provide the data on a confidential, non public, basis to the Government. In October 1970, a review was begun, in the Office of Science and Technology, of the general subject of hazardous substances existing in the environment in trace quantities. This review, known ultimately as the Panel on Hazardous Trace Substances, had as its major goal the identification of the needs for infor mation by the Government in making judgments about trace hazardous substances. The Panel was composed principally of non government experts in the fields of ecology, chemis try, biology, environmental and occupational medicine and geology. Three case studies were begun from which it was hoped to draw gencralizablc ex perience. The particular subjects for the case studies were chosen because they were thought to be of im portance, because regulatory or other governmental action had not yet been taken but could be expected at some time in the reasonably near future, and be cause it was thought that there existed sufficient information from which to draw conclusions. The choices were cadmium, arsenic and PCBs. Thus, as the Government began to develop its own position on PCBs in 1971, the OST-iniliated study was already under way. What followed, in part, was for the Government to borrow the experience devel oped by the OST Panel and even for the two exercises to be joined to some extent. Notwithstanding, a separate and identifiable PCB report was published by the members of the Panel on Hazardous Trace Sub stances.16 On I September 1971, the FDA held a meeting with the USDA, the EPA, the Council on En vironmental Quality, and the Office of Science and Technology, to explore options for further action concerning PCBs. The FDA and the USDA requested that the Office of Science and Technology take a lead role in handling this matter. OST acccedcd to this req uest and agreed to collaborate with the CkQ in the task. This became known as the Interdepartmental Task Force on PCBs. Die Task Force was announced on 5 September in a joint FDA-USDA press conference.11 On 15 September 1971, the OST Panel on Haz ardous Trace Substances and the governmental Task Force met jointly with representatives of the Mon santo Company. The principal agenda item of this meeting was a request for information concerning the amounts of PCBs produced, patterns of distribution and usage, and estimates of losses into the environ ment.16 Again, the manufacturers expressed their '* Polychlorinated biphenyl* - environmental impact, A review by the panel on hazardous trace jub<-tances, March 1972. Knvironmcntal Research, .5: 249-362 (1972), *' Press rrlease on interdepartmental PCD task force. Food and Drug Administration. Department of Health, l.ducalion, It Welfare. 3 September 197). ' Letter from l.dward J. Bur per. Jr.. M.D. of the OST to Mr. John Mason, The Monsanto Company, l S October. 1971. Journal ofthe International Society for Technology Assessment, Spring 19 76 3 I MONS 0dld6 1 I willingness to' supply information of this sort to the Government, but with the understanding that the data would not be released publicly except in a full and detailed fashion. In addition, the Monsanto Com pany expressed some concern over the seemingly disconnected character of the Government's activities up to that time and the difficulties involved in finding responsible spokesmen for each of the agencies in volved. Monsanto made a strong plea (in the form of a condition for iheir supplying information) that they be permitted to deal with a single spokesman for the Government. The office of Science and Technology, on the advice of the Counsellor to the President, did reach agreement with Monsanto on the terms of receiving the information.1* These were shortly rendered moot by a request from the Environmental Defense Fund for the same information. This information ultimate ly served as important background for the Govern ment's decisions and was leaned on heavily by both the OST Panel and the Task Force. The OST Panel combined the production figures and the data on distribution and use with knowledge of the physical properties of PCBs to develop a com posite pictuic of the rates and routes of environ mental transport and disposition. The data were reflected in a series of coefficients for a model of transport of PCBs. While this was necessarily a crude description, it served as a very useful instrument for placing PCBs In perspective. It replaced what other wise would have been a totally qualitative - even intuitive - exercise. It pointed up important gaps in knowledge. Finally, some verification was afforded by the results of physical measurement and monitor ing. This attempt at environmental modelling was a major contribution by the Panel to decision-making. The OST Panel report was also appropriately criti cal in its review of biological effects and analytic methods for PCBs. It considered what was known of the mechanisms of observed biological effects, and relationships between variations in chemical structure and biological activity, and it attempted to compare the effects of controlled laboratory experiments with observations made on animal populations in nature. The Interdepartmental Task Force reflected much of this information in its report. It explored addi tional territory as well - reflective of the fact that it was a Government report wliich focused on a number of specific, pragmatic, governmental or public problems. Thus, as well as serving as a review of the scientific aspects of PCBs, the Task Force explicitly reviewed a number of broad aspects of the PCB ques tion. Most important, perhaps, was the exploration of the benefits or utility of PCBs and of the industrial * Memorandum from John Dean, Counsellor lo (he Preiideni, lo lUlwnrd J. Uurger. Office of Science and Technology, concerning the eeduin of Information Act. 4 October 1*71. and commercial dependencies built up over the years. This explicit review of the benefits of PCBs. wliich is often not done for regulatory decisions, was of vital importance for decision making on PCBs The Nation al Bureau of Standards engaged in a review and analy sis of the benefits and even the "essentiality'' of ouch of the several uses of PCBs. In this, the NBS received advice from the National Industrial Pollution Control Council, especially concerning the electrical uses of PCBs. In each of the eases examined, the question of a possible and satisfactory replacement for PCBs was raised. This review became the basis for the ultimate decision to preserve electrical uses of PCBs (for which there were true dependencies and no satisfactory sub stitutes) and to restrict other uses.20 The Government Task Force report included a sys tematic summary of monitoring experience for PCBs in food. It had been tliis matter of PCBs in food as much as any other wliich liad brought PCBs to public notice. Hence, it was thought highly desirable lo sys tematically lay out the apparent extent of food contamination and to consider what the patterns of contamination would suggest for public policy and Government action. The Task Force Report explicitly reviewed all of the pertinent Federal regulatory laws for their appli cability to PCBs. This was, therefore, an exploration of the power of the Government to control and limit the manufacture, distribution, use and disposal of PCBs. Tliis review pointed out sometliing thai was already known - that existing regulatory authorities were capable of responding to specific incidents of contamination of