Document N2jYOZZ0XBBw9KBOq3LEqn8jV

criteria for a recommended standard.... OCCUPATIONTAOL EXPOSURE POLYCHLORINATED BIPHENYLS (PCBs) U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service Center for Disease Control National Institute for Occupational Safety and Health SEPTEMBER 1977 Par eele byPtrhiaMSinuipeOrifnfitceen.deWnet eoJfunDcotecnu.mOe.nCts.. U20.430. 3OeveiwwM / DHEYV (NIOSH) Publication No. 77-225 II r PREFACE The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and safety of workers exposed to an ever-increasing number of potential hazards at their workplace. The National Institute for Occupational Safety and Health has projected a formal system of research, with' priorities determined on the basis of specified indices, to provide relevant data from which valid criteria for effective standards can be derived. Recommended standards for occupational exposure, which are the result of this work, are based on the health effects of exposure. The Secretary of Labor will weigh these recommen dations along with other considerations such as feasibility and means of Implementation in developing regulatory standards. It is intended to present successive reports as research and epide miologic studies are completed and as sampling and analytical methods are developed. Criteria and standards will be reviewed periodically to ensure continuing protection of the worker. I am pleased to acknowledge the contributions to this report on polychlorinated biphenyls by members of the NIOSH staff and the valuable, constructive comments by the Review Consultants on polychlorinated biphenyls, by the ad hoe committees of the Society for Occupational and Environmental Health and the American Occupational Medical Association, and 905240 ill K 07926 by Robert B. O'Connor, M.D., NIOSH consultant in occupational medicine. aThe NIOSH recommendations for standards are not necessarily consensus of all the consultants and professional societies that reviewed this criteria document on polychlorinated biphenyls. A list of Review Consultants appears on page vl. n h a J r . rinklea, M.D. Diij^ctor, National Institute for Occupational Safety and Health 905241 iv N 079X7 Th Division of Criteria Documentation and Standards Dsvaiopmane (DCDSD), National Instituts for Occupational Safety and Health, had primary responsibility for the development of the criteria and recommended standard for polychlorinated biphenyls. From DCDSD, John M. Fajen served as criteria manager and developed the basic information with the asslatanee of John A. Wees, Ph.D. Personnel from other NIOSH Divisions that assisted in the development of this document were Robert H. Hill Jr., Ph.D., Alan K. Gudeman, and Dennis M. O'Brien (Division of Physical Sciences and Engineering); Mark W. Jones (Division of Surveillance, Hazard Evaluations and Field Studies); and Trent R. Levis, Ph.D. (Division of Biomedieal and Behavioral Science). The DCDSD review of this document was provided by Richard A. Rhoden, Ph.D., Chairman; J. Henry Wills, Ph.D.; and Howard L. MeMartin, M.D., with A. Blair Smith, M.D. (Division of Surveillance, Hazard Evaluations and Plaid Studies), and James H. Sterner, M.D. The vleve expressed in this document, the conclusions reached, and the recommendations for a standard are those of NIOSH after review of the evidence and consideration of the comments of reviewers. These views and conclusions are not neceasarlly those of the consultants, other federal agencies, and professional societies that reviewed the document. N 379 905242 CnJ J Cincinnati, Ohio 45267 Rudolph J. Jaeger, Ph.D. Department of Physiology School of Public Health Harvard University Boston, Massachusetts 02115 Carl C. Smith, Ph.D. Department of Environmental Health University of Cincinnati Cincinnati, Ohio 45267 James R. Allen, DVM, Ph.D. Department of Pathology University of Wisconsin Medical School Madison, Wisconsin 53706 Paul E. Brubaker, Ph.D. Mobil Oil Corporation Paulsboro, New Jersey 08066 Renate D. Kimbrough, M.D. Bureau of Laboratories Center for Disease Control Atlanta, Georgia 30333 David Kotelehuek, Ph.D. United Electrical, Radio, and Machine Workers of America New Tork, New York 10007 Charles E. Lawrence, Ph.D. New York State Department of Health Albany, New York 12237 William B. Papageorge Monsanto Industrial Chemicals Company St. Louis, Missouri 63166 vi 905243 N 07929 CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR POLYCHLORINATED BIPHENYLS Table of Concents PREFACE NIOSH REVIEW CONSULTANTS I. RECOMMENDATIONS FOR A POLYCHLORINATED BIPHENYLS (PCBs) STANDARD Section 1 - Environmental (Workplace Air) Section 2 - Medical Section 3 - Labeling and Posting Section 4 - Personal Protective Equipment andClothing Section 5 - Informing Employees of Hazards fromPCBs Section 6 - Work Practices and Engineering Controls Section 7 - Sanitation Practices Section 8 - Monitoring and Recordkeeping Requirements II. INTRODUCTION III. BIOLOGIC EFFECTS OF EXPOSURE Extent of Exposure Metabolism and Mechanism of Action Historical Reports Effects on Humans Epidemiologic Studies Animal Toxicity Correlation of Exposure and Effect Carcinogenicity, Mutagenicity, Teratogenicity, and Effects on Reproduction IV. ENVIRONMENTAL DATA AND BIOLOGIC EVALUATION Environmental Concentrations Control of Exposure Environmental Sampling and Analytical Methods Biologic Evaluation V. WORK PRACTICES 111 vi I 3 3 5 6 8 10 14 15 19 21 21 27 31 33 54 66 105 116 126 126 132 133 144 145 905244 vii K 37930 Tabi of Contants (Continued) VI. DEVELOPMENT OF STANDARD Baals for Pravlous Standards Basis for ths Recooaaaded Standard VII. RESEARCH NEEDS VIII. REFERENCES IX* APPENDIX I - Saapllng Procsdurs for Collsetlon of Polychlorinated Biphenyls X. APPENDIX II - Analytical Method for Polyehlorlnatad Biphenyls XI. APPENDIX III - Matarial Safaty Data Shsat XII. TABLES 148 148 152 164 166 191 196 208 218 N 07931 vili 905245 I. RECOMMENDATIONS FOR A POLYCHLORINATED BIPHENYLS (PCBs) STANDARD The National Institute for Occupational Safety and Health (NIOSH) recommends that employee exposure to polychlorinated biphenyls (PCBs) In the workplace be controlled by adherence to the following sections. The standard Is designed to protect the health and provide for the safety of employees for up to a 10-hour workday, 40-hour workweek, over a normal working lifetime. The standard is measurable by techniques that are valid, reproducible, and available to industry and governmental agencies. Compliance with the standard should substantially reduce any risk of reproductive or tumorigenic effects of PCBs and prevent other adverse effects of exposure in the workplace. Employees should regard the recommended workplace environmental limit as the upper boundary for exposure and make every effort to keep exposure as low as possible. Evidence Indicates adverse reproductive and tumorigenic effects In experimental animals exposed' to certain commercial PCB preparations. Currently available Information is not adequate to demonstrate that other commercial PCB preparations do not have these effects. Should sufficient information become available to Indicate that the standard offers greater or lesser protection from some chlorobiphenyl isomers or commercial preparations than is needed, it will be considered for revision. The Toxic Substances Control Act of 1976 (Public Law 94-469) required the US Environmental Protection Agency (EPA) to prescribe marking and disposal regulations for PCBs by July 1, 1977 (Federal Register 42{2656377, May 24, 1977). By this Act, the manufacture, processing, distribution 1 905246 N 07S32 in commerce, or use of PCBs in any but totally enclosed systems Is to be banned, effective 1 year after the date of its enactment, October 11, 1976. Two years after the enactment date PCB manufacture is to be banned, and processing and distribution in commerce are to be banned 2.5 years from that date. However, the Act allows the Administrator of EPA to rule otherwise if he finds that manufacture, processing, distribution in commerce, or use in other than totally enclosed systems will not present an unreasonable risk of injury to health or to the environment. The Act does not affect use of equipment already containing PCBs in totally enclosed systems, so that a potential for occupational exposure to PCBs will continue to exist for many years as a consequence of their transportation,. installation, use, and disposal. The part of the Act specific for PCBs is presented in Figure 1-1. "PCBs" are defined for this reconmended standard as coonereial preparations of chlorinated biphenyl compounds, Including those preparations which may be described as single Isomers or classes of Isomers, such as Decachlorodlphenyl. Biphenyl and its monochlorinated derivatives occurring in commercial preparations of PCBs shall be measured along with the polychlorinated derivatives, and shall be treated in this standard as the polychlorinated components of the preparations. "Occupational exposure to PCBs," is defined as working with PCBs or with equipment containing PCBs that can become airborne or that can spill or splash on the skin or into the eyes, or the handling of any solid products that may result in exposure to PCBs by skin contact or by Inhalation. The term "PCB work area" is defined as an area where there is occupational exposure to PCBs. In areas where no occupational exposure to PCBs occurs, 2 905247 N 07933 but where PCBs arc present in equipment in the workplace, adherence is required only to Section 8(a). Section 1 - Environmental (Workplace Air) (a) Concentration Occupational exposure to polychlorinated biphenyls (PCBs) shall be controlled so that no worker is exposed to PCBs at a concentration greater than 1.0 mlcrogram total PCBs per cubic meter of air (1.0 ig/cum), determined as a time-weighted average (TWA) concentration, for up to a 10hour workday, 40-hour workweek. (b) Sampling and Analysis The recommended TWA occupational exposure limit for PCBs has been determined to be the lowest reliably detectable limit by the sampling and analytical methods recommended in this document. Environmental samples shall be collected and analyzed as described in Appendices I and II, or by any methods shown to be at least equivalent in accuracy, precision, and sensitivity to the methods specified. Section 2 - Medical Medical surveillance shall be made available to all employees subject to occupational exposure to PCBs. (a) Preplacement or Initial medical examinations for workers shall Include: (1) Comprehensive medical and work histories with special emphasis on hepatic function, skin condition, and reproductive history. , 905248 07934 (2) Comprehensive physical examination with particular attention to the skin and to hepatic function including determinations of serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) activities. The responsible physician may also wish to obtain measurements of serum triglyceride concentrations or of other indices of fat metabolism. (3) A Judgment of the employee's ability to use positive pressure respirators. (b) During examinations, applicants or employees having medical conditions that could be directly or Indirectly aggravated by exposure to polychlorinated biphenyls or formulations containing polychlorinated biphenyls shall be counseled on the Increased risk of impairment of their health that might result from working with these substances. (c) Women in the work force who are of child-bearing age shall be advised of the potential adverse effects of PCBs on the unborn child. Those who bear children while working with PCBs shall be counseled concerning the advisability of nursing their babies. (d) Initial medical examinations shall be made available to all workers as soon as practicable after promulgation of a standard based on these recommendations. () Periodic examinations shall be made available at least annually and Include : (1) Interim medical and work histories, and (2) physical examinations as outlined in paragraphs (a)(1) and (a)(2) of this section. (f) If evidence of adverse effects of exposure to PCBs is suspected or confirmed, appropriate medical care shall be made available to the affected worker(s). 4 905249 N 07935 (g) Pertinent medical records shall be maintained for all employees exposed to PCBs in the workplace. Such medical records shall be maintained for the period of employment plus 30 years. These records shall be made available to the designated medical representatives of the Secretary of Health, Education, and Welfare, of the Secretary of Labor, of the employer, and of the employee or former employee. Section 3 - Labeling and Posting All labels and warning signs shall be printed both in English and in the predominant language of non-English-reading workers. Illiterate workers and workers reading languages other than those used on labels and posted signs shall be otherwise Informed regarding hazardous areas and shall be informed of the instructions printed on labels and signs. (a) Labeling The following warning label shall be affixed in a readily visible location on PCB-processlng or other equipment, and on PCB-storage tanks or containers : POLYCHLORINATED BIPHENYLS (PCBs) DANGER! CONTAINS POLYCHLORINATED BIPHENYLS CANCER SUSPECT AGENT Use only with adequate ventilation. Do not get in eyes, or on skin or clothing. First Aid: In case of skin or eye contact, flush with running water. 905250 5 K 07936 I :j (b) Posting Warning placards shall be affixed in readily visible locations in or near PCB work areas. The information contained thereon shall be arranged as in the following example. POLYCHLORINATED BIPHENYLS (PCBs) DANGER! CANCER SUSPECT AGENT AUTHORIZED PERSONNEL ONLY Do not enter unless area is adequately ventilated. Do not get in eyes, or on skin or clothing. First Aid: In case of skin or eye contact, flush with running water. Section 4 - Personal Protective Eoulpment and Clothing (a) Protective Clothing In any operation where workers may coma into direct contact with PCBs, protective clothing Impervious to PCBs shall be worn. Gloves, boots, overshoes, and bib-type aprons that cover boot tops shall be provided when necessary. Protective apparel shall be made of materials which most effectively prevent skin contact with PCBs where it is most likely to occur. Bsployers shall ensure that all personal protective clothing is Inspected regularly for defecta and that it is in a d e a n and satisfactory condition. (b) Eye Protection Chemical safety goggles, face shields (8-inch minimum) with goggles, or safety glasses with side shields shall be provided by employers and shall be worn during any operation in which PCBs are present. If liquid or 6 905251 N 07937 olid PCBs contact the eyes, Che eyes shell be irrigated immediately with large quantities of water and then examined by a physician or other responsible medical personnel. (A drop of vegetable oil on the eye has been found to reduce the resultant irritation.) Eye protection shall be in accordance with 29 CFR 1910.133 and ANSI Z 87.1-1968. (c) Respiratory Protection (1) Engineering controls shall be used when needed to keep concentrations of airborne FCBs at or below the recoomanded TWA occupational exposure limit. The only conditions under which compliance with the permissible exposure limit may be achieved by the use of respirators are: (A) During the time necessary to install or test the required engineering controls. (B) For nonroutinemaintenance or repair activities. (C) During emergencies when concentrations of airborne PCBs may exceed the permissible limit. (2) When the use of respirators is permitted by paragraph c(l) of this section, respirators shall be selected and used in' Accordance with the following requirements: (A) The employer shall establish and enforce a respiratory protection program meeting the requirements of 29 CFR 1910.134. (B) The employer shall provide reepirators in accordance with Table 1-1 end shall ensure that employees properly use the respirators provided. The respirators shall be those approved by NIOSH or the Mining Enforcement and Safety Administration. The standard for approval is specified in 30 CFR 11. The employer shall ensure that 7 905252 K 07S38 respirators are properly cleaned, maintained, and stored when not in use. TABLE 1-1 RESPIRATOR SELECTION GUIDE Concentration of PCBs Greater than 1.0 jtg/cu m or Emergency (entry into area of unknown concentra tion) Respirator Type Approved under Provisions of 30 C7R 11 (1) Self-contained breathing apparatus with full facepiece operated in pressure-demand or other positive pressure mode. (2) Combination Type C supplled-air respirator with full facepiece operated in pressure-demand or other positive pressure mode and an auxiliary self-contained breathing apparatus operated in pressure demand or other positive pressure mode. Section 5 - Informing Employees of Hazards from PCBs (a) All new and present employees in any area in which PCBs are used shall be informed of the hazards, relevant symptoms, and effects of overexposure to PCBs, and the precautions to be observed for safe use and handling of these materials. \ (b) All employees Involved with the manufacture, use, transport, or storage of PCBs shall be Informed that PCBs have been found to induce tumors in experimental animals after repeated oral ingestion and that because of these findings it is concluded that PCBs are potential human carcinogens; employees shall also be informed that adverse reproductive 8 N 07939 905253 e f f e c t s may result from occupational exposure to PCBs. (c) The employer shall Institute a continuing education program, conducted by instructors qualified by experience or training, to ensure that all employees occupationally exposed to PCBs have current knowledge of job hazards, proper maintenance and cleanup methods, and proper use of protective clothing and equipment, including respirators. The instructions shall include a general description of the medical surveillance program and of the advantages to the employee of participation. Special attention shall be given to women in the workplace. They shall be made aware of the potential adverse effects of PCBs on the unborn child, and of the known transport of PCBs to breast milk. Elements of the program shall also include: Emergency procedures and drills; Instruction in handling spills and leaks; Decontamination procedures ; Firefighting equipment location and use; First-aid procedures, equipment location, and use; Rescue procedures; Confined space entry procedures; Low warning (odor) properties of PCBs. (d) The information explaining the hazards of working with PCBs shall be kept on file and be readily accessible to workers at all places of employment where PCBe are manufactured, used, stored, or transported. Required information shall be recorded on the "Material Safety Data Sheet" shown in Appendix III, or elmllar form approved by the Occupational Safety and Health Administration, US Department of Labor. 9 905254 >' 07940 I Section 6 - Work Practices and Engineering Controls (e) Regulated Areas Access to PCB work arias shall be regulated and limited to authorized persons. A daily roster shall be kept of persons entering such areas. (b) Handling of PCBs and General Work Practices (1) Operating instructions shall be formulated and posted where PCBs are handled or used. (2) Transportation and use of PCBs shall comply with all applicable local, state, and federal regulations. (3) PCBs shall be stored in tightly closed containers in well-ventilated areas. (4) When PCB storage containers are being moved, or when they are not in use and are disconnected, valve protection covers shall be in place. Containers shall be moved only with the proper equipment and shall be secured to prevent dropping or loss of control during transport. (5) Storage facilities shall be designed to contain spills completely within surrounding dikes and to prevent contamination of workroom air. (6) Ventilation switches and emergency respiratory equipment shall be located outside storage areas in readily accessible locations which will remain minimally contaminated with PCBs in an emergency. (7) Process valves and pumps shall be readily accessible and shall not be located in pits or congested areas. (8) Containers and systems shall be handled and opened with care. Approved protective clothing as specified in Section 4 shall be worn 10 N 07S41 905255 by employee* engaged in opening connecting and dlaconnectlng FCB containers and systems. Adequate ventilation shall be provided to minimize exposures of such employees to airborne PCBs. (9) PCB-operating and storage equipment and systems shall be inspected daily for signs of leaks. All equipment including valves fittings and connections shall be cheeked for leaks isnediately after PCBs are introduced therein. (10) When a leak is found it shall be repaired or otherwise corrected Immediately. Work shall resume normally only after necessary repair or replacement has been completed, the area has been ventilated, and the concentration of PCBs has been determined by monitoring to be at or below the recommended TWA concentration limit. (c) . Control of Airborne PCBs (1) Suitable engineering controls, designed to maintai exposure to airborne PCBs at or below the limit prescribed in Section 1(a), shall be used. Complete enclosure of processes is the recommended method for control of FCB exposure. Local exhaust ventilation may also be effective, used alone or in combination with process enclosure. When a local exhaust ventilation system is used, it shall be so designed and operated as to prevent accumulation or recirculation of airborne PCBs in the workplace environment and to effectively remove PCBs from the breathing zones of employees. Exhaust ventilation systems discharging to outside air must conform to applicable local, state, and federal regulations and must sot constitute a hazard to employees or to the general population. Before maintenance work on control equipment begins, ths generation of airborne PCBs shall be eliminated to the extent feasible. U f.' 07942 905256 Enclosures, exhaust hoods, and ductwork shall be kept In good repair so that designed airflows are maintained. Airflow at each hood shall be measured at least semiannually and preferably monthly. Continuous airflow indicators are recommended, such as water or oil manometers properly mounted at the . juncture of fume hood and duct throat (marked to indicate acceptable airflow), A log shall be kept showing design airflow and the results of semiannual airflow measurements. (2) Forced-draft ventilation systems shall be equipped wit remote manual controls and shall be designed to shut off automatically in the event of a fire in the PCB work area. (d) Special Work Areas (1) PCB Hazard Areas A hazard area shall be considered as any space having physical characteristics and containing sources of PCBs, such as transformers, that could result in PCB concentrations in excess of the recommended airborne PCB exposure limit. Exits shall be plainly marked, conveniently located, and open outwardly into areas which will remain minimally contaminated in an emergency. (2) Confined or Enclosed Spaces ' 'V. Entry into confined or enclosed spaces, such as tanks, pits, process vessels, and tank ears where there is limited egress, shall be controlled by a permit system. Permits shall be signed by an authorized representative of the employer and shall certify that appropriate measures have been taken to prevent adverse effects on the worker's health as a result of his or her entry into such space. 