foodstuffs once they were rec ognised. However, it acknowledged that the Govern ment's legal armamentarium was generally .. inadequate to prevent more PCBs from entering the environment".10 In addition to the above, the Interdepartmental Task Force review considered the chemical and physi cal properties of PCBs, the occurrence, transfer and cycling of PCBs in the environment, and the known biological effects - especially on man. During the time that the Government review of PCBs was being pursued, the level of public concern over these chemicals continued to rise con siderably. For tliis reason, the Commissioner of the FDA felt compelled lo held a press conference lo ". .. try to help establish a perspective on PCBs. . rougldy a month after the Task Force had begun its work.21 This was an appropriately reasoned state ment which attempted to allay fears and discourage demands for a sudden, outright ban on PCBs (even if re Polychlorinated biphenyls and the environment. Interde partmental task force on PCUs. Washington, D.C., May 1972. National Technical Information Service. U.S Department of Commerce, Sprmclicld. Virginia. No. COM - 72- 10419. ii Statement by Clunks C. Ldwerds. M.O.. I'CU press brief ing, Food and Drug Administration, 29 September 1971. 32 Journal of the International Society for Technology Assessment, Spring /') 76 MGNS 081287 (he Government had been capable of invoking one). The statement deferred to the ongoing process of re* view and deliberation as the basis for considered dc* cision and action. There was, finally, a third review of PCBs under* taken within the Federal walls. One of the national institutes of health, the National Institute of Environ mental Health Sciences, had sometime before elected to conduct a series of "scientific" reviews of materials which were of impending regulatory concern and for which no systematic accounting of scientific informa tion had been done. The pliilosophy in this ease was to bring together, in a conference, spokesmen for the principal research projects - published or under way - in order to take the measure of .the available scien tific understanding. At the same time, members of the press - especially scientific writers - were invited to attend these sessions, in order to enjoy the pro ducts of (his review process. The aim was to educate both the scientists and the public. In December 1971, the National Institute of En vironmental Health Sciences held the first of this senes of conferences in Noith Carolina, and it was on PCBs.12(Since then, die NIH has held similar reviews on lead, automotive emissions, and other substances of current public and governmental concern.) Many of the same spokesmen who were engaged in the other reviews made presentations at the "open" conference. One of the major accomplishments of this meeting was to impart an understanding to the press and sci ence wiiters of the character of the scientific evidence and the scientists' own interpretation of experimental findings. The net (and immediate) effect of that ex ercise was to take the newsworthiness out of the PCB issue and to remove it from the category of the sensa tional. Very little was actually reported in the press of that meeting. More important, relatively little more was reported on PCBs in any form in the lay press. The principal "control" actions for PCBs were the result of persuasion by the Federal Government rather than by direct regulatory exercise. The Govern ment possessed no real regulatory authority to con trol the manufacture, distribution or use of PCBs. However, the persuasive influence of the several Government inquiries - especially the PCB Interde partmental Task Force - was not doubted. Thus, the major action was taken "voluntarily" by the Mon santo Company, the sole U.S. manufacturer. Beginning in 1970, the Monsanto Company had begun to reduce the sales of PCBs - especially for non-cicctrical uses. Domestic sales for PCBs for non- electrical uses had risen from 12,000 tons in 1968 to 16.000 tons in 1970. By 1971, this figure was re duced to approximately 4,000 tons.IJ In addition, the Monsanto Company quietly assumed for itself the role of distributor as well as manufacturer in order lo exercise some control over end-use of PCBs. In this way, the manufacturer was able to "discontinue sales of PCBs for use in paints, plasticizers, sealants, ad hesives and other `open-system' uses". Thus, during 1971 and 1972, the Monsanto Com pany also restricted (or attempted to restrict) sales of PCBs to installations in which food or animal feed was processed. The principal recommendation of the PCB Task Force was the discontinuance of all uses of PCBs ex cept in electrical capacitors and transformers. These latter were judged to be essential uses and represented "closed systems".M To the extent that it could exer cise this type of restriction on distribution, the Monsanto Company again undertook "voluntaiily" to control end-use through its contiol of the manu facture and sale of PCBs. OBJECTIVES The Interdepartmental Task Force report on PCBs was issued publicly in May 1972 and was accom panied by a statement of governmental "thinking" and governmental "action". Perhaps the major con clusion reached in the report, which became an objec tive in Government decisions, was that of limited restriction on PCBs. PCBs were seen as having certain essential uses in electrical transformers and capacitors and it was judged in the country's best interest not to be totally denied the use of PCBs. This was a direct reflection of the analysis performed by the National Bureau of Standards of the utility and essentiality of PCBs, which pointed to the possibility of an increase in fires and explosions from encased or enclosed transformers if PCBs could no longer be used repre senting the possibility of trading one hazard for an other hazard. In addition, it derived frum the attempts to map out the patterns of environmental dispersal of PCBs which lud been lost fium human use. Electrical applications were seen as "dosed" ap plications and were not thought to contribute to en vironmental distribution. Other uses of PCBs were reviewed as either not essential, potentially or actually contributory to the environmental "load", or were found to have suitable substitutes. This, then, pointed to an elimination of National Institute of environmental Health Sciences meet ing on polychlorinated biphenyl* (PCBs). Kougcrnount, North Ciirolinii, 20 2 1 December 1971. Proceeding- pub tithed in Environmental Health Perspective?;, Experimental Iflur No. I, April 1972, National Institute of Environmental Health Sciences, Keseureh Triangle Park, North Carolina. Monsanto Industrial Chemicals Company, press release: Monsanto releases PCB production figures to Department of Commerce, SO November 1971. m Press release accompanying the release or the I'CU interde partmentai task force report on PCBs. Washington. DC, 13 May 197?. Journal ofthe International Society lor Technology Assessment, Spring 19 70 33 HONS oeueti essentially all oilier uses - heat exchange fluids, hy draulic fluids, and (he miscellaneous category of "plasticizer" uses. The objective of limited restriction became (he basis for governmental persuasion of the Monsanto Company to restrict its distribution and sales of PCBs - in fact, the principal governmental action. Highlighting of the fact that true regulatory con* trol by the Government was limited, became the text for a plea for passage of a then-pending bill in Con gress to close