905257 12 N 07943 Confined or enclosed spaces which have contained PCBs shall be thorou& :ly ventilated to assure an adequate supply of oxygen, tested for PCBs and other contaminants, and Inspected for compliance with these requirements prior to each entry. Adequate ventilation shall be maintained while workers are in such spaces. Leakage of PCBs into such confined or enclosed spaces while work is in progress shall be prevented by disconnecting and blanking the PCB supply lines. Each individual entering such confined or enclosed space shall be furnished with appropriate personal protective equipment and clothing and be connected by a lifeline harness to a standby worker stationed outside of the space. The standby worker shall also be equipped for entry with approved personal protective equipment and clothing and have contact with a third person. The standby person shall maintain communication (visual, voice, signal line, telephone, radio, or other suitable means) with the employee inside the confined or enclosed space. (e) Emergency Procedures For all PCB work areas where there is a potential for the occurrence of emergencies, employers shall take all necessary steps to ensure that employees are instructed in, and follow, the procedures specified below as well as any others appropriate to the specific operation or process. (1) If PCBs leak or are spilled, the following steps shall be taken: (A) All nonessential personnel shall be evacuated from the leak or spill area. (B) The area of the leak of spill shall be adequately ventilated to prevent the accumulation of vapors. 13 905258 K 07944 i ! I * (C) If che PCBs are In liquid form, they collected for reclamation or sorbed in vermiculite, dry sand, earth, or similar nonreactlve material. (2) Personnel entering the spill or leak area shall be furnished with appropriate personal protective equipment and clothing. All other personnel shall be prohibited from entering the area. (3) Only personnel trained in the emergency procedures and protected against the attendant hazards shall shut off sources of PCBs, clean up spills, control and repair leaks, and fight fires, in areas where PCBs are used. (4) All wastes and residues containing PCBs shall be collected in PCB-resistant containers and appropriately disposed of (Federal Register 42:26563-77. May 24, 1977). (5) Safety showers, eyewash fountains, and washroom facilities shell be provided, maintained in working condition, and located so as to be readily accessible to workers in all areas where the occurrence of skin or eye contact with PCBs is likely. If liquid or solid PCBs are splashed or spilled on an employee, contaminated clothing shall be removed promptly and the skin washed thoroughly with soap and water for at least 15 minutes. Eyes shall be irrigated Immediately with copious quantities of running water for at least 15 minutes if liquid or solid PCBs get into them. A drop of vegetable oil may be applied to the eye to relieve the irritating effect of PCBs. Section 7 - Sanitation Practices (a) Employees occupationally exposed to PCBs shell be provided 905259 u N 07945 with separate lockers or other storage facilities for street clothes and for work clothes. (b) Employees occupationally exposed to PCBs shall not wear work clothing away from their place of employment. (c) Employees occupationally exposed to PCBs shall be provided clean work clothing daily, and cleaning establishments shall be informed as to the hazards of handling PCBs and proper disposal procedures for PCBcontaminated waste water. (d) Facilities for shower baths shall be provided for employees occupationally exposed to PCBs. Workers should shower before changing into street clothes. (e) Employees exposed to PCBs shall be advised to wash their hands and exposed skin before eating, drinking, smoking or using toilet facilities during the work shift. (f) Food, drink, or smoking materials shall not be permitted in areas where PCBs are handled, processed, or stored. Section 8 - Monitoring and Recordkeeping Requirements (a) Monitoring (1) As soon as practicable after the promulgation of a standard based on these recommendations, each employer who manufactures, processes, handles, stores or otherwise uses PCBs shall determine by an industrial hygiene survey whether occupational exposure to PCBs may occur. Surveys shall be repeated at least once every year and within 30 days of any process change likely to result in occupational exposure to PCBs. Records of these surveys, including the basis for any conclusion that there l5 905260 r: 079 4 6 survey has been completed. (2) If occupational exposure to PCBs Is determined to be possible, a program of personal monitoring shall be instituted to measure or permit calculation of the exposures of all employees. (A) In all personal monitoring, samples representative of the employees' breathing zones shall be collected. (B) For each TWA concentration determination, a sufficient number of samples shall be taken to characterize each employee's exposure during each work shift. Variations in work and production schedules and in employees' locations and job functions shall be considered in choosing sampling times, locations, and frequencies. (C) Each operation in each work area shall be sampled at least once every 3 months. (3) If an employee is found to be exposed to PCBs in excess of the recommended TWA concentration limit, control measures shall be initiated, the employee shall be notified of the exposure and of the control measures being implemented to correct the situation, and the employee shall be monitored every 30 days. Such monitoring shall continue until two such consecutive determinations Indicate that the employee's exposure no longer exceeds the recommended TWA concentration limit. Routine monitoring may then be resumed. (b) Recordkeeping Environmental monitoring records shall be maintained for at least 30 years after the employee's last occupational exposure to PCBs. These g records shall include the dates and times of measurements, job function and 16 * 079 47 location of employees within the worksite, methods of sampling and analysis used, types of respiratory protection In use at the time of sampling, TWA concentrations found, and Identification of exposed employees. Each employee shall be able to obtain information on his or her own environmental exposures. Daily rosters of authorized persons who enter regulated areas shall be retained for 30 years. Environmental monitoring records and entry rosters shall be made available to designated representatives of the Secretary of Labor and of the Secretary of Health, Education, and Welfare. Pertinent medical records for each employee shall be retained for 30 years after the employee's last occupational exposure to PCBs. Records of environmental exposures applicable to an employee should be Included In that employee's medical records. These medical records shall be made available to the designated medical representatives of the Secretary of Labor, of the Secretary of Health, Education, and Welfare, of the employer, and of the employee or former employee. i> 1 9 905262 17 N 07S48 i PUBLIC L A W 94-469-- OCT. 11,1976 90 STAT. 2025 AsbsthsmtsthhbptpommiifpsfytrRhhuehronniuhrauiaeeurrrfenpaecesocaaaeocoocae(ll(a(a((am(((atr(ttthhsylefmqi5t'ht4Cccn3aBemCBiecl2onlednru--utoesttuywsscee)ebak)a)enarp)no)axyorhsta)c)r))nnuubuaesgfshienfienett,ricee(tteoh(trfpssTyceshftblgoPmoaAloar((r(eAS(Fh(eedAA(ut,omrg,ei(wuTptohhabamliisirieinAclBrnh'cm--aecoeonui)iparvionfl)asletcre)inneh)eitpingt)d)wpcaiyaralmirtdlbs)ttrnfcy)ititrrnhieassyet.ent,wvtdhnoitoinnleaytEnEedspnitaannieyoeficetgetidraeaeocchqolvngdtieschrshstonrponpbiteaoAaftelxxnayoontenqeeusensuuesihssfhicerteaynreriqynsccctodypgnssgte,ud)bprdnuioelaaelilrdronwrrptoosueshetercedove,aeegrpaesesosntngmieroraeityrrpfipltararlrhsatbaisebcotcshirnpaurhsrredfyafuronmreerseebuctf)nttscsparreeoieeiufutnnaigroooseohqilraiaddpnsoichctoucnnacapteansnfecetpliy,bndrtldinonwpuieeowhhnimeottnosesatcthydoostrmrnadthdeism,atefyridieoroiehmtfavrnssciehmetotriamiteiapmbddsttiaiepdltla)snntunetrebeheseeprrneralntuyn(nepriyoemanebraneaasmynhatdcoranuAoldopgoncvonrcdcodcdundvirauptmofbnnyhoyilitentnpvolhroiiofhsciftvfsernioa.s)niiaraylnnebeobrtBhaosbariepmefolinreniipemtghtosrnndsdrconaeoutivpfdtnyerteosntnApariuhtsoicnhiaawmtteyoirepnnmeristeehpaohaorstn,seeaghofsidbeisodmlrrdtrimirhdcttenanconiifwoeoicoirpmasoeureesipotftasefohtsnelureponathttaAkreftnhyuosdeoelbtnlihtanxcmhhnsamitewntfrnpnedpeaocynntlfpyfnerisheedlnvdaeiepishcytnoyclottbaaehiLttoednssodaaAmihislcebsoooommahechttn(rylgfvrrsuyuafetretAutihemitrchabrraecesodbptesauncr(bnrpnanitiabieeeAwAgunoatdrlau.udnt1irhhgdmtorAsmnendthdd--ohsgnpipuamppdrbesttiiemtri)icfooAudbjteaeraceararhsseaiehldslaphp,uunhtinwtumanlnntlirorbpcme(ttnparrendipmahopealnAarerr1cpntcynainoopn(edynhthamyenaismi(uhnrhisrei)oaihtog2uhelbvntliyiaciseyAratne,ititsaf,syeysnsute*fcacionorrsisdtrui)eagrltmiAtuotnpsWtpacandtehadihsupto()ureshirnosrp(titrhstmhoy(he,pfte,gBeeetcisaa2hroosoaep(hstortto2rosmbmasrealiliestohhlotohrrr)naeplaaoalois.tstfar)oatsr.)ilti,eaaysyesrnrwnheranoheapotareni,otr,nrlbyaAfrtpuacozcAbhaadoiiyinyrhnioutndyenciea((tonchtnahbnehrmglhdlctmaoserseoyroBa3aniddtehhatlerdmmolphteebmrarsthnfbomhrryos),tmt(sfaf.ads)vtertasny"rohe,lhro(eoBaiaaarr(hyearb(peimietlopptix3dliifei3caaayrnesnroasrlsshnnoey.lnbhon)Aooerk)polnskocfeundypr)rrnaat,talabnum.billmmptierrmo(padhrbdsrtdtseyyetenstFecciieteoBudeweeelsehetbpsonikprmccsaareofble(rcfdaasxoldtyaef(eyuhvnrhoh)nsnoewa4msidictlepan0Aooi.xlnueitceit.ulltuutcbr)bcnleunnorheoioomhef}baahtanbisochdffttoiriiionbtysjsbmrrhniotrirehpa--apnjyhasreemiuvmniuuniieceeradncctfholhnnlmdpefprmarclladrtdcflattiwtjnoeergaayecsholailtatotwfuunhuoaiieaoonnoinuistfetalitctmenirriotoeenwayuraboneoemondtotinyybttsaeeeidoylodndn*h*ee*nd*eesrrfrrrtlfl.ll,,, Rule*. "TotallyHenclosed ePxeetimtiopntiofno.r Tcoenrmdistioennsd. FIGURE 1-1. SECTION 6() OF THE TOXIC SUBSTANCES CONTROL ACT 18 N 0 7 S 4 9 905263 II. INTRODUCTION This report presents the criteria and the recommended standard based thereon which were prepared to meet the need for preventing occupational disease and injury arising from workplace exposure to PCBs. The criteria document fulfills the responsibility of the Secretary of Health, Education, and Welfare, under Section 20(a)(3) of the Occupational Safety and Health Act of 1970, to "...develop criteria dealing with toxic materials and harmful physical agents and substances which will describe...exposure levels at which no employee will suffer Impaired health or functional capacities or diminished life expectancy as a result of his work experience." The National Institute for Occupational Safety and Health (NIOSH), after a review of data and consultations with others, formalized a system for the development of criteria upon which standards can be established to protect the health and to provide for the safety of employees exposed to hazardous chemical and physical agents. Criteria and recommended' standards should enable management and labor to develop better engineering controls resulting in more healthful work environments. Mere compliance with the recommended standard should not be used as a final goal. These criteria for a standard for PCBs are part of a continuing series of criteria developed by NIOSH. The recommended standard applies to the processing, manufacture, and handling of PCBs as applicable under the Occupational Safety and Health Act of 1970. The standard was not designed for the population-at-large, and any application to situations other than occupational exposures is not warranted. It is Intended to (1) protect 19 905264 N 07950 against acute and chronic PCB poisoning, (2) be measurable by techniques that are available to industry and official agencies, and (3) be attainable with existing technology. The standard is designed to substantially reduce the risk of development of carcinogenic, adverse reproductive, hepatotoxic, and dermatologic effects. Since 1970, `PCBs have been one of the more thoroughly Investigated environmental and occupational hazards. Nevertheless, there are Important gaps in the knowledge of chronic exposure effects in man at low concentrations of PCBs. Important research needs Include studies on the reproductive histories of women who have been exposed to PCBs, and quantitation of the dermal and respiratory absorption of different mixtures of PCBs. A better understanding is needed of the contaminants in commercial PCB preparations, particularly studies to determine the extent to which any chlorinated dibenzofurans in tissues of PCB-exposed American workers result from direct absorption or are derived from PCBs in the body. Another need is for an assessment of the hazards associated with the mobilization, during fasting or in other abnormal physiologic states, of PCBs stored in the body. 905265 N 07951 20 III. BIOLOGIC EFFECTS OF EXPOSURE Extent of Exposure Biphenyl (C 12H 10), diagrammed In Figure III-l, can be chlorinated by replacing any or all of its hydrogen atoms with chlorine [1]. 32 6` 5' 5 2' 3* Figure III-l. BIPHENYL MOLECULE AND RING NUMBERING SYSTEM Specific chlorobiphenyl molecules are designated by reference to the positions of the chlorine atoms according to the numbering scheme depicted in Figure III-l. The lowest possible numbers are assigned, and the phenyl moiety with the fewest chlorine atoms is assigned prime numbers [1,2]. Examples of the nomenclature used here are shown in Figure III-2. C1 C1 C1 C1 3-chlorobiphenyl ci 2,2',3,4',5-pentachloroblphenyl Figure III-2. EXAMPLES OF NOMENCLATURE SYSTEM OF CHLOROBIPHENYL COMPOUNDS There are three monochlorobiphenyl compounds, 2-, 3-, and 4chlorobiphenyl. The 5- and 6-monochlorobiphenyls are identical to 3- and 2-monochlorobiphenyl, respectively. There are 18 dichloroblphenyl 21 905266 K 07952 compounds. The number of possible chlorobiphenyl Isomers and the corresponding weight-percents of chlorine are presented in Table III-l. TABLE III-l NUMBER OF ISOMERS AND PERCENT CHLORINE FOR THE 10 CHLOROBIPHENYL (PCB) CLASSES Chlorobiphenyl Empirical Formula No. of Isomers Weight Z Cl mono di tri tetra penta hexa hepta octa nona daca C 12H9C1 C 12H8C1 2 C 12H7C1 3 C 12H6C1 4 C 12H5C1 5 C 12H4C1 6 C 12H3C1 7 C 12H2C1 8 C 12HC1 9 C 10C1 10 Adapted from reference 1 3 12 24 42 46 42 24 12 3 1 18.79 31.77 41.30 48.56 54.30 58.93 62.77 65.98 68.73 71.18 In the commercial synthesis of chlorobiphenyls, biphenyl is catalytlcally chlorinated with anhydrous chlorine; either iron filings or ferric chloride may be used as the catalyst [1]. The commercial preparations, commonly referred to as "PCBs," are isomeric mixtures. The weight-percent ehlorine in commercial mixtures has generally varied between 21 and 68Z and has been used to designate grades of commercial products. Commercial PCB products manufactured in the US, Great Britain, and Japan have been marketed under the trade name "Aroclor" [1-3]. Several grades of A r o d o r have been designated by numbers such as 1221, 1242, 1254, and 1260, where the last two digits represent the percent by weight of chlorine in 22 905267 N 07953 the mixture*. Another grede of Arodor, 1016, made primarily of tri- and tetraehlorobiphenyl compounds and containing 41Z chlorine by weight, was Introduced In 1971 to replace A r o d o r 1242 [2,4,5]. Other PCB products manufactured in Japan were marketed as "Santotherm" [1], and "Kanechlors" 300, 400, 500, and 600, containing approximately 42Z, 48%, 54%, and 60% chlorine, respectively [6]. In Germany, products marketed as "Clophens" A50 and A60 contained 54 and 60% chlorine, respectively [7]. In France, PCBs were marketed as "Phenodors" and "Pyralenes;" P h e n o d o r DP6 contains 60% chlorine [8]. Other countries reported to have produced PCBs are Italy, Spain, Czechoslovakia, Poland, Argentina, Brazil, the USSR, and India [1,9,10], The chlorobiphenyl constituents of several connnercial PCB products have been studied [6-8,11-16], Some data, both qualitative and quantitative, are presented in Table XII-2. About half the 209 possible chloroblphenyls do not occur in any of the commercial preparations. Among those compounds which do not occur, or which occur in trace amounts only, are 3-chlorobiphenyl, all of the trl- to pentachloro compounds that are chlorinated in only one ring, the penta-, hexa-, and heptachloro compounds that are completely chlorinated in one ring, and the penta- and hexachloro compounds that are chlorinated in four positions in one ring. Commercial PCBs ars insoluble in water, but are soluble in oil and many organic solvents. Some other physical and chemical properties of certain Aroclor products are presented in Table XII-1 [1], In addition to chlorinated biphenyls, the cosnnercial mixtures with 20-40% chlorine contained biphenyl from about 11% to traces, respectively, by weight. Many commercial PCB products also contain chlorinated 23 905268 r: 07954 dibenzofurans [17-- 23] and naphthalenes [18,19]. Concentrations of chlorinated dibenzofurans in various commercial PCB products are presented in Table III-2. TABLE III-2 CHLORODIBENZOFURAN TYPES AND CONCENTRATIONS (pg/g) IN COMMERICAL PCB PREPARATIONS Mixture* di tri Chlorodlbenzofurans tetra penta hexa hepta Total Ref. (1) 1016 (1) 1016 (1) 1248 (1) 1254 (1) 1254 (1) 1260 (1) 1260 (2) A-60 (3) DP-6 (4) K300 (4) K400 (4) K500 (4) K600 0.5 (c)*** (e) <0.001 0.5 0.1 0.2 0.1 0.2 1.4 0.7 (a) (e) (a) <0.001 1.2 0.2 0.4 0.4 0.3 5.0 10.0 (a) (c) (a) (a) <0.001 0.3 1.4 0.9 0.5 0.3 2.2 2.9 - (c) (b) (a) (b) 0.5 2.0 1.7 1.5 1.0 0.8 8.4 13.6 1-1.5 17-18 2.5-4 3-5 ** 21 21 21 21 21 21 21 21 20 20 20 20 ( 1 ^ A 1ms* ( n i et, \ **(I Pomerantz, written communication, January 1977) (a), (b), (c), (d), (e) represent relative amounts in increasing order Some commercial preparations that were marketed under the trade name A r o d o r contained chlorinated terphenyls in addition to chlorinated biphenyls. Aroelors 2565 and 4465 contained 75Z and 60Z chlorinated biphenyl compounds and 25Z and 40Z chlorinated terphenyl compounds, respectively. Both mixtures contained 65Z chlorine [1]. A broad class of nonflaomable synthetic chlorinated hydrocarbon insulating liquids used in electrical capacitors, transformers, nuclear 24 905269 N 07955 reactors, and accessory equipment is designated by the generic term "askarel" [4,5 ,24,25]. PCBs have been major components of most askarels used in the US since 1932. Two general classes of PCB-containing askarels are "capacitor,,-grade and "tranaformerM-grade [4,5]. A r o d o r 1242 was the major capacitor Imprgnant in the US before 1971; subsequently, A r o d o r 1016 has been used mainly for this purpose [4]. Transformer-grade askarels manufactured in the US include those marketed under trade names including "Asbestol," "Chlorextol," "Inerteen," "No-Flamol," "Pyranol," and "Saf-TKuhl" [4]. Transformer-grade askarels are usually mixtures of trichlorobenzene and more highly chlorinated (42-60%) biphenyls [5,24]. Some typical compositions are: 100% A r o d o r 1242; 70% A r o d o r 1254 and 30% trichlorobenzene; 60% hexachloroblphenyl and 40% trichlorobenzene; 45% hexachlorobiphenyl and 55% trichlorobenzene; and 70% pentachloroblphenyl and 30% trichlorobenzene. Another type of transformer-grade askarel contains 45% polychlorinated biphenyl (54% chlorine) and 55% of a mixture of trl- and tetrachlorobenzenes. Transformer-grade askarels also contain stabilizers such as glycldyl phenyl ether and 3,4-epoxycydohexylmethyl-3, 4-epoxycyclohexane earboxylate [24]. Exposure to commercial preparations of PCBs in the work environment may involve many different chlorinated biphenyl compounds, and also substantial amounts of biphenyl, tri- and tetrachlorobenzenes, and small amounts of many different chlorinated dibenzofurans, chlorinated naphthalenes and in special uses, chlorinated terphenyls. Commercial production of PCBs in the US began in 1929 and reached 85 million pounds in 1970 when the major producer began selling PCBs only for use in "closed" systems. Since 1972, only those A r o d o r s designated 1016, 23 905270 N 0795C 1221, 1242, and 1254 have been produced in the US, and total annual production has been around 40 million pounds [26]. Imported PCBs amounted to about a half-million pounds in 1972 and 1973 [26,27], A decachlorobiphenyl produced in Italy and Imported by one company for use in investment easting waxes accounted for 80-90Z of the total PCB imports [26]. The other 10-20% was imported from France for use in semidosed heat transfer applications [27]. Occupational exposure to decachlorobiphenyl could occur in the manufacture of the Investment casting waxes as well as in the preparation of the investment casting molds in the 25 US foundries which use the decachlorobiphenyl wax [26], Most of the PCBs produced in the US since 1971 have been used in electrical capacitors (70%) and transformers (30%). About 95% of the 100 million capacitors produced annually in the US contain PCBa [27]. There is potential occupational exposure to PCBs in the plants of the 17 reported companies that manufacture capacitors in the US. Capacitors are generally classified into two categories for disposal purposes. "Small" capacitors contain less than 2 pounds of PCBs; those incorporated