Uus gap. A second objective, then, be came the enactment of the Toxic Substances Control Act which would permit the Government to exercise useful control of industrial chemicals at their source. The regulatory tools wluch the Government did possess in this case permitted enforcement action after PCBs were found in foods for human consump tion and in animal feeds. Here, the FDA and (he \JSDA re-stated their thresholds for action (whjch had been evolving over the previous four years), and announced the strengthening of their monitoring and analytic efforts. The other avenue of governmental control was that over industrial effluents and ambient water quality, lleic, (lie Environmental Protection Agency stepped up its effort to assess the foreign chemical content of waters downstream from plants manufacturing PCBs and the Justice Department was close behind with enforcement teeth. The processes of review in (his case explicitly sought information for a broadly-based decision. Thus, there was a dedicated attempt, for example, to determine the benefits or utility of PCBs and of the costs that could be expected if their uses were re stricted or denied. This information was later found to have been highly influential and important in formulating the Government's position. One other element of information which proved to be important was the analysis of environmental distubution and dispersal. The analysis itself was some thing of an experiment. It was reasoned early on by the participants in the OST review that it should be possible, starting with somo elementary information on total amounts of PCBs produced, and patterns of distribution in commerce and disposal, and armed with a certain elementary understanding of physical and chemical properties, to build a model predicting PCB distribution in the environment. Tlus, in fact, was done, and the coefficients used in the model were partially tested or "validated" against the physical measurements of PCBs in the environment which had been reported in the literature. This exercise and (lie information from it became the basis, for example, of the judgment that PCBs used in electrical capacitors disposed of in the earth by burying in landfills would not be expected to migrate very far through (lie soil and would not represent a significant source of en vironmental pollution. INFORMATION The PCB "decisions" were perhaps among the best informed of governmental actions of this type in re cent years. There was, it turned out, a certain body of scientific and technical knowledge about PCBs and a modest documentation of past experience. In addi tion, this information was better assembled and analyzed than was usually the case. Perhaps time was an important factor since time was permitted for deli berate and reasonably careful study and reflection before decisions were announced. Thirdly, there was more opportunity for public airing and scientific interpretation before decision-making than is usually the case. A Swedish scientific meeting on PCBs had been held in 1970.6 The Office of Science and Tech nology had begun its review and analysis of PCBs by December 1970, and the results of its analysis were made available as they emerged. The Government's own scientists reviewed and interpreted the base of technical knowledge over roughly six months begin ning in September 1971. In December 1971, a third forum of scientists was convened by the NIH to re view much of the same material. Thus, the process of interpretation and maturation of data by scientific peers - while characteristic of the traditional scienti fic process but unusual in regulatory decision-making - was played out in this case. IMPLEMENTATION The principal "decisions" deriving from this exercise were to restrict PCBs to "closed-system" electrical uses. There soon emerged a few additional Issues which reflected either loose ends or areas which de serve some additional study. The principal reason for denying the use of PCBs as hcat-exchangc fluids was to avoid accidental spills and leakages of PCBs into foodstuffs (where heat was used to "pasteurize" the food material). However, there were often PCB heat exchanger applications. One of these, for example, involved (he use of heal on off-shore oil rigs to maintain low viscosity of the oil. PCBs had been chosen here because of the charac teristics of high thermal stability and low probability of fire and explosion, and many of the heat exchange devices had been designed specifically around the use of PCBs. Denial of the use of PCBs in this case raised the spectre of an increase in the number of fires in off-shore oil rigs or the continued use of PCBs from imported sources. This general question of worldwide (as opposed to U.S.) production and use of PCBs, became a matter of immediate concern. There was an early visit of a spokesman from the Swedish Government to live Office of Science and Tccluiology. The Tariff Com- 34 Journal of the International Society for Technology Assessment, Spring 197() 08 ily mission end (he Customs Bureau were pressed to They represented, instead, persuasion and voluntary in. search for signs of imported PCBs.2* Perhaps most action. It is worthwhile, perhaps, to examine some of IQ useful was the fact that the OECD was persuaded to the factors which contributed to any successes that he take up the question of the industrial production and can be claimed. re* commercial use of PCBs in the industrialized parts of nd the world. PCBs. in fact, became the major example 1 The PCB decisions represented, perhaps, a some in of intergovernmental "consultation" in a mechanism what more manageable challenge than many. which the OECD had established for this purpose. Only a single U.S. manufacturer was involved. TO The U.S. position and the information behind it be* Further, the majority of commercial and indus came major elements in the OECD position paper26 trial uses and the major users were known. T* and in (he deliberations at the OECD in November 2 There was some information which proved useful ny 1972. in decision-making. Quantitative figures showing oe Trace amounts of PCBs in packaging materials be production were provided - albeit only after a jn came a matter of particular concern. In part, (his was delay - which were essential in determining the of due lo uncertainly over their origin. There was some scale of the problem and its change with time. .ed evidence that trace quantities of PCBs were magnified Similarly, the corresponding figures for com ;al in the process of recycling paper. To the extent that mercial distribution were essential in ascertaining jig this was true, the Government and national policies the patterns of human use and dispersion. To ;l, aimed at recycling were seen to be in possible jeopar complement these data, there were at least some .re dy. One of the principal motives for exploring tills results of physical measurement and monitoring :al particular issue, apart from the economics of paper of FCBs in the environment or indices of dis .ad and cardboard production, was the contamination of persal. he food wrapped with PCB-conlaining paper. There fol In terms of hazards, there was a legacy of at of lowed, therefore, a scries of investigations by the least some documentation of previous human ex *n Food and Drug Administration into the process and posure and some laboratory data. However, .iid rate of migration of PCBs from packaging materials many questions remained. Perhaps, most impor Jil into foodstuffs which the