into electrical equipment such as television sets, home air conditioners, and light fixtures contain 2-340 ml of PCBs and have service lives of at least 10 years [26,28]. "Large" capacitors may contain about 25 liters of PCBs [26] and have a service life of 15-20 years [26,27], Potential occupational exposures exist in the servicing of appliances and in the disposal of used capacitors or equipment. Transformers that contain PCBs are used mainly in or near inhabited buildings where fire hazards from cheaper oil-filled transformers are greatest. The estimated 135,000 PCB-containing transformers represent 26 905271 U 07957 about 5% of all transformers in the US [27]. Occupational exposure to various askarels used for transformers may occur in their manufacture, servicing, and transportation, or as a result of leaks [29]. Other potential occupational exposures to PCBs exist through losses in storage [30], shipment [29], manufacture and use of heat exchange units [27.31] , and in use of previously manufactured items which contain PCBs, such as hydraulic systems, vacuum pumps, and gas transmission turbines [30.31]. The past use of PCBs in carbonless copying papers may result in exposure of workers currently engaged in paper reclamation [30]. Workers in plants that previously used PCBs may have current exposure in their working environments because PCBs have been shown to remain in the workplace air and on surfaces for years after PCB use has been discontinued [32,33]. Several occupations that may have Involved exposure to PCBs were tabulated in a 1966 publication [34]. NIOSH estimates that 12,000 workers have potential occupational exposure as a result of current uses of PCBs in their working environments [35]. In addition to their occupational exposures, PCB workers may be exposed to PCBs carried into their homes from the workplace [36], from general contamination of the ambient air [26,37,38] and water [26,37], and to PCBs and their metabolites in their diets [39-46]. Metabolism and Mechanism of Action A study of the metabolism of 4-chlorobiphenyl was reported in 1959 by Block and Cornish [47]. In this experiment, 1 gram of 4-chlorobiphenyl was fed to rabbits in a single dose and 4' -chloro-4-biphenylol and its 905272 27 It 07958 glucuroniside were recovered from che urine in amounts that accounted for 24 and 50%, respectively, of the administered dose. Subsequently, a substantial number of metabolic studies of individual chlorobiphenyl compounds [41-43,48-84], mixtures [85,86], and metabolites [48,49,87] were reported, and a comprehensive review was published in 1976 [88]. These reports collectively demonstrate through many study methods that some aspects of metabolism are of special significance to the toxicity of PCBs and that some Isomers are more toxic, or have different effects, than others [89-94]. Chlorinated biphenyl compounds are readily absorbed from the digestive tract, regardless of the degree or paetern of chlorine substitution [50,51,95,96]. It sees likely that similar absorptive characteristics apply to the respiratory system since chlorobiphenyl mixtures in air are rapidly absorbed [97], as is decachloroblphenyl [98,99]. Varying amounts of chlorobiphenyls, depending on degree and paetern of chlorination, are excreted in the feces [42,50,53-56,100], milk [41-44,51,101], and hair [102] of animals, but no more than trace amounts are excreted in the urine [42,51-55,57-62,103-105]. Metabolites of chlorobiphenyl compounds have been found in the urine of mammals including mice [52], rats [48,53-56,58-60,63,64,66,71,85], rabbits [65,67-69], monkeys [51,61,74,75], swine [72], goats [73], and cows [41,73], as well as in feces [48,50-54,56,58-65,76-80], and milk [41]. The metabolites excreted in urine [53,54,58,59,61,63,64,66,67], bile [50,51,53,81], feces [52-54,58,63,76], and milk [41] are, to varying degrees, conjugated with glucuronic or sulfuric acids. Differences in metabolism of PCBs among the aforementioned species are more quantitative 28 N 07959 905273 rhw qualitative [51,73]; however, metabolism in birds and fish may differ qualitatively from that in mammals [55,77]. Among mammals there are also quantitative differences in PCB metabolism and in effects related to age and sex [50,93,106]. Metabolites identified in mammals Include mono- to polyhydrorylated derivatives [41,48,49,51-56,58-81,85], and methoxy [59,60], hydroxymethoxy [64,65,68,70,76,87], dihydrodihydroxy [51,53,54,69,74,75,81], hydroxydihydrodihydroxy [51,74], and dechlorinated derivatives [48,65,70,77]. The lower-chlorinated biphenyl compounds are more readily metabolized than are the more highly chlorinated ones [41,50,51,55,61-64,66,82- 84,96,107-109], with no metabolism having been demonstrated for decachlorobiphenyl [66]. As a consequence, some of the more highly chlorinated compounds persist in the tissues for years after Intake has been discontinued [51,83,103,110]. The presence of at least two adjacent, unsubstituted hydrogen atoms, particularly in positions 3, 4, and 5, or 3', 4', and 5', is required for rapid metabolism of chlorobiphenyls [79,83,84]. All mono- di-, and trlchlorobiphenyls, and all tetrachlorobiphenyls except 3,3',5,5'- tetrachloroblphenyl meet this requirement. The latter compound, 3,3' ,5,5'- tetrachlorobiphenyl, was found to be particularly toxic to monkeys, and it was suggested that the chlorinated dlbenzofuran derivative may have been Involved [94]. While dlbenzofuran derivatives have not been demonstrated to exist as mammalian metabolites, they may have been Identified as PCB metabolites in chickens [111] and Curley et al [22] reported the excretion of dibenzofurans in urine of rats. In the latter case, however, dlbenzofurans were also identified in the administered PCB [22]. 29 905274 t: 0 7 9 6 U Dibenzofurans are of concern because they may be many times more toxic than PCBs [19,112]. Metabolites found in urine [48,51,53,56,60,61,64,66-74,85], bile [81], feces [51-53,56,58,60,61,64,66,76,79,80,113], and milk [41] include hydroxy derivatives. Such compounds have been demonstrated to be more toxic than their respective parent chlorobiphenyl [41,114] and their presence in milk [41] is of special concern. Hydroxylation may be direct through hydroxylating enzyme systems, or through formation of arene oxide intermediates [48,51,53,68,75,81,87,115]. This latter process is of particular concern because of potential carcinogenesis and mutagenesis as a result of covalent binding of arene oxides to nuclear components of the cell [51,68,74,82,86,116]. Such binding has been demonstrated both in vivo [51,86] and in vitro [51,82,86,116,117]. Additional evidence of hydroxylatlon through arene oxide intermediates included findings of metabolites in which chlorine, dueterium, or tritium were at different molecular locations than in the administered compound [68,115,116,118], and transdihydrodiols as mammalian metabolites [51,69,74,75,81]. Although adjacent unsubstituted hydrogen atoms are necessary for rapid metabolism of chlorinated biphenyls, it has been demonstrated that 2,2',4,4',5,5'-hexachloroblphenyl, which does not have this characteristic, can be hydroxylated [70,79], and oxidatively dechlorlnated [65,70]. It has been proposed that the metabolism of this compound may also involve arene oxide formation [65], and chronic exposure to potential carcinogenic activity of resulting arene oxides [86] may result from the metabolism of this and similar compounds [75]. 30 905275 K 07963- Historical Reports Smyth [119], In a paper read October 28, 1930, presented the results of his studies with biphenyl, 2- and 4-chlorobiphenyl, and two unidentified polychloroblphenyl mixtures. He reported the oral minimum lethal doses for rabbits and guinea pigs as 4+, 2.5, 3.5, 4+, and 4+ g/kg, respectively. Health problems associated with the manufacture of PCBs were the subject of a report by Jones and Alden [120] In 1936. The case history was presented of a man whose employment, from April 1930 to the end of 1933, Involved the distillation of chlorobipheny 1. In May 1933 he developed chloracne, a specific type of acne known to be caused by some chlorinated hydrocarbon compounds [121,122]. Jones and Alden [120] stated that the manufacturing process was not enclosed, that a different source of benzene (a starting ingredient) had been used from the summer of 1932 through October 1933, and that from March to October 1933, the dielectric qualities of the PCBs produced had been substandard. Of 24 men working In the manufacturing process during the period beginning In the summer of 1932, 23 developed chloracne. The first Indication of chloracne In the workers 'X appeared in January 1933. Following another change In the source of benzene, enclosure of the distillation apparatus and Installation of ventilation fans, a gradual Improvement In the acneiform eruptions was noted. In 1936, Schwartz [123] reported digestive disturbances, burning of the eyes, and Impotence in men working with chloroblphenyls. He also noted that nonachloroblphenyl was used as an Insulator for automobile electric wires, in capacitors, and as a delusterer of rayon. 905276 31 N 7S62 An early use of FCBs was for incorporation along with chloronaphthalenes into synthetic waxes [124-128]. These waxes contained 10-20% PCBs [124-126] and were used to Insulate electrical wire and cable. There were several reports that chloracne [125-128] developed in workers involved in the manufacture and use of these waxes, which were associated with at least one fatality in 1936 [125,1271. The fatal case was described by Drinker et al [125] in 1937. The patient, who had been exposed to low concentrations of tetra- and pentachloronaphthalenes (90%) and chlorinated biphenyls (10%) developed chloracne, followed by jaundice. He was hospitalized with abdominal pain and distention. At autopsy, cirrhosis of the liver with superimposed acute yellow atrophy was found. Two other fatal cases were described where the exposures had been to mixtures of penta- and hexachloronaphthalenes [125]. According to the authors, no similar cases had been reported in the literature. As a result of these fatalities, estimates of the airborne concentrations of chlorinated hydrocarbons In 30 different factories were made and animal experiments were performed to study the effects of exposure at such concentrations. Rats were exposed 16 hours/day, 6 days/week to trlchloronaphthalenes at 1.31 mg/cu m, to a mixture of penta- and hexachloronaphthalenes at 1.16 mg/cu m, to a mixture of penta- and hexachloronaphthalenes (90%) and chlorinated biphenyls (10%) at 1.37 mg/cu m, and to a chlorinated biphenyl mixture containing 64% chlorine at 0.57 mg/cu m. The authors [125] stated that higher concentrations had frequently been found In the factories, and that except for trlchloronaphthalenes, they did not consider that It would be safe to expose workers to any of the mixtures at the concentrations N 07963 905277 studied [125.]. Further details of the animal experiment were reported by Bennett et al [129] In 1938. These Investigators [129] found morphologic changes In the livers of two groups of rats exposed at the 0.57-mg/cu m concentration and also at 0,93 mg/cu m for 8 hours/day. These animal experiments reported by Drinker et al [125] and by Bennett et al [129] have continued to be erroneously cited [130,131] even though Drinker [132] reported In 1939 that the "chlorinated biphenyl" was actually a mixture of chlorinated biphenyls and chlorinated terphenyls. Drinker [132] stated that a followup inhalation experiment with chlorinated biphenyls containing 682 chlorine showed them to be of low toxicity and he recommended permissible limits for workroom air of 0.5 mg/cu m for mixtures of chlorinated biphenyls and terphenyls and 10 mg/cu m for chlorinated biphenyls. The first Indication in the literature that PCBe might be embryotoxlc or have teratogenic effects was the report by McLaughlin et al [133] In 1963, 5 years prior to the recognition of PCBs ae an environmental pollutant. The authors evaluated the toxicity of Aroclor 1242 by Injecting It Into the yolk see of fertilized eggs prior to Incubation, and then observing the effects on embryonic development. None of the eggs hatched after Injection with 25 mg of PCBs/egg; with Injection of 10 mg/egg, one chick hatched out of 20 Injected eggs, but it died 2 days later. Some of the embryos examined showed beak deformities, edema, and retarded growth. Effects on Humans (a) Effects from General Environmental Contamination In the United States, PCBs are present In ambient air [26,37,38], 33 905278 (' 07964 found on his forehead, scalp, face, and arms. Although the man had been removed from direct exposure to PCBs, their odor was present In the man's new work area. It was reported that this was the first case of chloracne In the plant, where more than 100 workers had been engaged In the process for more than 20 years. A company that used PCBs at two manufacturing facilities provided testimony on employee health in 1975 (In the Matter of General Electric Company, File No. 2833, New York State Department of Environmental Conservation). Examination of records submitted as testimony indicated that exposures were to an askarel [25] containing, by weight, about 602 of Aroclor 1254,402 trichlorobenzene, and 0.0115-0.1352 diepoxide scavengers. From the records submitted, it was not possible to determine the precise numbers of male and female workers. The exact occupations of the workers could not be determined either but a substantial number of "crimpers" was Indicated. The records showed that employees had reported to the dispensary complaining of skin rashes and dermatitis on 49 occasions during the previous 15 years. Only the fingers and hands were involved in 21 complaints, only the arms and hands in 5, and only the face and legs.in 1. In 7 other complaints the face, neck, and legs were mentioned in 4, 2, and 1 cases, respectively, in addition to the upper extremities. Associated with the complaints of skin rashes and dermatitis were some complaints of itching of the face (2), neck (1), eyes (1), arms (2), and hands (1). A generalized skin rash was the basis of 14 additional complaints. One worker developed the generalized rash on exposed parts of his body after only 2 days of working with the askarel. 52 N 07965 905279 water [26,37], and In many foods [39,45,46]. A common dietary Intake of 10-20 Mg/day has been estimated for teenage males in the US [46]. PCBs frequently have been found In various tissues and body fluids of the US population, eg, at ppm concentrations in adipose tissue [7,36,134-136], ppb concentrations in blood [137,138,140,141], and in milk [143,144] at ppm or ppb concentrations in the milk fat or whole milk, respectively. The Environmental Protection Agency's Human Monitoring Survey has analyzed human adipose tissue samples collected since late 1968 for PCB content [134]. According to this 1972 report, 637 ssmples had been analyzed, and 198 of these contained more than 1 ppm of PCBs. Positive findings were made in tissues from each of the 18 participating states. A detailed analysis of two samples collected in the Human Monitoring Survey was made by gas-liquid chromatography (GLC) and mass spectrometry (MS) and reported by Biros et al [135] in 1970. The samples contained at least 14 isomers ranging from penta- to decachloroblphenyls. Price and Welch [36] stated that of more than 4,000 human adipose tissue samplee examined by the Michigan State Department of Health Pesticides, none had chromatograms that exactly matched those of standard A r o d o r solutions. Their data show relative accumulation in adipose tissue of the more highly chlorinated compounde, and relative dilution or absence of the lese highly chlorinated compounds originally present in A r o d o r s 1254 and 1260. They [36] described the analyses of tissue samples at autopsy of a 77-year-old man in which PCB concentrations of 100-250 ppm (fat basis) were found. The highest PCB concentration was in the liver. The authors [36] found about 55Z of adipose tissue samples in the general population contained PCBs at <1.0 ppm, about 36Z at 1-2 ppm, and the remainder at more than 2 ppm. 34 905280 N 07966 During July 1972 through June 1974, 2,324 fat samples were analyzed by the Human Monitoring Survey, 1,277 in the first year and 1,047 in the second [136], In the 2 years, respectively, PCBs were not detected in 24.5 and 9.1Z, were present at <1 ppm in 40.2 and 50.6Z, were present at >2 ppm in 5.5 and 4.9Z, and were present at 1-2 ppm in the remainder of the samples. Penta-, hexa-, and heptachlorobiphenyl were the PCBs most frequently present. A complete analysis of PCB compounds in a composite sample of adipose tissues from patients at the University Hospital in Lund, Sweden, was reported by Jensen and Sundstrom [7] in 1974. Forty-five compounds, accounting for the total PCB content of the adipose tissues, were found and identified by comparison with known PCB Isomers. The biphenyl compounds Included three tetrachloro isomers, many penta-, hexa-, hepta-, octa-, and nonachloro Isomers, and decachlorobiphenyl. By comparison with Clophens A50 and A60, which had compositions similar to A r o d o r s 1254 and 1260, respectively, the authors [7] found the relative concentration of several compounds with chlorine substitution in the 4,4' positions of the biphenyl ring to have occurred, as did many compounds without vicinal, unsubstituted positions. Most of the compounds which underwent, relative dilution to the greatest extent had either vicinal, unsubstituted 3,4-positions or two pairs of vicinal, unsubstituted positions. Blood sera of 616 residents of urban and rural areas of South Carolina were analyzed for PCBs and the results were presented by Flnklea et al [137] in 1972. Analysis was accomplished by GLC with a Nl-63 electron capture detector after basic dehydrochlorinatlon. The amounts of PCBs present were estimated by Integration of five peak areas associated 35 N 07967 905281 with Aro d o r a 1254 and 1260. PCBa were not present In samples from all Individuals in quantities measurable by the technique used (Table III-3). Analysis of the data Indicated that measurable serum PCB concentrations were not related to the age 5 to >60 years) or sex (305 females, 311 males) of the donor, but that the concentrations associated with race and residence (Table III-3) were statistically different. TABLE III-3 PCB CONCENTRATIONS IN BLOOD SERUM BY RACE AND RESIDENCE Race and Residence No. in Sample PCBa Measureable In No. X PCB Concentrations Ave* Max ppb ppb Rural black Urban black Rural white Urban white 107 151 192 166 5 4.67 57 37.75 119 61.98 89 53.61 Average of measureable concentrations Adapted from reference 137 9.45 5.22 5.12 4.38 20.6 29.0 16.6 22.0 'v Maternal and cord blood samples collected in Tokyo, Japan from December 1973 through February 1974 were reported in 1975 by Aklyama et al [138] to contain PCBs at mean concentrations of 2.8 and 1.1 ppb, respectively (on a whole blood basis). The maximum concentrations found were 7.6 ppb in maternal blood and 3.3 ppb in cord blood. Quantitatively, significant correlations of PCB concentrations in 21 pairs of maternal and cord blood samples were not found. Qualitatively, pairs of maternal and cord bloods had identical PCB patterns resembling those of Kanechlors 500 905282 36 N 07968 and 600. The data suggested nonselectlve in utero transfer of PCB compounds from mother to fetus. Concentrations of PCBs in human embryonic and fetal tissues were reported by Shiota et al [139] in 1973 to not exceed those found in postnatal Individuals who died accidentally. The concentrations, found in 19 embryos 5-8 weeks old, were reported as <2 ppb. The concentrations found in 5 second trimester and 2 third trimester fetuses are presented in Table III-4, expressed on the bases of both whole tissue and on the fat content of the tissue. TABLE III-4 CONCENTRATIONS (ppb) OF PCBs IN TISSUES OF HUMAN FETUSES Age of Placental Basis Contents Cerebrum Tissue Analyzed Liver Kidney Skin 2nd trimester Whole Fat 3rd trimester Whole Fat *One sample Adapted from reference 139 2-23 150-60 2* 270* 2-33 230-800 6-20 17-83 60-1,900 550-1,300 25-90 6-10 48-769 1,000-1,300 420-470 880-1,400 PCB concentrations in the venous blood of nine patients hospitalized with severe wasting diseases were reported by Hesselberg and Seherr [140] in 1974. The investigators were concerned with the release of stored organo-hallde pesticides and PCBs during mobilization of body fat. They were unable to detect any PCRs in the blood of 15 apparently healthy 37 N 0 7 9 69 905283 control subjects. PCB concentrations found In the patients' blood (uncorrected for efficiency of recovery) ranged from 10 to 100 ppb. Information was not presented on the patients' occupations etc prior to their having become ill. PCB concentrations in blood plasma and in adipose tissue samples obtained from 28 people during routine abdominal sections had a correlation coefficient of 0.74 according to Inoue et al [141]. The average concentration of PCBs was 6.113.52 ppb in blood plasma, and in the adipose tissue (fat basis) it was 2.611.9 ppm. These investigators [141] also evaluated the effect of emaciation on PCB concentrations in blood plasma of these and other patients; they found an average of 8.414.26 ppb in 19 emaciated patients and 4,712.17 ppb in 30 unemaciated patients. Hair ' samples collected from a college barber shop were reported by Matthews et al [102] in 1976 to contain PCBs at 0.34-0.76 ppm. The samples were composites from five or more individuals collected on two occasions, 4 months apart. Hair was collected from the barber shop aprons, and care was taken to avoid possible contamination. Five commercial preparations of hair sprays, shampoos, and hair clipper lubricating oil were negative for PCBs. Blood samples were not collected for comparison. PCBs were reported in 1966 to have been found in hair samples from three members of a Swedish family [142], but no concentration data were given. It was speculated that one of the family members, a 5-year-old girl, had acquired PCBs from her mother's milk. A correlation, was found between the quantities and compositions of PCBs in sasiples of adipose tissue collected from four women during Caesarean deliveries and in milk samples collected 3-5 days later [143]. 