packages contained. In tant, was the luxury of critical review (in fact, n* December 1972, (he FDA produced an Environ several critical reviews) of this information. Fur mental Import Statement (perhaps the only one of its ther, these reviews engaged some very good scien kind from that agency) on its proposed rule-making tific talent - both inside and outside the for PCBs.27 Among other things, this document sum Government and in a way which permitted (he marized the FDA investigations and positions regard ing PCBs and packaging. decision-makers to be very well informed of their advice. In terms of benefits, a specific analysis was ;il commissioned of the utility and essentiality of ei CONCLUSIONS, OBSERVATIONS, AND PCBs. (It is interesting to note that while this was je* RECOMMENDATIONS done well, the National Bureau of Standards en tered into lids exercise very reluctantly, seeing in Bi The Government "decisions" on PCBs constituted an it the perils of the battery additive episode of lb unusual regulatory exercise compared lo much of the some years before.) tt experience of the past few years. In the first place, Finally, there was performed the unusual the Government's position was generally well pre but highly useful attempt at modeling the pat pared. Related to that was the fact that time was terns of rates and routes of distribution of PCBs el taken for deliberate study and deliberate action, even in the environment. This was done for the most ne In the face of public outcries for immediate action. part as an experiment lo determine whether such c- Thirdly, the "decisions" were taken without much an exercise could be performed. It did, in fact, ty tangible legal aulhotily for governmental control. provide some useful and immediate insight. ge 3 There was a single spokesman for the Govern se ment. The agencies involved early dcici mined ed in > Letter from Alvin Alia. Council on {environmental Quali ty, lo Mr. Vernon Aeree, Commiaaioner, Uurenu of Cuatoma, 22 June >972. that the PCD question cut across several depart ments. This, by itself, was probably not per m it OtRNitiration for (economic Cooperation and Develop suasive and the joint request from itic FDA and ment, {environmental Directorate, Sector Croup on the USDA to tltc OST lo "lake on" the I*CB to Unintended Occurrence of Chemicals in the (environment, Polydtloilnalod biphenyls - proposals for concerted action, question arose also from a desire on their part to er 13 October 1972. push on to someone else a tough or "hot" de ne n ("nod and Drue Administration, Final environmental Impact statement. Ilulc making on polychlorinated biphe nyls, Department of Health, (education, and Welfare, >8 cision. it should he noted, also.that the OST had already begun a review ol PCBs. :n* December 1972. The fact (hat ihcic was a single spokesman Journal of thv International Society Jar Technology Assessment. Spring / v 7/ 35 HUNS OBU90 proved important in arriving at an orderly de cision. The Monsanto Company insisted on deal ing only with a single spokesman after months of unconnected and frustrating interchanges with a variety of Government agents. The fact that there was a single spokesman also undoubtedly made it easier to amass and analyze in an orderly fasluon the variety of information from several sources. The fact that it was an Executive Office spokesman was probably important in soliciting certain other studies in parallel (such as the National Bureau of Standards' study of benefits) and the review of the Government-wide legal option for regulatory action. 4 Although already mentioned, the scientific infor mation (especially that related to biological ef fects) underwent the benefit of several reviews. Tills had two salutary effects. It assured scientific interpretation by peers and it developed a con stituency among scientists for the decisions ultimately taken. 5 The decisions were deliberately broadly-based. While tlus may appear elementary, this facet is generally not characteristic of regulatory de cisions concerned with human health. Both bene fits and hazards were explicitly explored. Economic consequences were considered. Each of several avenues of possible action was ex amined in turn. Again, a single spokesman for the Government and one placed above lltc opeiating agencies was probably a necessary feature in tius broad examination. 6 The decision process was a relatively open one. The fact that there was an Interdepartmental Task Force was public knowledge from the out set. The Task Force published its full report. Similarly, the reports of the OST Panel on Haz ardous Trace Substances and the report of the NU1 meeting on PCBs were published. Further, science writers and other members of the press were specifically invited to participate in the NIH meeting. (Note that the question of freedom of information was a matter of some concern during the deliberations of the Interagency Task Force in the Office of Science and Technology. 7 Time was permitted for deliberate decision making. At one point, in fact, the Commissioner of the Food and Drug Administration held a press conference in which he specifically an nounced that he would not proceed with an out right ban on PCBs and deferred to the study process that was then underway.** Tills, of course, contradicts the classical argument which insists that Governments must make regulatory decisions immediately without the luxury of time for good decisions. MGNS 081291 30 Journal of the International Society for Technology Assessment. Spring IV 76 iV'.i'-wppffl IT Ml L imvii oi <h.> *ni> Ai'rt ii M i'iukmai <u ih.v 32, 461 - 473 (IV75) A Comparative Study of Two Polychlorinated Biphenyl Mixtures (Aroclors 1242 and 1016) Containing 42% Chlorine on Induction of Hepatic Porphyria and Drug Metabolizing 'Enzymes1 Jc)V( I A. (im DSIMN. I'MHK I a I ll( k MAN, VlKI YN W. Hjjkm : AND lllNOA |)l IU.MAN / III IIHIIIIHIllllI t'l >(,, Hull .fl/l'/ll I . \tll<flHtl l III II HIIHII-Hllll Ni u lltl7/ ( I llll l . Ki m,m il lii,iiH!t. I'mk. \.-nh ( u,.,fiii,i 27711 Kt't tut i ii Jiiii,` 14, !'>74. ,t, n/H, ,i Km , nth, r 37, f/74 A Compui alive SUwly of Isvo IMysMorinatcd Hsphcnyl Mistures (Altklnrs 1243 and I0l(> ( 001.(11)1111: 42 '.. ( liloOOC no Indii.linn ol Ili'p.ilic I'oiphyru .io<l Drug-Mctahoh/mg l.o/ynics. (umsitiN, J. A , III! k.MA\, P. Ill .KM . v W AND UlUllStAN, II 4 1 *47 5) foMin/ !/>/>/. Ptutruutc i/ 32. 4<>I 4 73 An k lor I 242 and Arm.lor 1016 arc polyi Itionnalcd biphenyl ll'( II) mixtures will) similar thloi me content |J2 is 41 hut Arixtor 1242 contains H",, biphenyl liomv'logs with live or move ehhnmcs while Am>cIoi 1016 contains only I The cOccK of Auk lor 1242 and Ariklor lOlh on induction of hepatic porphyria and iliugnteiaboli/mg Ctt/yiPCs were compared m female t.UsJx^UH) ppm or $00 ppn> of cash Al I wk. Ariklor 1242 markedly increased Incf weight and all drtigmclahnhnng pathways tested imludmy cyinehioinc P-450, irver weight. .Vdemclhyl.isc. nitroreductase. uptime hydroxylase. ami gluvumnyl Ir.iOsli'i Use. while Anklor 101h had produced only very oiinini.il effects. Al h tin*, howe'er. ol cither Aioclor markedly iiurcascd drug- niclnhohsm. white at Ov lower dose. Aroelisr lUKswas mn.lt Ivss etfcctise .TTanXikho 1242. noth doses ol Ariklor f242'jTrbihiccd poiphyna, but pill) tile lirgliii dose til Aiikkn J 01K ii .is p.oi'liy iMgertk . Mic poiphyiin occulted altei a lay id l <t nui.md vs as chat as to wed by s'seivimn and hepatic storage ol iiii'poiph'rnis Aitkloi ii'Mic eoikcitlraiions weic sirnd.ii m fats led epu.il doses of ihe two mislnu's I Ivieloiv. the ui.n ketl dilleiences in the hioloek.il erVects of i\ toe lor UH<* .tint Aiiklm 1242 cannot he cvpi.iioed hi ditlcis'ikcs 111 ah' >i ptioii. Mk'i.iholism, i>i evsic'iion Polyihlotm.iU'd biphenyls (IVIU) :uc iMdusin.il clieitnciils winch have lieen widely used and aic n n lev pi c.ul , oot.iintii.iiils t if the cut n muncut ( K imI'i migh i7 ul . 