38 905284 Al 0 7 9 7 0 There were differences in chromatographic patterns between individuals, but for each individual the chromatographic patterns for the adipose tissue and the milk were qualitatively the same. PCBs in all samples contained principally 4-8 chlorine substitutions. Although the basis (fat or whole milk) for expressing the concentration of PCBs in the milk was not stated, comparisons with PCB concentrations found in-adipose tissue and milk by other investigators indicate that the whole milk basis was used [136,144] (EP Savage, written communication, February 1977). Concentration data are sumnarlzed in Table III-5. TABLE III-5 PCBS IN MILK AND ADIPOSE TISSUE OF FOUR WOMEN Subject PCB Concentrations, ppm Adipose Tissue Milk a b c d Adapted from reference 143 0.62 0.75 1.6 3.1 0.008 0.015 0.032 0.036 Concentrations of PCBs measured in milk samples from 39 women living in two small cities in Colorado were presented by Savage et al [144] in 1973. Two samples contained PCBs at concentrations of 0.05 and 0.1 ppm. Six other samples contained PCBs at 0.04 ppm, the lower limit of detection for the analytical method, or less. The time postpartum at which the samples were collected and the basis (fat or whole milk) for expressing the concentrations were not mentioned. (Comparison with data in the following 39 905285 ,N 07571 paragraph suggests that the whole milk basis was used.) Results of analyses of 384 human milk samples from 40 states for PCBs were presented in a written communication by EP Savage in February 1977. All positive samples that contained PCBs at less than 50 ppb on a whole milk basis were recorded as a "trace." Samples with 50 ppb or more of PCBs were reported as ppm in milk fat on the basis of 2.8Z milk fat. Only five samples were not positive for PCBs, and 112 samples from 27 states contained measurable amounts Cup to 12.6 ppm on a fat basis). Of the total number of samples, 141 were analyzed during December 1976 and January 1977. The time postpartum when the samples were collected was not stated. While no adverse effects have been associated with PCBs at the concentrations found in adipose tissue, blood, or milk of individuals whose only known exposures were from general environmental contamination [7,36,102,136-144], knowledge of these concentrations is important to the evaluation of reports on occupational exposures. That is, the data provide a basis for evaluating body burdens of PCBs added by occupational exposure and indicate that workers may have substantial body burdens before the added Insult of occupational exposure. (b) Effects from Consuming PCB Contaminated Rice Bran Oil An episode of poisoning associated with PCB ingestion occurred in Japan in 1968, and was the subject of a special issue of the journal Fukuoka Acta Medica in June 1969 [145-159]. These reports dealt primarily with the situation in Fukuoka prefecture where 325 poisoning cases had been identified through January 20, 1969. The episode resulted from consumption of a particular brand of rice bran oil [160] and ultimately Involved persons in 22 prefectures [161]. About equal numbers of cases 40 905286 N 07972 (approximately 450 each) were registered In Fukuoka and Nagasaki prefectures as of September 1973 [161]. In the prefectures of Hiroshima, Kochi, and Yamaguchl, there were 80, 45, and 40 cases, respectively, at that time. In each of the other 17 prefectures there were 1-25 registered cases. The total number of cases registered by March 1970 was 1,015; by September 1973, the number had Increased to 1,200, and by May 1975 to 1,291 [161.162] . The disease became known as "Yusho," or rice oil disease [145.163] . The outstanding signs of the poisoning were acnelform eruptions and eye discharges (a peculiar secretion from the meibomian glands) [146], Chloracne was suspected [164]. Hyperpigmentation of the skin, nails, and mucous membranes, swelling of the upper eyelids, and hyperemia of the eonjunctivae were other common signs [146,165]. Studies of the rice oils consumed by the patients indicated that the oil associated with Yusho was produced mainly during February 1968 [147,148]. The source of the contamination was determined to be a heat exchange unit containing PCBs that leaked through tiny holes when rice bran oil was heated at low pressure to remove odorous constituents [163,165]. By intensive chemical analyses, Including infrared spectrophotometry and GLC, the major contaminant in the rice bran oil was found to be Kanechlor 400 [147]. PCB concentrations in the oil varied, depending on the date of production or shipment. The highest concentration of PCBs, based on the chlorine content of the oil, was about 3,000 ppm which was found in canned oil shipped on February 5. GLC data were not quantitated. In oils shipped thereafter, PCB concentrations decreased rapidly, and only traces were found in oils produced after February 19, 1968 [147,148]. Minor contaminants in the rice oil included polychlorinated dlbenzofurans at 41 N 07973 905287 about 1/200 of the PCB concentration [20,160], traces of chlorinated naphthalenes, and bromine at about 2% of the chlorine content [147]. Recent analyses of some of the oil samples indicate that there may have been other chlorinated organic contaminants (F Cordle, written eomsiunlcatlon, November 1976). In one study [148], the contaminated rice bran oil was found to have been used largely for frying food (which may have altered the constituents). The oil was consumed for various periods during the spring through October 1968 [148]; the first reported clinical examination of a Yusho patient had occurred on June 7, 1968 [163]. Studies through January 1969 of patients in Fukuoka prefecture indicated that onsets of Yusho began as early as February and as late as December 1968, and first involved the eyes [146]. Onset occurred i n m o s t patients in June, July, and August U46]. Some attempts were made to estimate the amounts of rice oil and FCBs consumed by the patients [166,167]. Maximum consumption of oil was estimated at 4.4 liters [166]. Isono and Fujiwara [167] estimated that two Yusho cases may have resulted from the ingestion of PCBs at a dally rate of 67 ig/kg body weight for 3 months. For 146 Yusho patients who lived in homes known to have used oil shipped on February 5-6, the estimated average total oil consumption was 800 ml, a volume that contained an estimated 2 g of PCBs [166]. It was estimated that the maximum volume of oil consumed by an individual was 2.7 liters. Of 21 patients who had consumed more than 1,400 ml (3-4 g of PCBs), 18 were considered to have had major signs of Yusho. Among 80 patients estimated to have consumed less than 720 ml of the oil, 31 were thought to have had major signs of Yusho. From the seme 42 905288 N 07974 data, the minimum PCB ingestion among the 146 patients was estimated at 0.5 g [165]. Estimates of the amount of contaminated oil consumed by 13 pregnant women during the ingestion period ranged from 300 to 2,600 mg [167], but estimates of their PCB consumption were not made. Of the 13 babies born to these women, 8 had jaundice, 3 had marked dermal chromopexy, and 9 had excess secretion of tears [167]. Several studies of PCBs in the tissues and body fluids of Yusho patients were made at various intervals after ingestion of the contaminated oil [146,147]. The samples taken closest to the time of Ingestion were collected in October and November 1968 [146,147]. Samples from discharges of the acnelform eruptions of two patients contained PCBs at 32 and 45 ppm, and samples of subcutaneous fat from the face and abdomen of an 18-year-old man contained PCBs at about 75 and 13 ppm, respectively. PCBs with GLC patterns similar to those of the contaminated oil were found in these samples as well as in placental and fetal tissues [147], Preserved tissues from a baby that had been stillborn in October 1968 were later analyzed and PCB concentrations of 1.8, 1.2, and 0.1 ppm in fat were found in the liver, skin, and fat, respectively [168]. The baby's mother had been classified as a severe case of Yusho with onset about mid-June, but the amount of oil consumed, the period of pregnancy during which it was consumed, and the body burden of the mother were not. reported [149], PCBs Trere found in all sputum samples from 13 patients collected between December 1969 and May 1970 [169,170]. PCB concentrations were highest in December and detection was less common by May. Other data on concentrations of PCBs were obtained from body fat and other tissues taken from five Yusho patients at autopsy [168,171]. The 43 905289 N 07975 dates of death were between July 1969 and May 1972, Cause of death was heart failure In four cases and a ruptured liver In another case [171], Estimates of contaminated oil consumed by two of the dead patients were about 0,3 g and 1.6 g, respectively [171], One PCB, probably a hexa- or heptachloroblphenyl from the contaminated oil, was especially concentrated in the tissues. The peaks associated with tetrachlorobiphenyls were very low by comparison, suggesting that total PCBs in the body had been substantially decreased within a year after the end of exposure. The mesenteric fat contained PCBs at 0.9-15.1 ppm, and the liver contained 1.310.4 ppm in Its fat. PCB concentrations in fatty tissues obtained during 11 control autopsies averaged 2.6 ppm. Of the organs examined (liver, heart, kidney, brain, and skin), the liver and heart usually contained the highest concentrations of PCBs [168,171]. In an additional case, the subcutaneous fat obtained on autopsy of a woman who died in September 1972 (about 2 years after consuming contaminated oil) contained PCBs at 2.9 ppm [168]. Polychlorinated dlbenzofurans (PCDFs), mainly penta- and hexachloro compounds, were found in tissues obtained on autopsy of two Yusho patients who died in 1969 and of one who died In 1972 [160], No chlorinated dlbenzofurans were found in tissues obtained on autopsy of two controls, although PCB concentrations of about 1-1.5 ppm were found in adipose tissue and liver fat. The findings from the Yusho patients are summarized In Table III-6. 905290 N 07976 TABLE III-6 PCB s AND PCDFs (ppm) IN FAT FROM THREE YSHO PATIENTS AT AUTOPSY rijti*r Year of Death PCBs Adipose Liver PCDFs Adipose Liver 1969 3.4 1969 8.5 1972 2.1 irA Adapted from reference 160 'v 4.7 5.6 3.5 0.03 0.04 0.01 2.3 1.1 0.3 The ratio of PCBa to PCDFs In the rice bran oil was about 200, as in the adipose tissues obtained at autopsy. However, in the liver, ratios of 2, 5, and 12 indicate that considerable concentration of PCDFs had occurred. Information on PCBs [146,147,168,171] and PCDFs [160] in tissues Indicates some shifts in concentrations during the 3 years after ingestion of the contaminated oil was discontinued. Masuda et al [168] reported that a year after ingestion stopped, the concentrations of tetrachlorobiphenyl components had decreased and were near those found in persons who had not Ingested the contsminated oil. The more highly chlorinated PCB compounds were still retained in the fatty tissue 4 yeers after ingestion had stopped [168]. Blood from Yusho patients was first examined for PCBs 5 years after ingestion of the contaminated oil ceased. Three distinct GLC patterns were found among blood samples from 49 patients [172-175]. Two patterns (A and B) were peculiar to the Yusho patients, and the third pattern (C) was N 07977 905291 similar to chat of controls. Patterns A and B were characterized by peaks corresponding to those of certain penta- and hexachlorobiphenyl compounds that were present in the contaminated rice bran oil. Patterns A and B differed, however, as to the relative amounts of these compounds [172,173]. These patterns became diagnostic for Yusho [161]. The average concentrations of PCBs in the blood serum were 9, 4, and 2 ppb for patients with patterns A, B, and C, respectively, and 3 ppb for 27 control subjects [173]. The maximum blood serum PCB concentration found among 72 Yusho patients examined between April 1973 and March 1974 was 26 ppb [174]. Of these patients, 43 had pattern A, 26 had pattern B, and 3 had pattern C. Similar patterns were reported in 1975 by Abe et al [176] in a 1974 study of 18 female Yusho patients and their 30 children. Concentrations of PCBs in blood samples from mothers ranged from 3 to 33 ppb during 1974; PCBs in samples from their children ranged from 1 to 20 ppb, and in samples from 14 control children, from 1 to 8 ppb. PCB concentrations tended to be higher in the blood samples from children nursed by Yusho mothers. A sample of milk from a Yusho mother was reported in 1974 to contain PCBs with a GLC pattern similar to those in samples of fatty tissue from other Yusho patients [168]. Concentrations of PCBs in the mother's milk were 0.06 ppm on postpartum days 0-2, 0.04 ppm on days 3 and 4, and 0.03 ppm on day 5. The respective concentrations in the milk fat were 4.5, 3.0, and 2.6 ppm. In addition to the skin and eye conditions manifested by most people who consumed the contaminated rice bran oil [146,151-153,162], there was pigmentation of the nails [146] and of the oral mucosa [154]. A substantial array of clinical and laboratory findings were published on 46 905292 N 07978 Tjt j i i [tients with Yusho [150,152,155,156,177-180], Including slight increases activity of serum alkaline phosphatase, reduced serum iron j&ncentratlons [155], changes in the microanatomy of liver cells that were ^Sonaidered indicative of microsomal enzyme stimulation [156], symptomatic functional changes indicative of neuropathy [150,177], respiratory ,ireoivement [170,178], a decreased concentration of bilirubin in the serum ' 1 7 9 ] , and, in many patients, an elevation of the concentration of triglycerides in the serum [155,157,158,175,179-181]. Babies born to women with Yusho, both during and after the period of ingestion of the contaminated rice bran oil, were the subject of several investigations [149,159,176,182,183]. Babies of mothers who had ingested 'the contaminated oil became known as "black" or "cola" babies because of 'the abnormal - skin pigmentation that tended to persist for several months refter their birth [176,182,183]. Infants born up to 5 years after their mothers' last ingestion of contaminated rice oil were still affected to some extent [182]. In one study of four babies, other clinical and anatomical abnormalities (retarded intrauterine growth in three, edematous face and exophthalmic eyes in three, dentition in two, calcification on skull and wide, open sagltal suture of skull in three) were seen at birth [183]. These were not permanent, and postnatal body and mental development appeared normal in these and other Yusho children [160,176,183]. In at least one ease, an investigator concluded that a baby had developed Yusho from nursing [182]. The period of ingestion of contaminated rice bran oil was only a few months, but the effects have persisted for several years [160,161,174,175,179,180,184,185]. The skin lesions and hypersecretion 47 N 0 7 S 7 9 905293 \ from meibomian glands remained unchanged for long periods in many patients [174,184,185]; their magnitudes in 1974 appeared to be related to blood PCB concentrations [174], In addition, complaints of generalized fatigue, and symptoms referable to the peripheral nervous system and to the respiratory system became more prominent. In 1974 these complaints and symptoms were established as part of the diagnostic criteria for Yusho [161], These additional symptoms were not related to the PCB concentrations in the blood [174]. Elevated serum triglyceride concentrations were found to be related to the concentration of PCBs in the blood serum [175], and inversely related to the bilirubin concentrations in the serum [179], The average serum triglyceride concentrations measured annually in 14 Yusho males from 1969 through 1974 ranged from 159 mg/100 ml in 1969, to 174 mg/100 ml in 1972, to 160 mg/100 ml in 1974 without any significant changes from year to year. In 29 Yusho females, the concentrations initially (1964) averaged 153-161 mg/100 ml, but decreased in 1973 and 1974 to 129 and 111 mg/100 ml, respectively [180]. The Yusho population of about 1,300 persons has been followed closely and records Indicate that as of May 1975, 29 of them had died [162]. Deaths have been due to a variety of causes such as accidents, suicides, cardiac problems, and cancers. Malignant neoplasms were found in at least nine cases [161], from which Kuratsune et al [160] concluded that there was a suggestion of excess deaths but that no more could be said because information essential for analysis was not available. The relevance of the Yusho episode to occupational PCB exposure is compromised because: (1) the oil was Ingested; and (2) it contained large 48 905294 K 07980 concentration* of dibenzofuran* compared with those in the PCBs to which workers generally have been exposed in their occupations. Its relevance is further compromised because the effects observed from dally ingestion of 115 mg of PCBs [165,167] were peculiar and excessive compared to those observed in workers exposed by inhalation to PCBs at 1-5 mg/cu m [120,125], notwithstanding that the amounts absorbed may have been similar. Nevertheless, information obtained from the Yusho episode is relevant to the study of PCB toxicology and occupational exposure. The information establishes that PCBs can be transmitted from mother to fetus, and, in the milk, from mother to child. It also establishes that some PCB compounds are eliminated from the body reletlvely rapidly, and that others may require years for elimination. (c) Occupational Exposures Chloracne was among the earliest reported effects associated with worker exposure to PCBs [125-128], It was not clear in some early reports that PCBs were contributing to the chloracne because PCBs usually constituted 10-20Z of mixtures containing 80-90% chloronaphthalenes, a previously known cause of chloracne [121,122]. An early report that associated chloracne with PCBs in the absence of chloronaphthalenes was that of Jones and Alden [120] in 1936. The manufacturing process was largely an open one and the workers were also exposed to benzene, biphenyl, and other compounds incidental to PCB manufacture. Over the years, cases of chloracne associated with occupational exposure to PCBs have continued to appear [186-196], Other effects associated with PCBs in early reports Included digestive disturbances, eye irritation, liver injury, and impotence N 07981 905295 [123,125]. Elkins [130] reported In 1950 thet Che everege concentrations of PCBs in the workroom air of several plants in Massachusetts ranged from 0.1 to 5.8 mg/cu m. Maximum concentrations ranged from 0.2 to 10,5 mg/cu m. No evidence of Immediate toxic effects was observed except at PCB concentrations approaching 10 mg/cu m, which the workers found to be unbearably irritating. Three cases of severe chloracne were described by Puccinelli [186] in 1954, The affected employees worked in a factory that produced capacitors Impregnated with Aroclor 1254. The workroom was 24 x 9 x 5 meters. Capacitors were heated to about 100 C in a 3-cu m autoclave to remove moisture, and then Impregnated with the Aroclor while in the autoclave. The temperature in the autoclave was reduced about 12 hours later. When the autoclave was opened, the temperature of the Aroclor was 70-80 C. The capacitors were removed and carried to another location for finishing. Originally, one autoclave was used, but eventually eight were in operation, and PCB emissions to the workroom air occurred almost continuously. Concentrations of PCBs in 500-liter samples of air were found to vary from 5.2 mg/cu m in the center of the room, to 6.4 mg/cu m around the finishing operation, to 6.8 mg/cu m near the autoclave during removal of the capacitors. The three chloracne cases were in men, 18-24 years of age. They had worked in the factory for 2-4 years, and developed the first signs of chloracne 4-8 months after their exposures began. Other than chloracne, the men appeared healthy, and all findings, including liver function tests were reported as normal. Eight other cases of chloracne associated with PCB exposure during the manufacture of radio capacitors were described by Hofmann and Meneghinl '' 50 905296 N 07982 [187] In 1962. In the process, PCB vapors were generated by heat. The cases included one man and seven women, 20-37 years of age, who were exposed to PCBs 2.5-4 months before onset of signs of chloracne. The face was involved in six cases; other involved areas varied, but Included the arms, neck, upper torso, pubes, buttocks, and thighs. The case of a 21year-old woman was described in detail. The first signs of chloracne appeared on her face 4 months after she began work, and she was observed by the authors [187] 4 months later. On the face, a dirty brown coloring appeared. A hyperpigmented spot with shaded areas was present on the forehead. Subsequently, her buttocks and pubes became Involved. Exposure concentrations were not mentioned. Severe chloracne was described by Birmingham [188] in 1964 in 13 of 15 workers exposed to an A r o d o r which was a mixture of bl- and terphenyls (65% chlorine content). An enamel containing the Aroclor was painted onto glass and then baked in an oven. Faulty ventilation caused contamination by chlorinated hydrocarbon vapors. Exposure concentrations and duration of exposure were not given. An additional case history published in 1969 Involved a 43-year-old man exposed to PCBs in an electrical component factory [189]. He developed chloracne on the forehead, face, arms, and thighs within 3 months after beginning work handling racks of electrical parts that had been dipped in hot PCBs. Exposure concentrations and actual durations of exposure were not stated, but it was reported that the man had put his hands in the mixture without skin protection for a long time, and that his clothes often became impregnated with the PCBs. On examination 8 months after transfer to another job in the same room, papules, comedones, and pustules were 51 N 0 7 9 8 3 905297 The company physicians attributed the rashes to allergic or contact dermatitis caused by exposure to the askarel. Treatment included the use of creams, and temporary or permanent removal from exposure. Of the 49 complaints, 22 were second episodes, and in these cases the workers were removed permanently