10(iN) In the United Mates. I'l IN .tie sold uudsi the tt.ulcm.uk Arikloi l hey .ire tmvtoies eoiil.iiniMp varu'itv percent.ipcs *| oriMineally l*otoitl cliloiine by weight. I'CHs have Iki'lt found in hmnoM lustre and "ere levponsilde lor ail oiithrcak t*l cldoiaerie in * A pi i Inn in.n \ iipoti at ilitv u.tik was puv.nl,,l ,u (he aiHin.d iliivnng ol ihv I , lUnnion of Am, <k.i n S-s u in , I, *i t s|H rum ni.il I)ii>Io)-.\ . Allan lie t to . Nviv Jersey . \*i 0 l`D t |/.,/ 33. 2l`(pl7t)| ` I'li sent .nldiess: l ii'iiniei Pi otloels S.ileiy ('nonntvsion, 1 J3l) NV Peaeirli ee N\V. All.tnta , (i.i, JIMO'I l'lMlulH 1 I'O'I.. .1.1.1,.,... I',,..V. I.MAll I llll'lv l I.'I'..-I.I, I...,, Ml I.H ,,, I'lMIk'll Ml I ill ll III II .11,1 4M HONS 081292 ip 1 . J. <*f '"-syryF'+i * "Ml y* >' 9 < ft" "T * \ 462 t.OI |>\l I IN I T AL. Japan Oobhs. 1972; Kmal'imc rf ul, 1972) Chrome exposure to I*C Ms results to poipliwi.i icMinhlmg lic\achloiohcu/cnc poisoning, chai.uicn/ctl In delayed onset ami massive mcicascs in urinaiy .nul livei uiopoipliyints ((loMsiem </ n! . |*)74a) I'Clts aie also knmm to induce Hie admlv ol ilie hepatic imscil lumlioti ovulasc syslem which me I a boh as loicien chemical ami endogenous slctoids || nicisl , t ,,/ . 19/2) Miese authois icpoiieit dial diesis on the microsomal nuved luiiclioii oxidase syslem coi related dnccily with I he pcteenl eliloime. Il has Ken `spoiled that biphenyls with lughci numbers ol chlorine per molecule aie retained m tissues lor longer pcuock of tunc. while biphenyls with fewer numbers ol chlorines appear io be prcloreniially mclaholi/cd ami cveicMed (Weiael ami Smith, I`>74; Cm ley a a!, 1971). Ihcfcicniial relenitoo ol highly chlormaieil biphenyls could explain the greater hiologic.il cllcciive- ness <.t highly chlorinated PC H imstmes compared with mixtures with lower percent Chlotmalion Ai pieseni, sale of American-made I'C B> is limited largely to uses as dielectric lluiils in capacitors ami iransloinicis ( iiircmly, the major l`CIJ iniMtnc being maikctcd m the Umicd States is Atoelm H)l{>, a mixture containing 41 .V'.. ehlotmc with a veiv Imv pciccntaec (I *',,) of biphenyls with than lour ylUnnncs per molecule Only one study on the bioloeie.il elfesis of Aroclor 1016 has been published. 1 his - tmly enmpars-il the elleds ol Aroclor |0| 6 w till Arodoi 1254 (a biphenyl mi si me coni amine 54",, chlotincl on eettam pathways of drug metabolism leytoehrome P-450, ethvl- morphme A'dcmclltylasc. aniline hydroxylase, /oxa/olaimne, and hexoh.n biial- metabolism) alter ad minis! iai ion lo rats of 25 inekg day lot 6 days (Nickers ,/ </, 1972Aroclor 1254 produced up to a 3-fold increase in some drug-nietaboli/mg cn/.ymts, while the maximum increase produced by Aroclor 1016 was 40",,. l.tlvets of chronic al_minisliaiion of Aroclor It)jf were nAlLdetcnnincd. jl.iiterst w at. (1972) reported up It* threefold increases in mirorcuiKiion of/'-iiitrobcri/oic acid and hydroxyl-" ulion of pentobarbital by Aioclnr 1242, a mixture containing approximately 42",, chlorine. because of the reports that, in general, biphenyls with greater numbers of chlorines aie, esc re ted. it appeared possible that the lesser dice is ol Aroclor INI 6 could he clue lo in eat ei metabolism and or excretion because ol its \ eiy low eon ten I of lug lily chlorinated biphenyls In addition, u was not known ulirihu Aioelor 1016 oi Aroclor 1242 wete less poiphsiueeni. than other Aioelor nmiuirf 4 hciefoie, the pieseni study was iinileii.ikcn to cunpaie the elfects of Aroclor llilti with .moilicr chlonnaled biphenyl nusluie. Aioelor J242jA\nh siiml.n chloime eonteni (42"..) but containing 9"., biphenyls with live or moic chlouucs vs I loi Aroclor IOI6.ll Meets of two relatively high d.oses of Avoc h>i 101 6 an.I Aioelor 1242 w ere computed at both I w k and 6 mo on a Lore variety ol' di ue-metaboh/ing pathways as well as porphyim accumulation m.l esueiion In addiiioii, lotal P( M content ol liver ami hit weic comp.Hid ulin i.hmmslianon ol comparable doses ol (lie Iwo compounds Minions I bn iy I - mo old Iciuaie ShcMii.m iais wcic cl i s it led into live groups of six each and fed pi inmit Pm 11in labm .il.u y diim mi him uni conlaiiliiiu IIX) oi .'`IB) ppm Aioc lor 101 (i (lot No K M-06- 756) (Moi is.nil o ( hemic a I ( o . Si. I .outs, Mo ). oi plain chow. Hals wcic sac i diced by dceapii.ilion jlici I wk An additional >0 mis were Healed m a HUNS 0S1^93 siimi.u Is 24 hi ( i< .Mu < . as )>o saw* la.e m ' .1 glue tunny liesn-.pein use, ami i Amlin* by imiMlioA * asc by vhr lirodfv. (9 Pm phs i ol drug M mtctlVrc.l .ilkahot' - (Kali* .m*` phynt Hss removed j rc.icticMis 1 weic a.-p was picii| nates vet o.uinnopl Uii.illi'Cter Mit u s. On l ill a M pi ol.in (I (Cioldslei* .7 ph au.ily o .1 by i#*n|u KitsuM lest t>i 1 At I . I A den. lb t'lni ni.aiv nn'd. mlc com i .r i ..I sun on ai* pm . III <IM`I l.ll ,/. I.IM' ml' it'tl' Ii.il lltC' t i Ml ituU I III -i'iy Inis litis In I >11.ll MM- '/'I SSl i; % cl ..... 'I Ills t loi lllllv -llvil unit' I SSI I uk Will .veil* Illil Kill 1'< Us ON l-OKCM'l RiA SNI> DHL'l. Ml UUOI.ISM 463 similar fashion .uul saenliccd .il 6 me. Urine sens collected in metabolic ca^cs for ihe 24-hi |h>iiciI pieeedmp sacrdite Alter s-KiilKc, liver homogenates. 90(H) e Mipertiaies anil microsontcs svcrc prepared as presiously desci iheil ((told stem < r </ . 197*1.11 aAminolevulinic .uni (A l A)sen the* lasc was assayed m whole lisei Iwmioecnaics iMarsci ft ul. 19(i(a). Ammophciiol gltivmonyl (i.iiisleiase ss.is assayed nt imi'iiiMunes ei|iuvaleiH to >0 ill" ssei ssi of liver (resuspended in I IS'',, ktl) in (he piesencc of 0 .V'|( difilonm ami 2.7 mol ml ol linPUAK.cItUleiiiamlTamoe. I96M Aimimpyt ine A'-dcntclhy Ijtso. aniline hvdi osylasc. anil mhotcduct.isc sscie ass.tyesl m 9000 e supernalcs (tioldsiciii rt ul . 1973b) Aniline hwliosylasc ssas assayed in the d.uk Adcmcthyljsc was measitiesl hy deter mination of loi m.ildclisdc piodtucd l< oehm and Axcliod, 1959), ami a mime hydio\\ Iase by ilcteimm.uion .a /l.llnulol^Cl/olc acid from /'nitrol>en/o'c acid (I outs ,uh) Mrodtc, 1957) ssiili the followme incshliealitm. 1`iuplis i m m Inei iiaciicns li cm pcrpiiyi ie rats inicrlercti vs it h an.il> sis cf pit id nets id'dine itKiaholizme enzymes by pimbicin^ Inyh blanks In addiiicn. poiphyims inletI'crcil spcuhcalh ssitb analysis olp-aminophcuol sshieh is coupled with phenol in alkaline solution lo form an mdophcnol dye ami measured speedophclometiically (K.uu ami (ullcitc. 1965) The icactiou produel ssas uuslnblc in the pi esc nee of porphytic tissue, disappearing ' ai uibl) d urine the read ion period 1 herd me, we i oulmely removed porphsim Irom ail proiein-lree supcmnlani fiaebons of diiifmelaboli/mg reactions by l lie addition oi 50 me ml tale (o the incubation mu hires alia I he reactions yvcrc stopped with acid. 1 be talc, sshieh adsorbed the poiphynns in acid conditions, was precipitated by ccnirduj.'ahon at 2000 c lor 15 mm. and the porpits rut lice supernates svcrc analyzed for /'ummopbcnol, formaldehyde. /r-ammobcn/oic .iud. or n>ainmophenol elocuionitle as described above. Recoveries ol'all compounds sscie unallVcleil In laic. Wierosom.il cytochrome P-450 and protoheme svcrc determined by the methods of Omma anti Sato (P>Ma. hi mane an Amineo l)\V-2 spectrophotometer Mieitisonial protein (l.ossiy / ul. 1951). iismic poiphvuiis (l)oss. 1967). unn.ny pnrplnims (Ciolilsient i t <</. 1974a). anti urinary AI A anti poiphobihnoecn ll'M(i) (M.uver ct u!. 196bb) sscie measuieti as previously deseubed. 'I issue icsidues of PC Hs wete analyzed by pas thiomaiociaphs (IK) tisine a Mteio Tek M T-220 and iiy.intilatcd hv eomparm!' the miiii ol the peak hciehls with the sum ol total peak ticmhis in the cm rcspondm* Ann loi >1.uul.ml (l 'ui lev </ a! . 1971) Results tsi-ie ana Is zed In an.ils ms of sai lance tollossed by Duncan's multiple ranjjc lest (Steel ami I on ic. 19(>l)) KINUI.IS , Allut. '00 ppm ol Atoelor 1242 ntaiketlly meieased es iocliiome P-4M) (4-fiKt). A' tlemeilisl.i't' 4-- ' told), amlim' bstbosyl.ise (t> s loltl). mtiiuesluci.ise (3ddld|. fltti'inonyt ti.mslt tasc (-Mold), and nm iosom.il pioiotieme I 2.<'*toltl I. ami protlueetl imulfiate imit.i'cs in /\l /\ synitiei.ise tand bset wetelil (2S'`,,) (lip. I) In eon!i a4. 5(10 ppm Ai ol loi 11)| U jti o,luti'vl only a So iik ie.o-t' in hum ai/vmc JI tk'cts cl S()p ppm /\iu loi 101 (> wfic -uplift.mils Imsci itiau iliosc cl suo ppm Ai ctlet 1242 on all pai.imt ieis estept nitioietiiicUise. I lie smaller dose ol loti ppm Au'cUu 1242 MUNS 081294 ..vvl.WV '! 'lll.ll , iK i i.Mil 4'0 and \ wetphl PCIlS ON I'ORl'tlYKIA AND ORUO MI-TAIIOIISM 465 reductase (2-liilih, aniline hydro*y|,isc i2 loldh aiul liver weight (.20",,} (lig 2) llowe\er. ilk* elleets of 5tK) ppm Aroclor 1016 were sign idea nil) lower than I lie elleets of 500 ppm Aroelor 1242 on aniline h)drosylasc. nitroreductase, and gluemonyl lianslci.isc Al ilk' low iltvsc ol 100 ppm. Aioclor 1016 had icl.nnely slight elleets, in l<i*i> * lm m .. n*l(. uni Km. 2 l lUi l i>1 \nvtui ' 111 in ,ml 1242 >n cy loehronk' P-4$0. dniii-me'a holi/iii_cii/) n\o. pi outIH'IIK*. IllCI v*e'plil. Iiti'i Ilt>vi.`v>i|i|,,| PI..UIM, ,1 nil At A syillik'lM^; iklmli .11 |f> mu I < I mpv >>l m\ iviii.iW i.iis Uil H>U hi >nu i'ihii m Aiod.tts lUlfiJinl I 242 wcie s.iciiluul ,u iMm^Calnes lepicscni imam i M.. a SitmilK.inM> (lOMicr lli.m eomrokui /> - 11.05. h KM) ppm A metot | 2 12 m|!iiiIii .mlly jiK.Uvt item mo ppm AtHvliii lOMv ft U.U5. e 500 pjwn AhsJoi 12H Mgmttvamly gie.iUr lli.m 300 ppm Amt lor I0l>, /> : 0 0j. eontrast to the marked elleets ufQVtoeUn 1242. lliesc ddlvienves woe statistically sipiolk.Mil lm aniline liwhovyl.ise, nilrmeduelase, glui'iuoii) I liaiisleiase, and AI.A synthetase. Weight pain u.is Mi:inlaanfly decreased only hy the high dose of Arocloi 1242 at OnintlM i lIvsIOO ' 7 p)At 6 im >, I lie dose of Aiikimconsumed was 6 my/kg/day I'm nils led too ppm Aioelor 1212 or 1016 ami 40 mg/kg, day I'm rats led 500 ppm MOWS 0ai^9t> 1 -Mi.,. ' n' '1 'A i 466 <.Ot lMU\ t < .U . Amdcr 1242 or 1016. The uterineJtnms of most tats on both ilo-.es of Aroelors 1016 ami I 242 sscic swollen ;tl l ssk ami markedly swollen m (> mo. PiHfiimw Al I wk, neilhei Aiodor l()l< or Aiodor 1242 had .my ellevls on liver or urinary porphyrins m' I'lHJ tl n*s. .4 and 4) l iable I). A small increase in urinary AI.A was seen in rals led 500 ppm Aioelor 1242, but the si (mm treaties: of tins imo ease is vpiestiun able. At 6 mu, however, bodt dose.s ob*Arodo| 1242 ami MX) ppm 1016 produced larye increases in hepatic porphyrins fflOOOdbld/(Table ifTind uroury uroporphyrins (2<XMoUl| (I ie. 4) ami moilcrale intHHises in coproporphyrm {Hdnitl). urinary ALA and PIKi (approx. ) and JO-lold) (fiy 3). The porphyrin toutul m the livers of III. 4 | Its. I'lvaun. m is a the |ir, | vnui.i'K .1 ft i I leuvm Kit., .V I lh- in ol \rodors 10(6 ami 12-0 on unitary A (.A and IMK5 Wats were irealcd as described m l`i|ts. 1 .in,l in me iv.,s evilh'v icvl m iikIimiUi.iI meUlHilk sayc- lor 24 hi prcsetlun* s.ierihcc Values lepiv'em iik.ius ` SI I he ntintbcrs above the hats represent live ptsipoumn vl animals whose individual v.il.s nciv mils,de iIk* n uniideiiec Imnis of (lie emm oh a1p < 0.01. a Sipiilie.inUy ddeietw 1'ioni onwroh./ 0 0'. IM ll-iie.ilvd i.iis .is idcmdicd .is v and 7-carbovyporph\tuis foils' ol die vats Veil MXI ppm Amdoi lOlo showed .my eMilcnce of mcreitscd liver m nimaiy porphyrins Analysis *| iiim.iiv \l k. PIU*. ami porph)ims at 12 days. 2 mo. 4 mo. ami 6 mo showed ilvai potphwtmuu oveurred alter 2 0 mo. Theie was no dc.u imlicaiiou ol a vhlleiv iu nine vouise in ihe vlcvelopment of pot phyri.i in Aroelor I 242 v\ Atodut UIU lie,tied oils f (\MU' /'( 'It (m ( omp.iime the (( pi utile ol tissue I't Us horn Aroelor 1242 ami Atodoi HUhlcd .mniials with ilie (( po.ldc ol ihe appiopii.ue Arodor sl.nul inl, we louml disappearame ol a muuher ol peaks, changes in die i.ilios of die peaks, ami possible cmer|!eiicc Omtiol IIK) ppm Aro MW npm A.o UK) ppm Am300 ppm Aro Putphu , irea'cvl as <1, . < l ** of addili,... (isslirs lion. lido i. J ,mvl t al o* tu p.n oetil > and lal l'< 1 dose Ml s'*o M^mtica 'il COlUk'Ml " ' QN5 Uai^97 A ol Arodois >i or hi m.ii y is VI A was IV l|(ICSllOfl .aimed l.irpc M`}'l '( plU I Ills Min.iiy \l A ills' IlSS'lv ill' .1 .1' 1i'sO llvil . .Ill'l s.ls'l like tuuwals vslsvuv' S'SIIIlK'.llllIV ilie i.Mv I'al |MI I'llV I Ills. ' ,IUvl ( mt 't.ill. Ml ol ,1 Vio.lor MI|(< i.H imii lal 1 disappear - v ms i pent e PCDS ON PORI-IIYHJA AND DRUG MtMIIOt ISM 467 I n. 4. nfcco of Arockus KM 6 ami 1242 on urinary eoproporpli>rui .mil uropot ph>nn cuicdnn. Treatment is iliscrilxsl m I ij;. I Values represent means i. SL. FIk.* numbers jlmsc ilie lurs is present ihe pro|M>Mii>n ol jiimiulv whose iihIivhIu.iI values were ouivislc ihe '>>",, tonlukiice hmu> s>l she amnul> al p U OI. a Siuitilisonily dill'cicnt hum s ononis, p < (KM. TABLE I Emcr oi Ahoci.oks 1016 and 1747 on Livlr Pomimiyhins in mi Kai* 1 rcaimciil I Week 7-COO U H-COOH (Months 7-C'OOll K-COOU Conitol 100 ppm Aoxlor 1242 500 ppm Aros lor 1242 100 ppm Arm lot 1016 300 ppm Ainclor 1016 Trace'1 1 rave'1 1 race* ! race'1 Trace* Trace* Trace'1 Truce* Truec* Trace'1 Trace'1 /64 i 77 ( 227 J 59 ^Vf race'' 89 i 23 Truec* 7*514 t(*l 669 146 ' Trace* 141 65 l*oi|*hyiuis were nit'th>l.uod ami .iii.iI)A'J 6y iliin-loyor chTtmuiueruphy. Female tun were treated as de*u iK'tl in I ijs. I. Ucstills aic pven .is I he nx-.in it * -1 /#'! of additional iiitvcldiini! |H*:iks (Pi^s. 5 ;nul 6), The GC residue piolilcs of .ill iliree lissut's from Aroclnf 1242 fed ral> contained 11 major peaks, while those from AmkIoi 1016 leil iols contained live* major peaks flic lolaf l'( H content was similar tn liver ami I.it of animals fed comparable doves of Aroelor 1242 or Aioclor 1016 (I ig 7) ^fn p;otieul.o. rats led HH> ppm of either Aroelor for 6 mo had compa table liver, blood, ami fat I 'C ' 11 co|lee 111 ra(io11Alles pi1 e markedly diMcrent hndopical elfestv Al the liiyli dose of MM) ppm, (lie |'( II eontenl of livets from rats fed Aiot loi I 2 12 lor I vvk was sipmiictmdy lusher ttoun hver I'f 11 residues in rats led Aroelor MM6; however. tat content was comparable. MONS 08129a MONS 081299 I'l'tlS ON I'WKIMh IllA AM) 1)1100 Ml: I'AIH M tSM 469 I k. f* l.,iv v In om.ili'p ,h>Iik |" otilc il AriKk'i lMh M.iml.tnl .uni li*'u l.il >l i;iK 0*1 ||>0 |'|nt Ail'i I0U l.>i l mu. IVAn wctc muiilviiJ ioitscvuloi'1) ;koi>oIhhJ lo ictvniion Hint MONS 081300 470 coLOsuiN rr al. miFin. 7, Tissue amuitl of Iciiulc nils U\l \rncf<>r hit* ur t 24!. Huts were m.