from exposure to askarels. One female employee who had dermatitis of the fingers was removed from exposure for 12 days. Within 2 days of reexposure she again reacted to the askarel and was permanently removed from such work. Over the same 15 years, other kinds of complaints were made by the workers on 16 occasions. These complaints included burning sensations of the eyes (7), nose (1), and face (1); dry throat (1); asthmatic bronchitis (3); nausea (1); dizziness (1); and aggravation of acne (1). In most of these cases, the company physicians recommended permanent removal from exposure. The health status of eight laboratory workers who routinely analyzed dielectric fluids containing FCBs was reported by Levy et al [197] in 1977. The men were 25-49 years of age and had been employed 2.5-18 years. Breathing zone, point source, and general work area air samples were collected on magnesium silicate at 50 ml/minute over the workday on three occasions. The breathing zone samples contained PCBs at 0.014-0.073 mg/cu m. Samples taken near an oven contained 0.042-0.264 mg/cu m, and general room area samples contained PCBs at 0.013-0.15 mg/cu m. The blood PCB concentrations in the workers were 36-286 ppb. The most common complaint of the workers (6 of 8) was dry or sore throat. Other complaints were skin rash (3 of 8), gastrointestinal disturbances (3 of 8), eye irritation and headache (each, 2 of 8). Findings on examination of the eight workers were 53 905298 N 07S84 skin rash (1), nasal Irritation (2), rales (1), and elevated blood pressure (4). No liver, spleen or neurologic abnormalities were found by physical examination there were no cases of chloracne. Serum alkaline phosphatase, SCOT, SGPT, and total bilirubin, measured in seven subjects, were all within normal limits. In addition, medical records of 40 other exposed employees were examined, revealing two cases of slightly Increased SGOT, two elevated serum triglycerides, and one case each of increased serum alkaline phosphatase (SAP) activity, total serum bilirubin, and serum uric acid. Epidemiologic Studies An outbreak of dermatitis smong workers in a Connnectlcut chemical plant was described in 1954 by Meigs et al [190]. PCBs had been substituted for molten salt in a heat exchange unit without modification of the system. There were slight, but obvious, vapor leaks under certain conditions, and the concentration of PCBs in the workers' breathing zones was determined to be 0.1 mg/cu m. No employee worked regularly ,at points 'v of leakage, and the operations, as described, continued for 19 months. Mild to moderate Chloracne on the face, forehead, and ears developed 7in of 14 exposed workers; the mastoid region of one worker also was affected. The duration of exposure before the initial signs occurred ranged upward from 5 months and averaged 14 months, The average length of exposure was 11 months for those who did not develop chloracne, with one worker showing no signs after 19 months. Liver function tests were performed on the seven workers who had developed chloracne. Clinical tests Included direct and total serum bilirubins, 24- and 48-hour cephalln 54 905299 K 07985 flocculations, thymol turbidity, and SAP activity. Findings were normal in six workers, and borderline increases in cephalin flocculation and thymol turbidity were found in the seventh worker with chloracne. Thirteen months later, the thymol turbidity test had Improved, but cephalin flocculation had not changed. All cases of chloracne were stated to have cleared up after an unspecified treatment. Control of vapor emissions by welding all joints in the heat exchange unit prevented recurrence [190]. Exposures of workers to PCBs in six industrial plants were discussed by Hasegawa et al [191] in 1972. The concentrations of PCBs found are summarized in Table III-7. TABLE III-7 RANGE OF PCB CONCENTRATIONS Gig/cu m) IN WORKROOM AIR Factory Function No. Samples A PCB manufacture 6 B Capacitor manufacture 3 C Biphenyl recovery 2 D Capacitor manufacture 2 E 3 *1 sample **6,270 due to spillage Adapted from reference 191 PCB Concentrations Vapors Particulates 26-163 120-350 13-15 350-540 95-965 19-37 20-125 4* 48-6,270** 73-650 905300 55 N 07986 PCBs were manufactured in one plant and used in manufacturing capacitors in four plants (one had discontinued use of PCBs 1 month earlier). Biphenyl, not chlorobiphenyls, was present in the sixth plant [191], Air samples were collected in two fractions. A fraction associated with particles >0.1*1 was collected on filter paper, and a fraction containing vapors and particles <0.1y in diameter was collected in two serially-connected midget implngers containing n-hexane. Samples were collected only from places where high concentrations of PCBs were expected and not from the factory where PCB use had been discontinued. The vapor concentration exceeded the particulate concentration in all except the sample taken after spillage. Particulate matter was characterized by GLC as containing the same chlorobiphenyl composition as the PCB product used in the plant, whereas the vaporized material contained one less chlorine atom/molecule than the PCB used In the plant. PCBs were measured In the blood of the employees of six plants, including 99 exposed workers and 32 controls [191). Concentrations of PCBs In the blood sera of exposed workers averaged 370 ppb, whereas those of the controls averaged 20 ppb. The workers exposed to PCBs in the plant that had discontinued PCB use had serum PCB concentrations of 90 to 730 ppb (average 460 ppb). Based on data from three of the plants, no relationship was found between duration of exposure (from <1 to 20 years) and concentration of PCBs In the blood [191]. Complaints of dermal ailments seemed to be unrelated to the blood PCB concentrations and were considered to be due more to direct contact of the skin with PCBs than to generalized intoxication. The principal dermal findings included brown chromodermatosis of the dorsal joints of the hands M N 07987 905301 and finger* and of the nail bed, and acneiform exanthema. The latter also involved the jaw, back, and theighs in several cases. The investigators [191] considered that there was a definite effect of FCBa on fat metabolism, as shown by decreases in the concentrations of total, free, and esterlfied cholesterol* in the blood, and by trends in the same direction for neutral fats, total glycerides, phospholipids, and beta-lipoprotein in the blood. There was evidence of mild disturbances of liver function manifested by Increased SGOT, S6PT, and SAP activities and decreased activity of serum cholinesterase. These enzyme activity changes were not considered to be clinically significant. Studies of 38 current and 80 former employees of a capacitor factory in which Kanechlor 500 had been used from 1954 to about 1960 and Kanechlor 300 had been used from about 1960 to 1972, with PCB use having been discontinued in April 1972, were reported by Hara et al in 1973 [192] and again in 1974 [193]. (Presumably, this factory was the one stated by Hasegawa et al [191] to have discontinued use of PCBs.) Current workers Included 17 who were engaged in the capacitor immersion process; the remaining 21 workers were engaged in finishing and assembling operations. The study concentrated on the 17 immersion process workers. During exposure to PCBs in March 1972, the concentrations of PCBs in the whole blood of the immersion workers ranged from about 7 to 300 ppb, and were closely related to years of exposure. One year later, blood PCB concentrations had all decreased, but by varying amounts. For example, one of two workers who initially had PCB concentrations in their blood of about 180 ppb had a concentration of <10 ppb 1 year later, while the other one had a concentration >100 ppb. The average PCB blood concentration for the 57 905302 t' 0 7 9 SC 17 workers decreased to about 75Z of the original value. Based on blood samples collected about 6 and 12 months after use of PCBs was discontinued, the blood PCB half-lives for the immersion workers were calculated. It was found that the greater the duration of exposure, the greater the PCB halflife (1 year of exposure, 3 months half-life; 10-15 years of exposure, 30 months half-life). This indicated to the Investigators that blood served as a PCB carrier, whereas fat served as a depot tissue [1921. While working with PCBs, many of the total group of employees had dermal complaints (blackheads, 45Z; acnelform eruptions, 37Z; skin irritations, 13Z) [192]. A year after discontinuance of exposure to PCBs, these conditions had Improved noticeably and only one or two blackheads remained. No correlation waa apparent when concentrations of PCBs and. triglycerides in the sera of a large number of workers were compared graphically. The workers were aleo studied about 18, 24, and 36 months after use of PCBa had been discontinued [193]. During this period, blood PCB concentrations decreased to about 10-20 ppb in all but two workers who had been exposed to FCBe for 9 and 15 years. The skin disturbances were reduced to veetiglal markings on a few indivlduala. Comparisons with the concentrations of triglycerides and PCBs in the sera of these workers indicated that the proportion of workers with significant Increases in triglyceride concentrations increased as the concentrations of PCBs -increased. Of nine workers with blood PCB concentrations >50 ppb, five had elevated triglyceride concentrations. Examinations of 13 workers from an electrical capacitor manufacturing plant for clinical manifestations of PCB toxicity were reported by Kitamura et al [194] in 1973. Examinations were performed when the company 58 N 07S89 905303 discontinued the use of PCBs in June 1972, and were performed twice subsequently at 3-month Intervals. The average length of worker exposure to PCBs had been about 2.5 years. Imnediately after discontinuance of PCB use, the average PCB concentration in the blood of workers was 820 ppb, ranging from 320 to 2,100 ppb [194]. The mean concentration fell to 310 ppb after 3 months, and to 200 ppb after 6 months. From these observations, Kitamura et al [194] estimated the biological half-life of the PCBs in the blood Immediately following the cessation of exposure to be about 90 days. No consistent correlation could be found between the concentration of PCBs in the blood and the duration of exposure to PCBs. Nall, hair, and gum color and color of the mucous membranes of the oral cavity all were normal. Ten of the workers had varying degrees of skin disorders on different parts of their bodies. The skin disorders included eeborrhea adipose, acne vulgaris, and follicular papules on parts of the body where direct contact with the PCBs normally did not occur. The authors [194] concluded that PCBs probably had been an important factor in the etiology of the skin disorders and that results of blood tests, hepatic function tests, and urinalyses were normal. Serum triglycerides were not determined. A study by Inoue et al [195] of the health of workers in family-owned silk-thread glossing factories in which PCBs were used was published in 1975. The study was initiated because PCB concentrations exceeding 100 ppb had been found in the blood of a 73-year-old man who had undergone surgery. His family operated a household thread-glossing factory. The family members and the hired helper were studied. Serum concentrations of PCBs resembling Kanechlor 500 ranged from 130 to 520 ppb. There was a close 5g 905304 K 07990. i correlation between the PCB concentration in the blood and the degree of involvement in the glossing work. The head of the household had skin lesions and comedones on the face, back, and ears and had blood PCB concentrations of 190-210 ppb. The rest of the people had practically no skin abnormalities, and other findings (not described) were, in general, considered of minor significance. A study of PCB contamination of the premises and the air of the same factory was reported by Fujiwara et al [33]. At the time the samples were taken, use of PCBs had been discontinued. However, PCBs were found in air at 0.25 mg/cu m, in floor boards at 80-130 ppm, in the dirt under the machinery at 10-900 ppm, and in the dust on steel frame beams at 110-180 ppm. The PCBs were similar to those in Kanechlor 500. Subsequent to the above study, Inoue et al [195] reported on the PCB concentrations in samples of blood obtained from 54 other similarly employed people. PCB concentrations of over 100 ppb, 50-99 ppb, 10-50 ppb, and 0-9 ppb were found in 2, 5, 19, and 28 persons, respectively. Correlative comparisons with the various functions performed in the factories showed that those workers who had direct contact with the glossing machines, those who maintained and repaired the machines, and those who had over 20 years of work experience had the highest concentrations of PCBs in their blood. Skin abnormalities and other findings in these 54 persons were described as relatively mild. One of the persons studied, a woman in her 10th month of pregnancy, had a serum PCB concentration of 24 ppb. Following birth, the mother and daughter were described as healthy with no evidence of abnormalities. The concentration of PCBs in the mothers's milk was found to be 0.25 ppm, and after 60 905305 consultation, she stopped nursing her baby [195]. In 1974, Sato and Hasegava [32] discussed their findings on PCB residues in the workers and in the air of pressure-sensitive ("carbonless") copying paper manufacturing plants 2 years after PCB use had been discontinued. A PCB product comparable to Kanechlor 300 was still detected in the workroom air of four of five factories at concentrations ranging from 0.13 to 4.4 jig/cu m; in one factory PCBs comparable to a mixture of Kanechlors 300, 400, and 500 were found at concentrations ranging from 0.15 to 1.2 Mg/cu m. Concentrations of PCBs in the blood sera of these workers, as measured by GLC, ranged up to 73 ppb, compared to a maximum of about 20 ppb in controls. The authors [32] concluded that the blood PCB concentrations in the workers were still elevated. 'PCB concentrations in the blood of three groups of employees with different PCB exposure histories were presented in 1972 by Karppanen and Kolho [198]. The first group of four men and five women had no known occupational exposure to PCBs. The six women of the second group had been exposed while handling PCBs in an analytical laboratory. The third group ' *v. of eight men and four women had worked, since 1968, in a plant where A r o d o r 1242 was impregnated into capacitors. The authors [198] stated that the workroom air of the capacitor factory met internationally accepted limits (presumably <1 mg/cu m), and that protection of the skin had been given special attention. PCB measurements were made by GLC, using electron capture detection. The unexposed group had blood PCB concentrations of 5.6-12 ppb, the analytical laboratory workers had concentrations of 36-63 ppb, and the capacitor plant workers had concentrations of 74-1,900 ppb. Subcutaneous adipose tissue samples from two of the unexposed workers 61 905306 K 07992 contained- PCBs at 1.5 and 2.3 ppm; PCBs In their blood expressed as concentrations in fat of the blood were 6.6 and 9.9 ppm, respectively. In three capacitor plant workers, adipose tissue samples contained PCBs at 160, 285, and 635 ppm; PCBs in their blood, expressed as concentrations in their blood fat, were 400, 305, and 700 ppm, respectively. All persons examined were in good health. The capacitor plant workers had been under special medical observation but the investigators were unable to detect any biologic effect from the PCBs. An epidemiologic investigation of 37 refuse workers who were potentially exposed to PCBs emitted from Incinerated waste was described by Bumgarner et al [199] in 1973. The control group consisted of 36 workers from a lumber yard. Paired samples of scalp hair and blood were collected. PCB residues in the hair and blood plasma were extracted and analyzed by GLC with electron capture (EC) detection; rough quantitation was by evaluation of five peaks associated with Aroclors 1254 and 1260. The lower limit of detection was 1 ppb. Hematocrit, blood cholesterol, and blood pressure also were determined. PCB residues in the blood plasmas of the controls were detected in four workers and the maximum concentration was 4.2 ppb. Measurable concentrations of PCBs were found in the blood samples of 32 of the 37 refuse workers; the average and maximum concentrations were about 4 and 14 ppb, respectively. The concentrations of PCBs in plasma were not related to duration of exposure, age, or race. PCBs were not detected in hair samples (limit of detection, 1 ppb). Hematocrit, blood cholesterol, and blood pressure values did not change at different PCB concentrations. 62 905307 A survey of the health of 34 workers exposed to Aroelor 1242 during manufacture of capacitors was discussed by Ouw et al [196] in 1976. The Aroelor was an electrical-grade material that contained "no impurities." Breathing zone samples were collected in lmpingers containing Isopropanol. It is not clear if all samples were collected from the breathing zones. Nineteen workers were assigned to fill capacitors with Aroelor 1242 heated to 70 C. These workers were exposed to PCBs at 1.08-1.44 mg/cu m. The other 15 workers, located in a different room, were assigned to assemble Aroclor-dipped capacitor components. These workers were exposed to PCBs at 0.32 mg/cu m. None of the 34 workers used protective clothing. PCBs in the blood were separated by GLC and identified by their retention times relative to aldrin. PCBs were not detected in the blood of 30 control subjects. For the two groups of PCB-exposed workers, averages of measurable blood PCB concentrations are presented in Table III-8. TABLE III-8 AVERAGE OF DETECTABLE BLOOD PCB CONCENTRATIONS (ppb) OF TWO GROUPS OF WORKERS Exposure Group No. Workers PCB Retention Time Relative to Aldrin - 0.69 1.31 1.47 1.96 Fillers 19 602(19)* 314(17) 391(13) 475(4) Assemblers 15 140(14) 100(14) 899(5) (0) Numbers in parentheses are the numbers of workers in whom more than a trace of the PCB peak was detected. Adapted from reference 196 63 905308 N 07994 Distribution of PCBs in the blood of workers exposed while filling the capacitors differed from that of workers who assembled the components. The higher boiling components were present more frequently and to a greater extent in the fillers. Twelve of the workers (5 of 19 and 7 of 15) complained of mild burning and irritation of the face, eyes, and skin, and 5 of these had eczematous rashes on the hands and legs. One filler had chloracne. Although individual abnormalities were found in SGPT, SAP, and bilirubin, the average values for the exposed workers were within normal limits. Bromsulphothalein retention tests were found to be elevated in four of the seven fillers whose blood PCB concentrations were >500 ppb. The investigators [196] reported no evidence of significant adverse responses to PCB exposure in the workers with blood PCB concentrations below 200 ppb. Subsequently, "more efficient" exhaust ventilation was Installed and the workers were advised to wear "suitable Impervious gloves" [196], Air measurements, made after the ventilation change, Indicated that the fillers were being exposed to PCBs at 0.18-0.75 mg/cu m and the assemblers at 0.08 mg/cu m. These were substantial reductions. However, blood PCB concentrations that were found in 15 workers reexamined 2 months after the ventilation change did not show any substantial reductions. The Investigators [196] speculated that this might have been because the workers did not strictly follow the recommendation to wear protective clothing. Based on a search of chart records, Bahn (HA Sinclaire, written communication, June 1976) reported a preliminary study of the incidence of cancer in a group of 51 research and development employees and 41 refinery 64 n 0 7 9 9 5 905309 plant employee at a New Jersey petrochemical facility who were considered likely to have been exposed to A r o d o r 1254 for various periods between 1949 and 1957. The eight cancers observed in the study population through December 31, 1975 were not significantly more than would be expected (5.7) in a similar sample of the US population [200]. However of the eight cancers, the three melanomas and the two cancers of the pancreas were significantly different from calculated expectations. Some findings of this preliminary investigation were described in a letter from Bahn et al [201] to the editor of the New England Journal of Medicine. In this preliminary study, PCB exposure histories were based on recollections of two company employees. Exposures to other chemicals could not be ascertained. The expected cancer rates were based on US population data rather than on a rate for the locality of the petrochemical facility. To correct these deficiencies in the preliminary study, a more Intensive investigation is being conducted (BN Kightlinger, written communication, November 1976). A substantial change has occurred in the cohort since release of the preliminary report by Bahn and her coworkers, and it seems likely that the findings on this new cohort will differ significantly from those of the preliminary study. The final report is not yet available. In a study of current and former employees engaged in the manufacture of PCBs, no cases of malignant melanoma or pancreatic cancer were found from a review of the case histories of more than 300 employees (G Roush, written communication, September 1976). Seven cases of lung cancer were found from the death certificates of 50 former employees compared to an expected number of 2.7. The data are preliminary and were not corrected for age or smoking habits. The final report is not yet available. M N 0799 905310 Aw-tuxl Toxicity Although there have been a few reports of dermal and Inhalation experiments with animals, most of the information on animal toxicity has Involved ingestion of PCBs in the diet or by intubation. Several animal experiments have Involved oral administration of PCBs for the lifetime of the animal. These studies have desionatrated chronic changes in the microscopic anatomy of the liver and other organs, effects on reproduction, embryonic and fetal toxicity, effects on offspring from nursing, and carcinogenic and teratogenic responses. (a) Inhalation and Dermal Application Studies of PCB Mixtures Absorption and distribution of inhaled PCBs were studied by Benthe et al [97] in 1972. Groups of 4-6 male Wistar rats were exposed to aerosols of a commercial PCB mixture containing 42Z chlorine, Pydraul A 200, commonly used in hydraulic fluids. Absorption and distribution of the PCBs were studied through the measurement of PCB concentrations in liver, brain, and adipose tissue. The aerosols were produced in an aerosol generator at 180 C. The aerosols were cooled, the larger particles were separated out, and the airborne PCBs were Introduced into a chamber at a concentration of 30.4 3 . 