\tli`il as nt lug. I Values represent means SI., a ?00 NiocUtr UM(> sigmtkanll) dilkicnl Horn tyN) ppni Ai ivloi |UU ppm VukUm' lOlftsignilkunUy dillereiii Iroin 508 ppni Arueloi- IN'. DISCUSSION Wc show that Aroclor 1242 markedly increases liver weight, cyloehromc P-450, /V-demcihylasc. aniline hydrovylaM.*, nitroreductase, ami gloeuronyl tiansfcrase activity when led u> lem.de ra's for I wk, while Aroclor 1016 has only very slight ellcvls on h\cr drug-melaholi/mg cu/yuics and no elVevt on liver weight. Dickers </ al. (19721 similarly found only JO",, increases in cytochrome P-450 and ethylmorphme ,Vdcmothylase ami no increases in tivvf weight alter tix daily (Jon's of Aroclor 1016 |25 mg kg. day). J luncvcr. he compared Aroclor 1016 with Aroclor 1254, a mixture with higher chlorine content, ami concluded that the lesser clVccts of Aroclor 1016 prnhahty related lo the loner chlorine content. Similarly. Utters! ef ul, 11972) showed that the potency of !*< It miNiorc* as inducers ul* drug-metabolizing enzymes increased with ineicasinc percentage o('chlorination. 5Vc show that Arovloi 1016 is much less edective than Aon lor 1242. despite similar chlorine content. Therefore, the ability of l`('Hs to induce druir-mciaboli/inc enzymes does not depend simply on percentage ofchlorination Aioclnr 1242 may he a more potent inducer than Aioclm 10(6 because it contains a higlicxj^i^njj^uan * iw'nta- ami Itg^chUwobiplienyls, wlncli may be tite most active imlmors in the imwmc. ' '. In coni last lo its nninm.il elicits at ( wk, 500 ppm Aroclor 1016 maiVYdly uh i cased jihuunmyl o.mslei.ise. aniline hydroxylase and nitroreductase activity as well as live) ucight ami c.insed porphyrin at 6 too lhc>e results were completely nnc\|celcd in view of the cailicr study ol Hickcts i t al. (197?) which repotted nummal olivets of Aroclor MH<> <n dim*. uiciuhoh-au amt live* weight, apparently because they studied only a 6 day dosage pei iod fhe present study demonstrates that the olivets oi\lmmc evposmc e.mtuM he picdteicd hy shoit-tcnu dosage. In particular. the (Htrphyria produced by Aioclor lOlf* could not have been predicted on the hash, of slmi t-term studies. I lie cll'ecis of AiocIst 1242 also differed with leilglh nl administration. Some ,-Uvt.o a*ci I'.,..ii i[... m<iul ili.it pi.......uni.. IIIIH I'iiI ' AomJ-" urn tan Ar eyiovluom and an m* spectrum v I liese v ha. PC lib. UI.I Doth A> PC Us will on the rat as Aroeloi 1016 ou < s i I'im.Mi hep.'*n n step in h > 100 ppm the high >I Id U lit1'" tune, sun 500 ppm similar ini (Oiknei i acetanmh |Dc M ill' The 1: mci.ihr'li in our lal gcnrr.dl'. 05 t. ciii'>im v.ldotnn . u'lul"" P an pOIMld > I ... I I.limit.a. < 1970) t Al \ -\m 147 0. n'< 147V, I of ding mons ouiroi 1 u-d it. mi t ig I. f*|U XioJor fOHli* P 450. Cl.1'0 .MOM) '! Meets on ./.(/ 1197?) I*|1||(||||K* A\roloi 11)16 f a miMiirv \lH I'M' 1016 '>7?) showed ti'N inwcascd is much less ills' .ihdrty pCKYMlilgC '016 lli'i.lllsc Mill lll.l) be 11s llli li'.lss'kl w JI .is tiu-l' '|Vi ii'il in *1 elicits i>| ili.i studied Ol s'lllilllW |*'I |dll I l.i ' hoii-tcim bon Nome .--? in 'Hw^.rvrr Mfi , "jjfi ppi-w t i -n rfn i 'ii i* l*rns UN [VIHHIYHIA AND t>*UO MITAIIOLISM 471 rlVccl* were less noliccitblc .U 6 mo lh;m at I wk: oilier p;iihw;iys wore increased com parably or even more markedly idler long term administration We have previously noted lhal elicits of pipcronyl hutmide on glucuronyl transferase were much more piomninccd after 2 mo, silide most oilier drug-mciaholirrng enzymes were maximally incieascd alter I wk (Goldstein ft til., 1973b) . Aroclor 1242 shifted the maximum of the CO-dilferenee spectrum IVom 450 to 449 mn. but Aroclor 1016 had iKidisccniahleciVeci. possibly because Aroclor lOlbinvicased cytochrome P-4 50 content only minimally, A similar shift of t lie CO-dillcroncc sited rum uml an increase in the 455 4.10 ratio of the peaks of the ethyl isocy.tmdc dillcicncc spectrum has been noted idler Aroclor 1254 administration (Alvaies ft at., 1973). These chances ;ne similar to those produced by polycyclic hydrocarbons; however, I'CHs. unlike polycyclic hydrocarbons, stimulate a variety of pathways, Holli Aroclors 1016 .nub 1242 produced swelling of the uterine horns. DDT and mis with less than 54",, chlorination have been reported to ha\c estrogenic elicits on the r;it uterus (Human and Cecil. 1970), Aroclor 1016 appears at least as etfediie as Aroclor 1242 in the present studyj_Al ptescni, no studies of the elicits of Aroclor j lOWnrw reproduction have lx*en reported, Previously, wc showed that 100 ppm Aroclor 1254 increased urinary excretion ami hepatic accumulation of uroporphyrins ami induced ALA synthetase, the rule-hunting: step in heme synthesis, after a lag of several months (Goldstein ft at.. 1974a) doth 100 ppm and 500 ppm Aroclor 1242 produced similar ellecls after i> mo, while only the high dose of Aroclor 1016 was cllcclivc. Apparently, the lag m development of I'CH-induccd porphyria did not depend on greater tissue accumulation of PCHs wuh time, since rats fed 100 ppm Aroclor 1242 for 6 mo were porphyric. while rats fed 500 ppm Aroclor 1242 were not porphyric at I wk despite higher tissue PCB levels. A similar unexplained lag has been observed in hcxnchlorobcnicnc-.induccd porphyria (Ockncr and Schmid. 1961), in contrast to porphyropcnic drugs such as nllylisopropyl- acetamide which increase excretion of porphyrins and their prccursois within hours (Dc Matieis and Prior, 1962). ( The lesser vtVccts of Aroclor 1016 than 1242 eoukl not be explained by greater f metabolism and excretion, since tissue concentrations were comparable. Other workers -in our laboratory-found plasma, kidney, brain,(fiver, andjat content of PCIls were generally higher in raNsjecI l(X> ppm Aroclor lOlftTIuu in rats fed Aroclor 1242 for 0.5. 1. 2. 4. 6. 8. or It) mo^Hurxe ft at.. 1974). It is probable that induction of liver cn/.ymcs and hepatic porphyria by PCHs depends on both the lym^jcr and position of chlorine atoms on the PCI) molecule Significantly, Hush ft at. (1974) found high correlation between occupation of the 4.4' positions, tissue retention, cytochrome P-450, ami aniline hydroxylase activity alter adminisli.ilmn of Aroclor 1254. ( (im pounds wnh (me or both/'-positions open were not persistent in tissue. two t-.urnpean commercial preparations of PCHs have been reported to be eon- l.onin.iled willi 5 20 ppm of 2.3.7.K-ittraililomdii>cnzoluran (l(`l)l ) (Vos cf at. 1970) I he related compound, 2.3,7,8-ietrachlorKlihcn/iHlio\in |K DO), induces AI A synthetase m the cluck embryo at doses as low as (1.5 pgr kg (Poland ami Glover, 1973). induces hepatic poi phy lia in the mouse at doses of UK) /ig.kg itioldslcin <7 <//.. 