4 g/cu a. Groups of the rats wereexposed for varying periods up to 2 hours. It was found that 15 minutes of exposure was sufficient to attain more than 50Z of the PCB concentration of 69.7 Mg/g liver wet weight that could be attained with 2 hours of exposure. Consequently, the investigators used an exposure time of 30 minutes to study distribution of PCBs to the tissues. Ismedlately after 30 minutes of exposure, PCB concentrations were maximal, at about 52 pg/g liver tissue, whereas they were at low 66 M 079 97 905311 concentrations In the other tissues at 14 u g/g in adipose tissue, and 9 Ug/g in brain tissue. After 24 hours the PCB level in the brain attained a ma^Hmuffl value of about 18 u g / g and within 36 hours the PCB concentration in the adipose tissue attained a maximum of about 250 u g / g . By 48 hours the concentrations of PCBs in the liver were reduced to about 3 u g / g end in the brain to about 5 u g / g , whereas the adipose tissue concentrations remained above 200 u g / g . Experiments were reported by Rozanova [202] in 1943 in which rats were exposed to a technical mixture of "tetrachlorodlphenyl" and "pentachlorodlphenyl." The mixture, known as Solvol, was a transparent, colorless, oily, very viscous liquid used for filling capacitors. The "tetrachlorodlphenyl" component of the mixture had a distillation range of 220 to 245 C and the "pentachlorodlphenyl" component had a distillation range of 242 to 260 C. The animals were exposed in a 22-liter chamber through which air was drawn continually at a rate of 1-1.5 liters/minute, after first passing through a glass gooseneck containing the liquid PCBs. Air samples were taken from the chamber from time to time to determine the PCB concentrations. The analytical method was not reported. . Four rats exposed for 3 hours at about 10 mg/llter became uncoordinated and comatose and died within a day [202]. Autopsy findings included liver necrosis and fatty degeneration, cloudy swelling of the epithelial cells of the renal tubules, congestion in the heart and spleen, and necrotic signs in the spleen. Three rats were exposed repeatedly to vapors of Solvol at 0.5 mg/llter. One rat died after eight exposures, and the other two were killed after 11 exposures. Five other rats were repeatedly exposed at 0.25 mg/liter; one was killed after 16 exposures, and 67 N 07998 905312 the others, which appeared to be in satisfactory condition, were killed after 69 exposures. In these chronically exposed rats, gross and microscopic findings were similar to, but less marked than, those found in the acutely exposed animals. In addition, hyperplasia of the Kupffer cells was found in the liver. Treon et al [203] exposed groups of animals each comprised of 10 rats, 10 mice, 6 guinea pigs, 4 rabbits, and a cat to Aroclor 1242 or A r o d o r 1254 vapors 7 hours/day, 5 days/week for up to 31 weeks. Aroclor 1242 exposures at concentrations of 8.6 jug/liter (0.83 ppm) for 3 weeks, 6.83 f i g / l i t e r (0.66 ppm) for 17 weeks, or 1.9 jtg/liter (0.18 ppm) for 31 weeks. Exposures to Aroclor 1254 were at 1.5 <g/liter (0.11 ppm) for 31 weeks or at 5.40 jjg/liter (0.41 ppm) for 17 weeks. No consistent changes ' in mortality, growth, pathology, organ size, liver function, or hematologic parameters were found in animals exposed to Aroclor 1242. The animals exposed to Aroclor 1254 vapors showed no changes in growth or mortality but microscopic evidence of apparently reversible hepatic cellular Injury was found in all species except the cat at both exposure levels. Enlarged livers were found in the animals exposed at 5.40 pg/liter. An appreciable Incidence of pneumonia was found among the exposed and control animals, a fact which could have confounded some of the results, but it is important to note that liver changes, including fatty degeneration, were found in exposed animals that were free of pneumonia. Inhalation experiments with the commercial PCB product "Decachlorodiphenyl" were reported by Berezy et al [98,99] in 1974. The oral toxicity of this PCB product was investigated by Hunter et al [204], who administered it in the diet to Sprague-Dawley rats at 1,000, 2,000, 68 07999 905313 [ 1 5,000, and 10,000 ppa for 4 weeks. All animals fed Decachlorodiphenyl gained more weight than the controls and had greater liver to body weight ratios. Other effects observed at 10,000 ppm Included Increased spleen, thyroid, and kidney weights relative to body weights, reduced hemoglobin concentrations, and in males reduced rbc counts and hematocrits. In one Inhalation experiment [98], five male and five female rats were exposed for 6 hours to particles of the PCB product at an average concentration of 2.54 mg/llter. Seventy-eight percent of the particles were in the range of 1-5 m in diameter, 17Z in the range of 5-15 /an, and the remaining 5Z were >15 /an. During exposure there were repeated episodes of blinking and sneezing. Signs of irritation disappeared after cessation of exposure. During the subsequent 14-day observation period, food and water consumption and growth of the rats were considered by the authors to have been similar to those of the controls. No gross pathological changes were seen when the rats were killed 14 days after removal from exposure [98]. Subsequently [99], three groups of rats, each consisting of 8 males and 8 females, were exposed 6 hours/day, 5 days/week for 4 weeks at average concentrations of 4, 80, and 777 jig/llter. A similar group of rats was used as a control. In this experiment, where 85-90Z of the particles were in the 1-5 im range and 1-3Z were >15 /on, no signs of irritation were seen during the exposures at the lower concentrations and growth rates were normal compared to controls. At the highest concentrations, frequent blinking and sneezing were noted during the exposures, and the growth rate of the males was slightly retarded (final body weights of 395 g vs 435 g for controls). The liver weights, relative to body weight, were Increased 69 905314 M OfcOOO in males exposed ae Che highest concentration, and in females exposed at the medium and high concentrations. Microscopic findings in the livers of the rats exposed at the high concentration included occasional focal aggregations of mononuclear cells with either parenchymal or periportal distribution, and minimal degrees of periportal hepatocytic vacuolatlon, and decreased centrllobular or periportal glycogen. These findings were not considered by the authors [99] to be of toxicologic significance. A statistically significant decrease in packed cell and mean cell volumes was found in male rats exposed at the high concentration. In this group there was also a low white cell count due to a decrease in the number of lymphocytes, and Increased thrombocyte activity. Blood glucose, SGOT, and serum sodium concentrations were decreased. Von Wedel et al [205] described in 1942 the results of an experiment performed to determine the systemic effects of exposure of mice, guinea pigs, and rabbits, by inhalation, ingestion, and dermal application to an unspecified Aro d o r . Concentrations and durations of exposure were not specified for the inhalation and ingestion experiments. However, 0.5, 1.0, or 1.5 ml of solutions containing 0.5 g Arodor/ml were used for the dermal applications. Within 5 days after the dermal applications, small papules and blisters formed on the exposed skin areas and the external epidermal layers becsme desquamated. In addition, subacute yellow atrophy of the liver with some fatty infiltration was observed. Similar liver lesions were produced in the inhalation experiment. In 1944, Miller [206] administered A r o d o r 1242 to rats, rabbits, and guinea pigs by subcutaneous (sc) injection, by oral intubation, and by dermal and corneal application. The PCB doses ranged from single doses of 70 N 08001 905315 69 mg co small drops (approximately 17 mg) applied daily to the cornea of rats for 25 days, to 1,380 mg injected daily into rabbits for 10 days. Fatty degeneration and atrophy of the centrllobular cells of the liver were the characteristic signs of toxicity. The greatest amounts of liver damage were seen in guinea pigs, less was seen in rabbits, and the least amount in rats, regardless of the dose, duration of expoeure, or route of administration. Necrotic lesions were also seen in the skin of animals that received sc injections; signs of dermal irritation were seen after applications to the skin. The conjunctival tissue presented no gross changes when examined under magnification in the living animals. Since the pathologic changes in internal organs were similar regardless of method of administration, this experiment indirectly demonstrated that PCBs could be absorbed through the skin and the eye. The effects of Solvol applied to the ears of rabbits were reported by Paribok [207] in 1954. Solvol was applied for 6 hours daily in doses of 0.7 to 3.76 g. A single application caused edema and inflammation of the ear, and one rabbit died 7 days after the application. With multiple doses, the animals died after 6-17 days. The dead animals, including the one that died after the single application, had fatty degeneration of the livers. Vos and Beams [208] reported in 1971 on the dermal toxicity of PCBs in adult female New Zealand rabbits. Three comercial preparationa of PCBs were used: Clophen A60, Phenoclor DP6, and A r o d o r 1260. Twenty-seven 1-ml (118 mg) applications of each of these products (in isopropanol), 5 times /week over 38 days, to the clipped and shaved backs of tha rabbits resulted in various manifestations of toxicity. " N 08002 55' - 905316 In general the toxic signs were most pronounced in the Clophentreated animals and least pronounced with Aroclor 1260. Dermal findings included thickening of the skin due to hyperplasia and hyperkeratosis of the epidermal epithelium and dilation and plugging of hair follicles with keratinous material. Microscopic study of liver sections showed a considerable diversity of lesions, Including centrllobular degeneration 9 focal hydropic degeneration focal necrosis, atrophy of centrllobular parenchymal cells, cytoplasmic hyaline degeneration, pigmentation of Kupffer cells, and, to a lesser extent, pigmentation of parenchymal cells. Renal damage was found in all PCB-treated animals. The most common findings were hydropic degeneration of the convoluted tubules, with nuclear pyknosis, and bursting and lysis of the tubular epithelial cells [208]. Dilation of the renal tubules, filled with casts of necrotic epithelial cells, was found in half the rabbits. These findings indicate that the dermal application of PCB mixtures causes systemic lesions of the liver and kidneys besides the direct effect on the skin. However, in other studies [19,21,23], it was determined that Clophen A60, Phenoclor DP6, and Aroclors 1248 and 1254 were contaminated, to varying degrees [21], with highly toxic tetra- and pentachlorodlbenzofurans. (b) General Effects of Oral Administration of PCB Mixtures Single-dose oral LD50's of several PCBs reported in rats (JW Cook, written cosmninicatlon, June 1970) generally indicated that as the degree of chlorination Increased, the acute toxicity decreased. The more highly chlorinated products (Aroclors 1248-1268) were of approximately equal toxicity (LD50's of about 10 g/kg), whereas the LDSO's of the less highly chlorinated products (Aroclors 1221-1242) ranged from about 4 to 9 g/kg. 72 H 08003 905317 The minimum lethal doses of these PCBs applied to the skin of rabbits were generally in the range of 1-2 g except for 1221 which was in the range of 2-3 g and 1268 which was >2.5 g. The immunosuppressive activity of A r o d o r 1260 was described in 1972 by Vos and de Roij [209] who fed three groups of 12 4-week-old female albino guinea pigs the PCB at 0, 10, or 50 ppm in their diets for 8 weeks. Aroclor 1260 was analyzed and found to be free, of contamination with chlorinated dibenzofurans, although it appeared to contain a minor acnegenic impurity. In each group, six animals received sc injections of aluminum phosphate-adsorbed tetanus toxoid to stimulate the lymphoid system (antitoxin production), the other six animals in each group served as positive or negative controls. Cellulose acetate electrophoresis was used to determine serum proteins, including gamma-globulins. The gamma globulin-containing cells in the popliteal lymph nodes were significantly reduced in the stimulated animals fed PCBs. Serum gemma-globulin levels were significantly decreased in the guinea pigs stimulated with tetanus toxoid and fed 10 ppm of Aroclor 1260 in their diet. Increased serum alpha-globulin levels were found in the stimulated guinea pigs fed either 10 or 50 ppm of the PCB, and significantly increased concentrations of albumin were found in the sera of both the stimulated and the unstimulated guinea pigs fed the PCB at 10 ppm. Also, both the absolute end relative weights of the cervical lymph nodes in the unstimulated group fed 10 ppm of Aroclor 1260 were significantly reduced whereae those of the mesenteric lymph nodes in the stimulated guinea pigs fed 10 and 50 ppm of PCB were significantly increased. These findings Indicate that some immunosuppressive effect wae produced by the feeding of PCBs. However, the 73 905318 K 08004 decreases of the gamma-globulin levels were noe found to be dose-related. No evidence of any FCB-induced change was observed In microscopically examined stained sections of liver kidneys adrenals, and skin. Vos and Van Drlel-Grootenhuls [210] reported their studies of the effects of PCBs on the humoral and cell-mediated Immunities of guinea pigs in 1972. Three experiments were performed with different protocols. In the first experiment, the authors investigated the humoral immune response of guinea pigs fed 0, 10, 50, or 250 ppm of Clophen A60 in their diets and stimulated with a single sc injection of tetanus toxoid 3 weeks after the feeding regimen began. Suppression of humoral Immunity was observed at the 50-ppm level. Microscopic examination of the livers revealed centrllobular degeneration, cellular atrophy, cellular necrosis, and nuclear enlargement. At the 250-ppm level, no antitoxin production was observed. The diets of guinea pigs in a second experiment [210] contained 0, 10, or 50 ppm of ClophenA60 or 50 ppm of Aroclor 1260. Primary and secondary antigenic stimulations with tetanus toxoid were given after 3 and 5 weeks. The experiment lasted 6 weeks. Suppression of the humoral immune response was observed in groups fed 50 ppm of either PCB product. Decreases in the weights of the thymusesand increases in liver weights were observed at the 50-ppm Clophen A60 level and, to a lesser degree, at the 50-ppm Aroclor 1260 level. The residual liver concentrations of PCBs increased as the dose level and the duration of exposure increased. In their third experiment, Vos and Van Drlel-Grootenhuis [210] fed 30 guinea pigs diets containing Clophen A60 at 0, 50, or 250 ppm. After 3 weeks, the animals were challenged with 0.05 ml of Freund's complete adjuvant followed in 47 days by an injection of 0.1 ml of avian tuberculin 905319 74 K 08005 antigen. The animals were killed 2 days later. All animals of the 250-ppm group died during the experiment, exhibiting retarded growth, atrophy and depletion of the lymphoid system, and liver damage. Significantly decreased thymus weights and increased liver weights also were observed, and total white blood cell counts were reduced significantly. Bruckner et al [211] administered Aroclor 1242 to rats by oral intubation to determine its acute and subacute effects. Two groups of six rats each were given single doses of either 2.5 or 6.0 g/kg of Aroclor 1242. The initial effects observed at both dosages were the same for the first 4 hours, le, diarrhea, decreased spontaneous activity and muscle tone, decreased response to pain stimuli and mild chromodacryorrhea. However, during the next 24 hours the group receiving 6.0 g/kg had profuse diarrhea, adipsia, oliguria, anorexia, erythema of the limbs, lack of response to pain stimuli, and general weakness. Eventually, ataxia, coma, and death followed. The condition of the rats receiving the lower dosage gradually improved after the first 24 hours and was normal at the end of 72 hours. Another group of rats [211] that received single oral doses of 4 g Aroclor 1242/kg showed weight loss, elevated packed rad cell volumes, increased serum polymorphonuclear leukocytes, crenated red blood cells, and increased SCOT activities. All organs appeared normal except the livers and kidneys. The livers exhibited foci of sudanophllle vacuolatlon. The kidneys showed widely scattered foci of vacuolated tubular epithelial cells. In the subacute studies conducted by Bruckner et al [211], six rats were given 100 mg of Aroclor 1242/kg orally every other day for 3 weeks; 75 N 08006 905320 three control rate received 100 mg/kg of peanut oil on the same schedule. Changes observed In the treated rats Included Increased liver weights, decreased packed red blood cell volumes, Increased SGOT activities and marked Increases In liver microsomal hydroxylating and N-demethylatlng enzyme activities. Microscopic examinations of the livers and kidneys revealed greater Increases In generalized lipid vacuoles than had been found with the acute doses. When single ip doses of 100 mg Aroclor 1242/kg were given to rats, Increased N-demethylase and aniline hydroxylase activities were observed after only.24 hours [211]. The effects of lower dietary levels of Aroclor 1242 on rats were reported by Bruckner et al [212], who fed It to groups of six male SpragueDawley rats at concentrations of 0, 5, or 25 ppm for 2, 4, or 6 months. Small reductions in hematocrit and hemoglobin levels similar to those found In other studies by Bruckner et al [211,213] were seen. Urinary excretion of coproporphyrin was significantly increased and dose-dependent increases in liver microsomal hydroxylase activity were measured at the time of each sampling. Similar dose-dependent relationships were found in other experiments [213,214]. Proliferation of the hepatic endoplasmic reticulum was seen after 2 months of Ingesting a diet containing 25 ppm of Aroclor 1242; after 4-6 months of such Ingestion, lipid vacuolization of the liver was evident. In 1974, Bruckner et al [213] reported reduced weight gain, hepatic and renal damage, and an increase in urinary coproporphyrin excretion in rats Injected Ip with a total of 1.6 g/kg of Aroclor 1242 during a 10-week period. The hydroxylacing and N-demethylatlng activities of the liver were significantly elevated 24 hours after a single Ip injection of 100 mg/kg of 76 K 08007 905321 Aroclor 1242, with hydroxylating activity shoving the greater increase. Cytochrooee P-450 and b5 and NADPH-cytochrome reductase activities of the liver all were significantly increased 3 days after dosing. A single dose of 50 mg/kg gave similar but less marked effects, whereas 25 mg/kg produced significant increases in only hydroxylating and N-demethylating activities. Kimbrough et al [215] described in 1972 some effects of chlorobiphenyl mixtures on the livers of rats. Groups of 3- to 4-week-old male and female Sherman strain rats were given A r o d o r s 1254 and 1260 at 0, 20, 100, 500, and 1,000 ppm in their diets. Each group consisted of 10 males and 10 females. Food consumption was measured periodically. The animals were fed the PCBs for 8 months. One female fed 100 ppm of Aroclor 1260 died after 6 months and two females fed 500 ppm died after 1 and 2 months. Eight females fed the 1,000 ppm diet died in 2-6 months. The rats fed 500 and 1,000 ppm gained leas weight than did the controls. At autopsy, livers of the male rats, fed Aroclor 1260 weighed significantly more than did livers of control male rats. Livers of the females were larger than normal but the weight differences were not statistically significant, although at 500 ppm the fractions of body weight represented by the livers increased significantly as a result of the reduced body weight gain. Microscopic findings in the livers included hepatocytie hypertrophy, inclusions in the cytoplasm, brown pigment in the Kupffer cells, lipid accumulations, and, at the higher dietary levels, adenoflbrosls. The nodular greyish-white areas that represented extensive foci of adenoflbrosls consisted of fibroblasts and collagen that surrounded rosettes of epithelial cells [215]. 