1973a), and metcast's hepatic cytochrome P-450, glucuronyl transferase, and a number of drug-met.iholi/mg enzymes at doses as low as I /ig/kg (I ucier <7 /., 1973). Vos MUNS 081302 B B 1 ll il 472 GOLDSIMN T AL. <`t ill. (1970) could not detect TCDP in American-nude PCBs at a sensitivity limit of l ppm. hut Curley cf n/. (1972) reported contamination of Aroclor 1254 with .i trace nt Tt'Ul jlc>< than I ppm)- 1C l)l> was hoi Selected. It is doubtful whether eonl,limitation of Arnclors with less lltau I ppm I'C t)l- could attribute appreciably to the hepatic ellcels of IVIIs, .since a mitnlvcr of synthetically proputvd Ue\ael)lot'obtphenyl> nuluec AI.A synthetase, cytochrome P-450, glncuronyl trunslcruic, auU porphyria in the chick, while T( 1)1 does not induce porphyria, even al letlutl doses, has Uule ctlcct on cytochrome P-450. and no ellcei on gluutrniiyl (ranslera.se or ALA synthetase (Goldstein <7 til., 1974b). Similarly, 1(1)1* did not induce pofphyria in the mouse at 4(Mimcs the porphyrogcnic llose of TCPl) under identical conditions (Goldstein <7 al., _ J1974b). Therefore. it is probable that dilfcrences in the effects ot` various Pt H mixtures on the User are due to the effectiveness of (he various chlorinated biphenyl homology'' in cacti misiurej Aroelor 1016 is less pojent in Hs elfeets on the liver, probably because it contains fewer of ihe biphenyls winch arc the most active inducers of liver drug-' mcinMt/ing cn/.ymev| Ai.vahiv. A. P.. Hickihs, I) It. ani* Kai-i*ai, A. (197.1). Polychlorinated biphenyls: a new type of inducer of cytochrome P-450 in ihc liver, /'w, Ntii.. u-tul .V< /. 70, IJ21 1325 I). It., IIaioiik, L. ('., Kaitax. A. and Ai.vamfs, A. P. (IV72). Pulyehloiinaied lliphenyU . Comparative efleets of high amt low chlorine containing Aroc)or> ' on hepatic mixed function osidase. Hv>. Comtmtu. Chvtfi. Puihal. Phoninuul 3. 505 512. Human, J. ano C icii.. N. C (1970). Estrogenic activity of DOT analogs and polychlorinated biphenyls. J. Axt. AWCVn/n. IH, 110X1112. Boast, V. W , Kimukoouii. H I)., Viii.anofva, C.. Jennings. R.. Linihn. R H. and Sov*cum. (.5. W. til>74). Polychlorinated biphenyls. Storage, distribution, excretion and recovery; liver morphology alter prolonged dietary ingestion. Anh. loirinm II,-tilth 2V, JOI 307. 0OXH, II., I.o, 1 . C. ano Bach*. F. D. (1974). Computer-assisted reduction and display of gas chromatograph* data from long-term toxicity studies of eommvtcial mixtures of polychlorinated biphenyls in chickens and in rats. 7iw<<d. Appt Ph,oouuvt. 29, 105. Cochin, J. anii Axii.moo. 1. (1939). Biochemical and pharmacological changes in the rut following chrome administration of morphine. nalorphine, and (uumorphmc. J PlmnHutot. rjr. 7 Ait. 125, 105 110 Cunuiv, A.. Boast. V. W , GatM. M E., Jinningx, K. W. anij Linihn, K. I: (1971) Poly chlorinated biphenyls: distribution and storage in body Hinds amt tissues of Sherman rats. Ltnirou Hr*. 4. 4X1 495. Com t v. A.. IMnisi. V. W. ani> Jt nnjno.s. ft. (1972) Mcfalroliie or contaminant ol Aiocltn ' 12.54 found in i,il urine lou-i. ( hroi Mot Ut.Ut! Mrn. Dtr. l\-*t Chrm. Ih\n (tux Dim.viims, I and 1`kiom, H ||9n2) Experimental hepatic porphyria caused by feeding 3A-dk'tho\yc.ut'nn>t-1. t dd>>di>-2.4,(-trmcih))pyrnhnc. Htothrm J H.\ I X |>\s. M. t 11*- nn.mot.iove separation of poi (thynos and protohaemm as methyl esters hy llnn-l.no i In mnatogiaplt) J ( hi0010101:1 .Ml, 2(5 270. tools, .1 It ami Munmi. II M. H937). I he e/y malic rvdui lion of chloramphenicol, p-nitro- iKn/oiv ,n id amt oilier aiomalic nitro compounds 111 mammals. J Phot toot >/. l\\/> I7i,-r. 147. M2 119 (J01 pxji in, J A , tin cman, I*.. Him.Man. II. and Vox. J. O (1973a). Hepatic porphyria imOikcU by ?.`,7.X teo.iclilon>dit'c,n/o-r*-diosin in Ihe mouse. Kt-\. Conttntot ( In to I'othol. Ptuootorol h. 9)9 927 HONS (nn ns 11 in, J \ ICsIlOK.ll lo\ool Iftftl I* Cm u ns 11 in. I A induced In p- ! (}<! I >M I IN, J A , ' It (1974b) III. (1(1)1) on h*p GoIOSIIIN.J \ 1 in rut* prcoo.iioj KaIO, R ANO ciU liver nuciosoii'c I KohaVsonv. M , J poisoning can's I Pi i Vi*i r. I. Iiv | Lit 11 mu. C I I chloim.ucd b)' 23. 112 M2 Lowity. (> II . It'. inent Aid' die 1 Lll( UK, (1 W , x? t AlOIM, f it Hvohh t'x/ . ' Mamsih. list. and synihvi.wc Mahvui, Vt S . I s1 lie dele1 nuiMii Oo-nim. H k vs. bcii/ene inmv 1* - Omoma. T aso-Sv I rvulvncv U' > Omoma. T and n II Stilubiii/jo.i Pot AM). A ANO t of *aimnotev irl 1 Risraiioooo. R v. Polythluniijied Srui.K. G O sj McCifaw Mill 4 Vos. V G km-i j K H C )*?< t cilliii m il, d 1..' N, i.r IM2 W.m.h . W W > (Olin in 1 ><- > Vmitis, A It M>* > popiilaliu'i 1*1 0 081.303 Wl|t lMiy,yr,' m yi V ' .*'* t.: -m?. .. .' - ... 1 ^ M j 1 WIIS ON rnRPHYKIA AND DKUCi MIIAHOUSM 473 4 (ioiDSIliN. J A . Hickman, I* ani> Kimhhouom, k O (I97jhl, ERccts of purified and l lcvhmc.il piivionyl hiiioside nn drug-meiaholi/ing cn/yntc* and iiltrusiniclnrc of rat liu-r, . '/imi.../ U'l>l Phui;</ 26, 444 45S (ituminN. .1. A . Uunman. I* and Jut. I> I.. (I974ay. ITxperimvntal hepatic porphyria 1 mdintd hv poljvhloi nulcd biphenyls IhiW It'i'l I'luiniimul 27.417 44.H, ' (!i ii dm i in, .1 A , Mi KiNsn.J I), l.ni ii u. < i W , M miii, J A , Mh kMan, I*, and Hi hi.man, It. Il974hf l.llecis ol hes.iJtloi obipheny I isomers and 2.1.7.8-leirachlorodilxn/olui;in I ( K'DI ) on hcp.iia ilmg mci.ibolistn and poiphyim accmmikition. 16. 2)9. ; Got nsii in. i. A ANi 1 Ai-H'Ki, A. I 196H) t'.nhanced hih.uy cAvrelinn iiftbryoxmc gHiciirpmde in nils prcirvaied with lvi\/p> rcno llwvhrm. Plannnu .1/ 17. 104v 1065. Kaio, tt. anii (in 11 in . J U. (l%5). Hlc\ i of stars.uino on NADPH-dupemlcrh enzymes in liver mierosomes of umIc .iiiJ lonalc rats J. Plitinnniiil L.\p. t'hvr. 1541, 279 284. k Kiinaisdni, M . 1iimiimi'ha. T. Maius/vka, J ani> YamiiUoii. A. (1972). Yusho. a poisoning caused In me oil conuminulcd with polyvhiotinalcd biphenyl. Liu iron, itruhh . Pvrxpwt I. 119 128 , ( Ln I ms i, ('. I. . I a m in m , I. M.. Baki k. A. M. and Van Loon, E. J. (1972). filled of poly* chlorinated biphcnvls on hep.me microNom.il cn/ymev in (he rut. To\frol. Appl Pluu imuol 2J.112122 , LiIWUV.O. II . Kosi MKOt'on, N. J., Fakk. A. L. and Randall, R. J. (I9$l. Protein measure ment wiih ihe lolin phenol reagent. J Hint. Chvni. 19.3. 265-275. c LtrciLN. G. w . McOamii, O S . Hook. G. IT. R.. lowun. B. A.. SOnawanl. 0 R. and l-Aiiitit. I:. ICl)l)ihdticcd changes in nil liver micrusonMl cn/ymes (197.1). Environ. '" Hvnllh 5. 1W 209. Manvi h. It. S.. I\< m os. I) IV. Pimimooi, M. G. andColuNS, A. (1966a). > Aminolevulinic T aeiil Nynilu'iMsc. t Studies in liver homogenate*. J. Oml. Chvm. 2*11. 2803-2809 MAHVI n. II S . I s< hods. D. P . Pi ni.nohi. M (i . On i ins, A. and HoNti n, (i . Jh i 1966b). The vloiernmuium ol .unmokciones in biological Hinds Anal. Bknhvm. 14. 5.1 60. Oi KHtN. K. K. and Si iimio. K . (196)). Acquired porphyria in man and rai due to hcsachloroIvn/ene mtosic.iiion ymun- {l.timkm} 189,499. OMiirtA, 1. am Said. R I lor*4al The carbon monovide-binding pigment oltiver microsomcs I. ITvidencc I'm U\ hemoprotein naiiuc J liiof Chvni. 2.19, 2.170 2179. . Ompna. T. and S vio, M. (1964b). The carbon monoxide-binding pigment of Ucer micn'M'wes. II. fiohibili/.ilMin. ptinlicaiion. and pio|xriie>. J. Hint ( hvm. 239. 2179- 2185. Pdi.ano. A. and CiioviK, I*. (1971). 2.1.7.8-Teliuchloroilitx'n/o-/>-ttio\in: u poieni inducer ol'd-jinmnlcMilimc acid synihetase. Svivmr 179.467-477. ' RiMHKotn.il, K. W.. Un tin. P,, Pi aKai i . I>. B., HtHMAS. S. G. and KkgvtN. M.N 11968). Pvdyvhlmmated biphenyls in the global ecosystem. ,Y/mr<* (l.omfau) 22^. 1098-1)02. Sim.. H (i. D. and Tohmii . J (19(4)). In t'rim iplvs anti Procednrvx of Stufiwi< \. pp. 107-109. McGraw-Hill. New Yotk Vos, V. G . Koi mas. J. II . Van Di k Maas. H. L . Tin Noivcn De Bnau, M. C. and De Vos, K. M l 1970). ItieniilK.ition and loxicological cvuluaiion of chloriniucd dibenzofuran and t hlorin.ntil oaphihalenc m luo commcicial polychlorm.iied biphenyls. Ft/. Ctnmvi. I'uucol. 8.625 612 M i mi i. \V. vv ano Smi m. (` {19741 Mciabolisin of a polychlorinated biphenyl (Aroelor " Ml 14) in iis. Evil Pm, 11. 499 (Absii |. . Yomis. A. I< 11972) I cveIs of polyclilonoalcd biphenyls in ud((Xtse tissue of tlw general popul.ilimi ol the n.iiioii f/nnnn. Urtthh /Vo/at/. I, 7*1 81. i i i *i i i j i i *, i 11 MONS 081304