905322 77 N 08008 Aroelor 1254 produced similar results [215]. One female and tvo male rats died at 500 ppm, but none died at the lover dietary levels, and the rats fed 500 ppm gained less weight than did controls. Ultrastructural changes in the livers of exposed animals consisted of proliferation of the smooth endoplasmic reticulum (SER) and atypical mitrochondrla. Similar changes have been observed In other experiments with FCBs [131,212,216218]. A major difference between the effects of the two products was the much higher incidence of hepatic adenoflbrosls at a lover dietary level of A r o d o r 1254 (100 ppm). In general, the effects of A r o d o r 1254 on the liver were more pronounced than those of A r o d o r 1260. In 1973, Kimbrough et al [219] reported the results of a study conducted to determine whether morphologic changes produced in the liver' would regress after Ingestion of PCBs was stopped. Fifty male SFF Sherman strain rats were given A r o d o r 1254 at 500 ppm In their diets for 6 months, and then were returned to normal diets. Groups of five rats were killed 0, 1, 2, 3, 4, 6, 8, and 10 months after Ingestion of PCBs had been discontinued. The livers and adipose tissues of the 10-month group were analyzed for PCBs. Control animals were used In all evaluations and were fed only laboratory chow. The livers of exposed animals killed when exposure to A r o d o r 1254 was discontinued were enlarged and most of the 40 livers studied microscopically showed enlarged hepatocytes, Increased lipid contents, and adenoflbrosls. A brown pigment was seen in the Kupffer cells and In other macrophages of 15 livers. Small adenoflbrotic lesions consisting of glandular epithelial cells that formed duets surrounded by slight amounts of fibrotle tissue were seen; larger lesions had more extensive flbroeis 78 N 03009 905323 and contained collagen. Similar findings had been reported earlier by Kimbrough et al [215] and both in the areas of adenofibrosls and in othevlse normal hepatic tissue, Kimbrough [220] later reported finding small clusters of glandular type cells, resembling those of pancreatic tissue in general appearance and staining characteristics, in 15 of 36 rat livers with adenofibrosls. The cells stained red with the stain used for esterase, and developed a blue granular appearance with the stain used for protein bound tryptophan. These staining reactions were suggestive of those of salivary gland tissue to the author. The cells may have been derived from either ductal or vascular epithelium, but there is no evidence to substantiate either suggestion [220]. Signs of regression of the adenoflbrotlc lesions were not noted except for the'disappearances of epithelial cells from the centers of the lesions [219]. Liver weights did regress to normal after 10 months without PCB exposure, but the lipid accumulation and the hypertrophy of the hepatic cells remained unchanged. Analysis of adipose tissues from the final group of rats killed showed that the PCB levels ranged from 924 to 1688 ppm (mean, 1192 ppm). Liver PCB levels ranged from 17.3 ppm to 26.2 ppms (mean, 22.7 ppm). The PCB concentrations in the adipose tissue and livers of the control animals were less than 1.0 ppm. The authors [219] were unable to decide whether contamination of A r o d o r 1254 with dlbenzofuran was responsible for the observed liver lesions [219]. Kimbrough and Linder [221] reported in 1974 the results of a PCBfeeding experiment which they undertook to Induce adenoflbrotlc lesions in the livers of BALB/cJ Inbred male mice, le, lesions similar to those previously observed in rats fed Aroclors 1254 and 1260. Two hundred mice, 905324 N 08010 ;-6 weeks old, were distributed randomly into 4 groups of 50 each. Two groups were fed a ground diet ccr.taining 300 ppm of Aroclor 1254. At the end of 6 months, one of these exposed groups was placed on a PCB-free diet while the other exposed group continued on the test diet for another 5 months. The other two groups served as controls and were fed the plain ground laboratory diet for the entire 11 months. The average PCB intake was 49.8 mg/kg/day in the mice fed the PCB diet for the entire 11-month period. Livers of 45 of the 58 surviving control mice were found to be normal. The other 13 had focal round-cell Infiltrates and sometimes small areas of necrosis and fibrosis. Skin abscesses, usually near the groin, were identified in all 13 control mice with hepatic round-cell infiltrates. These skin lesions were thought to be abscesses of the preputial glands. In comparison, 10 hepatomas were identified in 9 of the 22 survivors in the group fed the PCB diet for 11 months. These tumors consisted of well- differentiated hepatocytes, relatively uniform in size but usually smaller than the surrounding liver cells. They were well circumscribed and surrounded by compressed hepatic parenchymal cells or strands of fibrous tissue. In the larger tumors, there were are.es in which the sinuses were dilated and filled with a pink-staining amorphous material. No metastases were seen on gross Inspection of the organs, although no detailed screening, such as serial sectioning of the lungs, was undertaken. Only one small hepatoma, composed of well-differentiated hepatocytes, was identified among the 24 survivors fed the PCB diet for only 6 months. The authors [221] noted that the mouse strain used in this study rarely develops hepatomas spontaneously. 80 N 08011 905325 Adenofibrosis was identified in the livers of the nice subjected to the 11-month PCB diet. These lesions, according to the authors [221], may or may not be precursors of malignant lesions. They were seen In several areas of each liver as fibrosis and as glandular formations of proliferated epithelial cells replacing parenchymal cells. They formed ducts which produced mucus and which were surrounded by connective tissue of varying abundance. Allen and Abrahamson [216] reported on morphologic and biochemical changes in the livers of rats given A r o d o r s 1248, 1254, and 1260 at 1,000 ppm in their diets for 6 weeks. A control group was fed unsupplemented chow. Each group contained 24 rats. Four rats were killed after 1,3,7,14,21, 28, and 42 days of exposure. White blood cells, hemoglobin (Hb), hematocrit (Ret), differential white cell count, total serum proteins, and blood urea nitrogen (BUN) were measured at each Interval. Selected tissues were prepared for microscopic examination and the livers were homogenized and analyzed for cytoplasmic protein, DNA, and RNA. Liver mlcrosomes were examined for aryl hydrocarbon hydroxylase, nitroreductase, N-demethylase, and nltrophenylacetate hydroxylase activities, and for cholesterol content. All of the PCB-dosed rats failed to gain weight. The most severe effects were noted with Aroclor 1248, followed by A r o d o r s 1254 and 1262. All blood samples showed Increases In Hb and Hct, with no changes in the white blood cell counts. Neutrophils were Increased In the sera of all treatment groups. There were no changes in BUN or In total serum protein levels. Organ weights in all of the experimental rats constituted higher percentages of total body weights than In controls; the livers showed four- 905326 81 N 08012 fold Increases in weight in all PCB-dosed groups. The Increased liver weights were discernible after only 1 day of exposure. Liver hypertrophy was attributed to proliferation of SER, development of large concentric arrays of membranes, and increases in lipid droplets within the cytoplasms of the affected cells. A r o d o r 1248 was the most, and 1262 the least, toxic PCB product as judged by changes in liver histology. Liver homogenates contained increased concentrations of protein and RNA, and decreased concentrations of DNA. These changes were seen within 2 weeks after initiation of feeding Aroclors 1248 and 1254; the protein and nucleic a d d concentrations then either leveled off or decreased after 4-6 weeks. Aroclor 1262, however, did not induce these effects until 4 weeks after the beginning of feeding; the initial changes were followed by reversals [216]. Liver microsomal fractions had Increased protein and phospholipid concentrations. These changes occurred earlier in the rats fed Aroclor 1248 and 1254 than in the Aroclor 1262-fed animals. Microsomal nitroreductase activity, expressed on the basis of microsomal protein, was variable in the animals fed Aroclors 1248 and 1254; however, all animals fed Aroclor 1262 had progressive increases in nitroreductase activity. N- demethylase activity Increased early in the experimental period and Increased progressively in all treatment groups as the exposures continued. Aryl hydrocarbon hydroxylase, glueose-6-phosphatase, and other esterase activities Increased initially, followed by continuous declines in activity in the groups fed Aroclors 1248 and 1254. The rats fed Aroclor 1262 had similar, but leas marked, changes. When enzyme activities were expressed as activity per total liver, all showed marked increases. After 6 weeks, other degenerative changes in the liver occurred, such as dissolution of 82 905327 O bO ls the concentric arrays of membranes, veslculetion of the endoplasmic reticulum, and accumulation within the cytoplasm of lipid droplets that had developed during the hypertrophic phase of the intoxication [216]. Allen et al [222] administered PCBs (Aroclor 1248) and polychlorinated terphenyls (Aroclor 5460) to rhesus monkeys. Sixteen male monkeys were distributed into three groups. Group 1 consisted of six animals and was fed a basal diet supplemented with 300 ppm of Aroclor 1248. Group 2 consisted of six animals fed a basal diet containing 5,000 ppm of Aroclor 5460. The remaining four monkeys constituted the control group and were fed the standard colony diet. Each animal had access to 400 g of diet daily. The physical status of the animals was evaluated daily and "complete" blood studies were performed biweekly. Approximately 10 g of liver tissue were removed from each animal during the 6th week (via laparotomy) and during the 12th week (at necropsy) for biochemical and microscopic evaluation. Animals fed Aroclor 1248 lost an average of 26Z of body weight; those receiving Aroclor 5460 lost an average of 19Z of body weight. Gross changes seen in the animals fed Aroclor 1248 included loss of hair from head, neck, and back, puffy faces, edematous lips, and swollen eyelids with purulent exudates around the eyes. These changes were seen within 1 month; similar, but less marked changes were seen in the animals fed Aroclor 5460 [222], Hematologic changes developed gradually. After 3 months, hemoglobins had decreased by about 2 g/100 ml, and hematocrits had diminished from about 40Z to 33Z. Total white blood cell counts did not change; however, 905328 83 N 08014 there was a shift to the left in the differential count. Total serum proteins decreased by about 1.5-2 g/100 ml* and there was a gradual shift in the albumin/globulin ratio of the serum protein. No changes were seen in SGOT or BUN. Both experimental groups had similar patterns of changes [222]. At necropsy, both groups of animals showed extensive alopecia, acneiform lesions of the skin, subcutaneous edema, liver hypertrophy with fatty infiltration, and gastric mucosal hypertrophy and hyperplasia. Liver hypertrophy was attributed mainly to proliferation of the hepatocytlc SER. Gastric hypertrophy was characterized by thickened gastric mucosa, numerous large cystic areas filled with mucin, and hyperplasia. Ulceration was seen, as was invasion of the underlying mucosa by glandular-type epithelial cells [222]. The authors [222] noted that, biochemically, the decreases observed in the DNA concentrations of the livers of both experimental groups reflected the hypertrophic cells observed microscopically, and the increases' in protein and RNA were said to be compatible with the proliferated SER. Levels of microsomal protein per gram of protein were not markedly altered, but decreases in the specific activities of esterase, aniline hydroxylase, nitroreductase, anct glucose-6-phoaphatase became apparent within 6 weeks, and persisted. N-demethylase activity was increased at each examination. The results of a toxicity study conducted on four young male rhesus monkeys fed A r o d o r 1242 at concentrations of 3, 10, 30, or 100 ppm were reported by Bell [223], McNulty [94], and in a conmunicatlon written in H 08015 905329 March 1977 by UP McNulty. All four monkeys on these diets died within 9 months. The monkeys had facial swelling, red and swollen eyelids, conversion of all secretory-type cells of the stomach to raucous cells, growth of mucous glands into the muscular walls of the stomach, multiple ulcers in the stomach, atrophy of the thymus gland, and either disappearance of sebaceous glands or conversion of these glands to keratin cysts, particularly in the eyelids. Allen et al [104] and Allen and Norback [224] found gastric hypertrophy and hyperplasia and focal ulceration of the stomach lining in adult male rhesus monkeys fed single doses of 1.5 or 3.0 g of Aroclor 1248. (c) Studies Involving Individual PCB Isomers In 1972, Vos and Notenboom-Ram [225] discussed the comparative toxlcltles of dentally applied 120-mg doses of 2,2',4,4*,5,5'- hexachlorobiphenyl and Aroclor 1260. The PCBs, dissolved in Isopropanol, were applied 20 times to the clipped and shaved backs of three groups of four rabbits each, 5 times/week for 4 weeks. The control group received only isopropanol. The Aroclor 1260 sample was found to be "free" of chlorinated dibenzofurans (limit of detection, 1 ppm), and because of the nature of the chemical reactions utilized in the synthesis of 2,2',4,4*,5,5'-hexachlorobiphenyl. Dermal applications of these PCBs resulted in early macroscopic skin lesions and morbid liver changes similar to '.hose found by Vos and Beema [208]. These liver lesions included centrllobular degeneration and liver cell atrophy, focal cytoplasmic hyaline degeneration of the hepetocytes, enlarged nuclei, loss of glycogen and proliferation of SER. The authors [225] concluded that, although the 905330 85 N 08016 major acnegenic action o crude PCB mixtures results from the presence of chlorinated dibenzofurans, PCBs have acnegenic actions of their own. Hansell and Ecoblchon [217] described the effects of a series of chemically pure chloroblphenyls on rat liver morphology. Biphenyl and a series of isomerleally 'pure mono-, di-, tetra-, hexa-, and octachloroblphenyls of known composition were administered Intraperitoneal (lp) injections In daily doses of 50 mg/kg to groups of seven young male Woodlyn strain Wlstar rats for 3 consecutive days. The rats were killed 4 days after the final injections had been made and sleeping times after phnobarbital administration had been determined. The major microscopic alterations observed were proliferation of the hepatoeytic SER, changes In the rough endoplasmic reticulum, and Increased numbers of lipid droplets and mlcrobodles. However, in the rats administered isomerleally pure hexaand octachloroblphenyls, there were additional changes in hepatic morphology, including large numbers of hepatocytes with cytoplasmic vacuoles and small foci of necrosis involving five or six cells. Biphenyl and 2,2'-dlchlorobiphenyl appeared not to Induce extensive proliferation of the SER, but with the other compounds the SER proliferation appeared to be related to the degree of chlorination, especially to the presence of a chlorine in the 4 and/or 4' positions. The investigators [217] also Injected groups of seven rats ip with daily doses of 100 mg/kg of either 4-mono-, 4,4*-dl-, or 2,5,2',5'tetrachloroblphenyl for 7 days; all rats from each group were killed 24 hours after the last injections. This regimen caused more pronounced alterations in hepatoeytic ultrastructure than those observed after the 3day experiments. Marked proliferation of SER and increased numbers of 86 N 08017 905331 mierobodies and lipid droplets were noted, as were a large number of necrotic foci, centrilobular necrosis, and proliferation of biliary ductules. The most severe lesions were seen in the group receiving 4,4'dichlorobiphenyl. There was not the increase in hepatic weight and cell size noted by other authors [219,2261. Hansell and Ecobichon [217] observed that this apparent anomaly may have been due to the duration of PCB administration, only 3-7 days, and to the relatively low dosages. Allen et al [226], in a series of experiments, studied the toxicity of 2,2*,5,5'-tetraehlorobiphenyl in rats and rhesus monkeys. In the first experiment, 5-week-old rats were separated into five groups consisting of five males and five females each. After being fasted overnight, each of these groups was administered by gavage a single dose of one of the following amounts of the compound dissolved in corn oil: 0, 0.5, 1.0, 1.5, or 2.0 g/kg. Each dose had a total volume of 1 ml. After the dose had been given, blood was taken for complete blood counts. Eighteen of the 40 PCB-dosed rats died within 3 days. The dead animals included all those given 2.0 g/kg, 7 rats from the group given 1.5 g/kg, and 1 rat from the 1.0 g/kg group. The rats were observed for 21 days after which complete blocd counts were performed and the surviving animals were killed and necropsled. The major pathologic changes observed in the animals that died were marked regressions of lymphocytes in the spleen and lymph nodes and of cortical thymocytes. With the exception of hemorrhage and atrophy of the thymus, which were related to the decrease in the cortical thymocytes, and enlargement of the liver and kidneys, all tissue samples were normal when compered with those from the nonexposed group. N 08018 905332 The second experiment was conducted to determine the effects of hepatic microsomal enzyme activity on the responses of male Sprague-Dawley rats to 2,2',5,5'-tetrachlorebiphenyl [226]. The rats were separated into 6 groups of 10 animais each. Group 1 was a positive control given four ip injections of 75 mg/kg of the microsomal enzyme inhibitor, SKF 525A, at 8- hour intervals. Group 2 was given four daily sc injections of 75 mg/kg of phnobarbital. Group 3 was the general control. Groups 4, 5, and 6 received 1.25 g/kg of the chlorobiphenyl in 1 ml of corn oil by gastric intubation; group 5 was dosed with the chlorobiphenyl 24 hours after 4 days with daily sc doses of 75 mg/kg of phnobarbital. Group 6 received 75 mg/kg of SKF 525A ip 2 hours prior to administration of 2,2',5,5'tetrachlorobiphenyl, and every 8 hours thereafter for 24 hours. Within 4 days, all the rats in group 5 and 50Z in group 4 had died whereas none had died in group 5, which was pretreated with phnobarbital. The findings that pretreatment with phnobarbital allowed complete survival of rats after an LD50 dose of the FCB, whereas pretreatment with SKF 525A caused 100Z mortality, indicated to the investigators that metabolic transformation by endoplasmic reticulum enzymes resulted in deteriflcatlon [226]. The third experiment was performed to compare the differences between the responses of rats to 2,2',5,5'-tetrachloroblphenyl and A r o d o r 1248 [226]. Twelve male rats were placed in three groups of four animals each; group 1 was fed 100 ppm of Aroelor 1248 in its diet, group 2 was given 100 ppm of the 2,2',5,5' Isomer in its diet, and group 3 (control) was fed the staple ground meal diet. After 4 weeks of these feeding regimens, the rats were fasted for 24 hours, killed, and necropsled; blood was also collected 88 N 08019 905333 at this time. There were no detectable differences In general appearance, food consumption, activity, growth rate, or blood chemistries between the two experimental groups and the control group. The only significant difference at autopsy was an Increase in liver weight as a percentage of body weight of the animals fed Aroclor 1248: 4.46 0.11Z, compared with 3.38 t 0.131 for those fed 2,2*,5,5'-tetrachlorobiphenyl and 3.0 0.12Z for the controls. Proliferation of the endoplasmic reticulum within the hepatic cells was observed in the Aroclor 1248-fed animals. The Ndemethylas activity and the cytochrome P-450 content of the microsomal fraction of homogenized liver from th Aroclor 1248-fed rats were increased whereas the activity of aniline hydroxylase and glucose-6-phosphatase in this fraction had decreased. There were increases in the concentrations of protein and RNA and a decrease in the DNA content of the liver homogenates from the Arodor-fed animals. The livers of rats fed the Isomer had similar but less marked changes in concentrations of protein, RNA, and DNA. The mean concentration of microsomal protein in liver was identical with that of the controls but was more variable. A significant increase in the mean activity of N-demethylase was found. The fourth experiment [226] was performed to determine the effects of 2,2',5,5'-tetrachloroblphenyl on non-human primates. Seven adult male rhesus monkeys were given 18 mg/kg of the PCB Isomer dissolved in 2.5 ml of corn oil and three controls were given 2.5 ml of corn oil, all by gavage after a 24-hour fast. Complete blood counts had been done on each animal prior to intubation. Immediately after treatment, the animals were placed in metabolism cages and their urine and feces analyzed for 2,2',5,5'- 89 N 08020 905334 tetrachlorobiphenyl by GLC. On the 14th day of the experiment the animals were fasted for 24 hours, killed, and neeropsled. Tissues were taken for light and electron microscopy and GLC. No overt clinical effects were seen In the treated monkeys. Over 12% of the PCB was recovered unmodified In the feces but only minute amounts were present In the urine. Only the adipose tissue and adrenals had high PCB assays, and microscopically, except for a moderate proliferation of hepatocytlc SER, all tissues were normal. ONA was slightly decreased In liver homogenates of exposed animals and hepatic microsomal cytochrome P-450 was Increased. Torok [227], In 1976, reported a study of pregnancy In NMRI mice treated with 2,2'-dichloroblphenyl. The mice were separated Into three groups, with group 1 (37 mice) serving as the control; group 2 (18 mice) received the PCB in oral doses of 375 mg/kg/day on days 1-3 of gestation, and group 3 (37 mice) received 750 mg/kg/day on the same schedule. Administration of the PCB at either level resulted In longer intervals from breeding to parturition: 18.2 days for controls, 19.4 days for mice treated with the PCB at 375 mg/kg/day, and 21.8 days In mice treated at 750 mg/kg/day. There also were reductions In the numbers of dams with litters and in the mean litter size. Reductions were greatest in group 3. The authors [227] concluded that the effects were due to delayed implantation. (d) Reproductive and Teratogenic Effects of PCB Mixtures Curley et al [101] studied the transplacental movement of PCBs In rats. Three groups of 90-day-old female rats were paired with male rats of the same age. All were fed standard laboratory chow by the authors, who designated the day of Insemination as day 0. Aroclor 1254 was given in N 08021 90 905335 j doses of 0, 10, and 50 mg/kg in peanut oil (presumably by oral intubation) once a day on days 7 through 15 of pregnancy to groups 1, 2, and 3, respectively. On the 20th day after insemination, fetuses were taken by Caesarean section from three rats of each PCB-exposed group and from tvo control rats. The fetuses from each experimental group were divided into two lots and analyzed as duplicate samples for PCBs. Ten rats from each of the three experimental groups were allowed to deliver spontaneously. When the offspring were 5 days old, six mothers from each exposed group and two from the control group were separated from their litters for several hours and then returned for 1 hour of nursing. The contents (milk) of the pups' stomachs were analyzed for PCBs. Litters from three rats in each experimental group were allowed to survive until weaning at 21 days of age. These baby rats then were killed and their tissues analyzed for PCBs by GLC with EC detection [101]. The rats subjected to Caesarean section had normal fetal complements, in both size and number, and in the rats allowed to deliver spontaneously there were no significant differences in average litter size and'weight among the three groups. However, the three groups, with 0, 10, or 50-mg/kg doses of A r o d o r 1254, had 0, 1, and 4 stillbirths on the average, respectively [101]. Analyses of the tissues of the Caesarean-delivered pups showed measurable levels of PCB-derived components in the exposed groups only. The mean PCB concentrations were <0.12, 0.63 0.06, and 1.38 i 0.06 jug/g, respectively, for groups 1, 2, and 3. Although the PCB dose for group 3 was five times that of group 2 (50 vs 10 mg/kg A r o d o r 1254), the average 91 905336 N 08022 amount of PCB-derived components measured In the fetuses from these two groups differed by only two-fold The authors suggested that the PCB distribution between the mothers and their fetuses may not have been uniform and that a partial (unspecified) barrier may have existed [101], Livers were increased in size and had enlarged hepatocytes in 15 of 21, and 15 of 20 weanling rats from groups 2 and 3, respectively. Some rats from group 3 showed vacuolization of the hepatocytic cytoplasm (10 of 20), and 5 of 20 exhibited bile duct proliferation. Morphologic changes in the liver were more pronounced at the higher dose [101], PCB-derived components were detected in litter-pooled milk at mean concentrations of <0.75, 20.60 t 1.59, and 66.34 t 8.36 jig/g in groups 1, 2, and 3, respectively. The authors [101] concluded that the morphologic changes identified in the livers of exposed weanling rats were probably caused by PCBs transmitted to the pups in the milk from the dams [101]. Reproductive effects of feeding A r o d o r s 1254 and 1260 to Sherman strain rats for two generations were reported by Linder et al [228] in 1974. In preliminary experiments, the two mixtures were fed to groups of 10 females at 100 and 500 ppm in the diet. Two similar groups served as controls. The diets, fed for 67 days before the first mating, were continued through gestation and lactation. After weaning of the first litters, the parents continued to be fed the diets. After being fed PCBs for a total of 186 days, they were again mated and the diets fed through the second gestation and lactation. Feeding Aroclor 1254 at 500 ppm resulted in only 4 first litters being born (2 alive), with no survivors to weaning. Consequently, feeding Aroclor 1254 at 500 ppm was discontinued. With Aroclor 1254 at 100 ppm, there was little indication from eithar the 92 N 03023 905337 first or stcond mating of reduced fertility! or Increased death in utero or during the nursing period. Aroclor 1260 fed at 100 ppm for 67 days had no apparent effect on reproduction! litter size, or survival of the first litters; however after being fed for 186 days, only 5 second litters were born from 9 mated females, compared to 9 out of 10 in the controls. At 500 ppm, Aroclor 1260 resulted in more pups dead at birth in first litters, reduced second litter size, and fewer litters being weaned (3 of 8 first litters; 2 of 6 second litters). Subsequently, Linder et al [228] fed groups of 20 female Sherman rats Aroclor 1254 at 1, 5, 20, and 100 ppm and Aroclor 1260 at 5, 20, and 100 ppm. Appropriate control groups with similar numbers of rats were used. The experimental plan was similar to that described above except that the FI generation pups continued to be fed the F2 generation diet until they reproduced the F2 generation. The first matings of the FI generation were after they were exposed to PCBs in utero, in milk, and in the diet' for 125- 129 days. The FI generation rats fed Aroclor 1254 at 20 and 100 ppm were mated a second time after a total of 274 days of PCB exposure. Rats exposed to Aroclor 1254 at dietary levels of 20 ppm or more had fewer pups in their litters than the controls [228]. There were also fewer F2 generation pups than controls. Second litters born from rats fed 100 ppm of Aroclor 1254 had increased mortality and markedly decreased mating performance. Dietary levels of 5 ppm Aroclor 1254 and 100 ppm Aroclor 1260 had no effect on reproduction in rats exposed through two generations. Liver weights were Increased in 21-day-old FI male weanlings at 1 ppm of Aroclor 1254 and in either sex of FI and F2 weanlings at 5 ppm or higher of both Aroclors 1254 and 1260. 905338 93 N 08024 1 Villeneuve et al [229], in 1971, wrote about fetotoxic effects of Aroclors 1221 and 1254 in rabbits. Twenty-four mature female rabbits were divided into six groups each comprised of two control and four experimental does. Experimental animals were given the Aroclors orally at 1.0 and 10 mg/kg/day beginning after mating and continuing through gestation.z They were killed 28 days after mating. Neither A r o d o r had a fetotoxic effect at either dose level. Liver weights expressed as percentages of body weight were significantly heavier in th does fed 10 mg/kg A r o d o r 1254 than in controls (4.29 vs 2.79%). Liver weights of the other experimental does and of all fetuses were not significantly different from controls. In another experiment reported by Villeneuve et al [230], 16 mature female rabbits were separated into four groups and, after mating, weredosed orally with 0, 12.5, 25, or 50 mg/kg of A r o d o r 1254 dally for the first 28 days of gestation. The 50-mg/kg group had three pregnancies.z One pregnant female died on the 11th day and contained nine fetuses. A second one died on the 17th day and contained six resorption sites. The third female aborted three dead fetuses on the 28th day. Two rabbits in the 25mg/kg group had normal fetuses. A third rabbit aborted her litter on the 28th day and died. The four animals in this group showed an average weight loss of 26 g and liver weights found at autopsy 29 days after mating averaged 5.11% of their body weights. Autopsies were performed on the fetuses of the two rabbits which had conceived in the 12.5-mg/kg group; the first rabbit had two normal fetuses, with six resorption sites, while the second aborted two fetuses on the 27th day and was found on autopsy to contain one partially resorbed and two dead fetuses. The two dead fetuses obtained on autopsy showed subcutaneous cephalic hemorrhages and had '* N 08025 905339 asymmetric skulls. Average weight gain of the females during pregnancy was 265 g, and their liver weights averaged 6.03Z of their body weights. Controls gained 654 g during pregnancy, and their livers averaged 2.66Z of their body weights. In their third experiment, Vllleneuve et al [230] gave each animal in three groups of six female rabbits 25 mg/kg Aroclor 1254 in corn oil (orally). Controls received corn oil .alone. A control group and one exposure group were dosed from day 1 through day 28, and another control and an exposure group were dosed from day 7 through day 28. Administration of Aroclor 1254 at 25 mg/kg/day from day 1 through day 28 resulted in abortions in two of four rabbits. Their average weight gain was 245 g and liver weights averaged 6.03Z of their body weights (controls, 531 g weight gain; liver weights, 2.65Z of body weight). In the second group administered PCBs, one of four rabbits aborted. Average weight gain was 156 g and the liver weights averaged 4.82Z of the body weights. PCB concentrations in various tissues of six rabbits and their fetuses, chosen at random from the above groups, were determined by Grant et al [231]. Concentrations of PCBs were higher in the livers of the fetuses than in their mothers: 5.4 vs 2.1 ppm at a dose of 1 mg/kg; 78.1 vs 69.5 ppm at 12.5 mg/kg; and 375.3 vs 124.2 at 25 mg/kg. In other tissues, PCB concentrations were generally less in the fetuses than in the dams. Allen et al [232] in 1974 presented evidence of possible fetotoxlclty in a short term PCB feeding experiment with 12 adult female rhesus monkeys. The monkeys ranged in age from 7 to 10 years and had an average weight of 5.6 kg. Each previously had delivered at least one Infant and the menstrual cycle of each had been recorded for at least 2 years. Six of the " 905340 N 08026 monkeys were fed an unspecified diet containing 25 ppm of A r o d o r 1248 for 2 months. The other six monkeys were controls. After 2 months, the PCBexposed animals were placed on PCB-free diets of commercial monkey chow. The monkey which had consumed the largest amount of PCBs died on the 128th day of the experiment [232]. At the beginning of the 5th month, ie, 3 months after the test animals had been removed from the PCB-containing diet, the remaining five test monkeys and the six controls were mated again. Three PCB-exposed monkeys were thought to have conceived since each showed the characteristic post-conceptual bleeding, lack of the subsequent menstrual period, and an enlarged uterus. Two either aborted or reabsorbed their fetuses during the 2nd month of pregnancy and the third monkey delivered a well-developed but smaller-than-normal (375 g 1 g vs 544 g t 101 g) Infant. High concentrations of PCBs were found in the adipose tissues and adrenals of this Infant with means of 27.7 and 24.4 Mg/g respectively, as compared to a range from 0.01 to 0.98 jig/g In Che other infant tissues analyzed. The PCB levels in the placenta averaged 0.9 fig/g, and 50 ig/g in the mother's adipose tissue. Two additional attempts were made to breed the nonpregnant females during the next 5 months.' Only the controls became pregnant and all delivered normal Infants. Six of the monkeys were fed an unspecified diet containing 25 ppm of A r o d o r 1248 for 2 months. The other six monkeys were used as controls. After 2 months, the PCB-exposed animals were placed on PCB-free diets of commercial monkey chow. In 1976, Barsottl et al [233] and Allen and Barsotti [234] reported their findings on reproductive dysfunction in female and male adult rhesus monkeys fed Aroclor 1248 in their diets. One test group of female monkeys m .N 08027 905341 received 2.5 ppm and the other group received 5.0 ppm of Aroclor 1248 in a commercial diet. The control group, containing 12 females and 6 males, was fed the commercial diet alone. Females received 200 g, and the males received 300 g of their respective diets dally. Food left in the feeding cups at the end of the day was removed and weighed to determine the daily Intake. After the end of the first 6 months, the average PCB Intakes were 180 and 364 mg for females fed the 2.5- and 5.0-ppm diets, respectively [233], Some of the exposed females began to exhibit the characteristic skin and blood chemistry signs of PCB intoxication within 2 months. At 6 months, all exhibited these signs in varying degrees. Menstrual cycles were Irregular and menstrual bleeding was excessive and prolonged [233]. The conception rates for the control females and for those fed the 2.5-ppm Aroclor diet were 12 of 12 and 8 of 8, respectively, whereas 6 of 8 females fed the 5.0-ppm Aroclor diet conceived [233]. All 12 of the control group pregnancies resulted in normal births, compared to 5 and 1, respectively, for the exposed females fed the 2.5- and 5.0-ppm diets. Three of the eight fetuses of monkeys fed the 2.5-ppm Aroclor diet were resorbed shortly* after conception. Profuse uterine hemorrhaging was observed rather than the implantation bleeding which usually occurred 17 days after conception, according to the authors [233], The two females from the group fed the 5.0-ppm diet who did not conceive initially were bred five times without success. Of the six females of this group that did become pregnant, three aborted at 46, 67, and 107 days of gestation; one fetus was resorbed, one was stillborn, and one delivered normally. The six live infants born to PCB-fed mothers had body weights that were less than 97 905342 N 08028 normal for the colony by one to two standard deviations* These Infants began showing signs of PCB toxicity (acne, swollen eye lids, increased skin pigmentation) after nursing their mothers for less than 2 months [234]. In samples obtained from three of their mothers after the infants developed the poisoning signs, the milk contained PCBs at 0.154-0.397 ppm, and the milk fat from a fourth mother contained 16.44 ppm. Three of the infants died 44-112 days after birth. The effects of A r o d o r 1254 on reproductive performance and fetal integrity were evaluated in beagle dogs and Hormel miniature swine by FL Earl et al (written communication, 1976). A r o d o r 1254 was administered o r d l y in capsules as a solution in corn oil to 46 purebred beagle bitches once daily after the 1st day of gestation. Ten bitches were given 0.25 mg/kg/day, 16 were given 1 mg/kg/day, and 20 were given 5 mg/kg/day. Sixteen untreated bitches served as controls. The data presented show that A r o d o r 1254 at 5 mg/kg/day significantly interfered with reproductive performance and was teratogenic in the beagle. When A r o d o r 1254 was administered at 0.25 and 1.0 mg/kg/day, no effects on reproduction were observed but the incidence of patent fontanelles in the offspring of the 1.0-mg/kg/day group was increased sharply. Dosage at 5.0 mg/kg/day resulted in 45.5% resorptions (4-fold increase over the control rate) and an average of only two live pups per litter. Patent fontanelles were present in 50% of the offspring. Earl and his coworkers fed A r o d o r 1254 to Hormel miniature swine in doses of 1.0 (4 sows), 10.0 (6 sows), and 30.0 (7 sows) mg/kg/day for 21 days before breeding and throughout gestation. Five sows served as controls. the 1-mg/kg/day dose produced a statistically significant 98 N 03029 905343 percentage of fetal resorptions (23Z). Increasing the dose to 10 mg/kg/day lowered the fertility rate to 50Z (80Z in controls) and Increasing the dose to 30 Dg/kg/day lowered the fertility rate to 43Z. Cleft palate and syndactyly in three feet were observed in one fetus from the group fed 10 mg/kg/day. At this dose level, there was also a significant decrease in survivability with only 71Z of the offspring alive after 5 days. At the 30-mg/kg/day dose, 14 of the 15 implantations were resorbed and teratogenic abnormalities were present in 100Z of the observed fetuses. Cleft palates, syndactyly, and patent fontanelles were the teratogenic effects observed. The fact that pigs are normally born with closed fontanelles Increases the signflcance of the teratogenic findings. (e) Studies on Mutagenicity and Cytotoxicity To evaluate the effects of PCBs on the testes of rats, Dlkshith et al [235] administered, by oral Intubation, 50 mg/kg/day of Aroclor 1254 dissolved in corn oil to a group of 18 adult male Sprague-Dawley rats for 7 consecutive days. A control group of 18 rats received corn oil without PCBs. Three rats from each group were killed 1, 7, 15, and 30 days after the last PCB administration. The testes and epldldymises were separated and weighed, as were the livers. Microscopic, hlstochemical ( a d d phosphatase), and cytogenetic examinations were performed. Rats used for cytogenetic examination were Injected ip with colchicine 2 hours before being killed and the chromosomes in testicular tissues were examined. No effects on weight or gross appearance of either the testes or epididymis were noted, nor was there evidence of atrophy or hypertrophy of the testes. The only structural changes noted in the testes of the exposed group was a proliferation of interstitial tissue cells. These cells showed 99 905344 N 08030 an lnereaaa In acid phosphatase activity, which, according to the authors [235], denoted a change from particulate enzyme localization in testicular interstitial cells of the controls to a disseminated, diffuse localization in the testes of the exposed group. Cytogenetic analyses shoved similar chromosomal configurations in both the control and the exposed groups. In the PCB-treated rats, some apparently sporadic abnormal chromosomes were seen in a few of the metaphase figures; chromosomal abnormalities also Included breaks, exchange figures, chromatin bridges at anaphase, and chromosome fragments. The significance of these findings was unclear to the authors [235]. Green et al [236] looked for mutagenic effects in the bone marrow and spermatogonial cells of male Osborne-Mendel rats fed various doses of PCBs. Rats were given Aroclor 1242 either in single oral doses of 1,250, 2,500, or 5,000 mg/kg or in multiple oral doses of 500 mg/kg/day for 4 days. Aroclor 1254 was administered orally in daily doses of 75, 150, or 300 mg/kg for 5 days. The A r o d o r s were mixed with corn oil, except the 5,000mg/kg dose of Aroclor 1242, which was given undiluted. Controls were fed uncontaminated corn oil. The animals were given Colecimld (a colechlcine derivative) at 4 mg/kg 24 hours after PCB dosing was completed and they were killed 3 hours later. Aroclor 1242 produced no statistically demonstrable evidence of chromosomal damage in bone marrow cells at doses of 1,250 or 2,500 mg/kg, or at the 500-mg/kg dose level [236]. At 5,000 mg/kg, there appeared to be an increase in the number of chromosomal abnormalities. However, since most of the changes occurred in one animal, the findings were not considered to be significant. Aroclor 1254 did not produce statistically 100 r 18031 905345 significant numbers of chromosomal abnormalities in bone marrow cells at any dose level tested. A statistically significant number of chromosomal abnormalities was not identified in spermatogonial cells from rats fed A r o d o r 1242. Spermatogonial cells from rats given A r o d o r 1254 were not examined since the results with the more acutely toxic A r o d o r 1242 were negative. All observed chromosomal lesions were single chromatids. The authors [236] did not exclude the possibility of point mutations since the procedures used in this experiment would not have detected such damage. Green et al [237] also investigated the possible induction of dominant lethality in rats given A r o d o r 1242 or A r o d o r 1254 by oral intubation. Except for the positive controls, results showed nonreprodudble positive effects that were not related to dose or stage sensitivity. The authors concluded that the two Aroclors did not appear to be mutagenic. Wyndham et al [116] performed the "Ames" bacterial test for mutagenicity on a variety of PCBs, using Salmonella typhlmurium mutant strain TA1538. A comparison was made of the mutagenic potentials of A r o d o r 1254, 2,2',5,5*-tetrachlorobiphenyl, A r o d o r 1268, A r o d o r 1221, and 4-chlorobiphenyl. The results showed clearly that as the degree of chlorination decreased, the mutagenic potential Increased. A concentration of 100 jig of 4-chlorobiphenyl in the test medium gave over 2,000 revertant colonies/plate. The more highly chlorinated biphenyls showed very little activity as mutagens. Hooplngarner et al [238] studied the toxicides of various Aroclors at 50 ppm in the culture medium of Chinese hamster cells, and found increasing toxicity (measured by cell population survival) with decreasing 101 905346 N 08032 chlorination. Aroclor 1016 appeared to be disproportionately cytotoxic, on the basis of Its chlorine content, suggesting to the authors chat this product contained certain toxic components in higher proportions than either Aroclor 1232 or Aroclor 1242, which it resembled chromatographically. Aroclor 1254 at 100 ppm showed no apparent effect on the chromosomal integrity of human lymphocytes in vitro. Popper et al [239] studied the effect of hepatic microsomal biotransformation systems from control mice and from mice treated with PCBs on the mutagenic potentials of the primary carcinogen N-methyl-N'-nitro-Nnitrosoguanldine (MNNG), and the secondary carcinogen dlmethylnitrosamlne (DMN). Hepatic mlcrosomes were Isolated from male Swlss-Webster mice that had been given 500 mg/kg of Aroclor 1254 4 days earlier, and from untreated' control mice. The mutagenicities of MNNG and DMN were assayed by a bacterial auxotroph reversion test using Bacillus subtllls. Mlcrosomes prepared from the livers of the PCB-treated mice had 2-3 times as much cytochrome P-450 activity as the controls [239]. DMN added directly to the cultures was not mutagenic at concentrations as high as 300 mM. However DMN was converted to a mutagen when exposed to such mlcrosomes la the presence of an NADFH-generatlng system. When MNNG was Incubated with isolated mlcrosomes, its mutagenic activity was reduced. The authors concluded that Isolated hepatic mlcrosomes can modify the biologic activities of mutagens and that the hepatic microsomal biotransformation system could play a key role In chemical mutagenesis. (f) Studies on Tumorigenesis Kimbrough et al [218] distributed 400, 21- to 26-day-old weanling, Sherman strain, "COBS" female rats randomly Into two equal-size groups. 102 N 08033 905347 Half of the rats were fed- a plain commercial laboratory chow. The other 200 were fed laboratory chow containing 100 ppm of Aroclor 1260. The dosed group of rats was fed the PCB diet until 6 weeks before they were killed at the age of 23 months. Autopsies were performed on these rats as well as those that died before the exposures ended. Microscopic examination was completed on 184 dosed animals and 173 controls. From a few to multiple elevated tan nodules were found on the liver surfaces of 170 PCB-fed rats. The nodules varied from 0.1 to several cm in diameter. Only one such abnormality was found in the controls. Of the tumors, 26 of those in exposed animals and the 1 from the control animal were hepatocarcinomic; the other 144 experimental animals had hepatocellular nodules that were described as characteristic of neoplastic nodules or synomously, hyperplastic nodules. The authors [218] said "neoplastic nodules are part of the spectrum of response to hepatocarcinogens and must be included in the evaluation of tumorigenesis." Tumors identified and analyzed from other organs had no unusual features; no apparent differences in incidence were observed between the experimental and control groups [218]. ' V. Evidence of PCB-induced hepatoearelnomas was reported by a group of Japanese Investigators in 1972 [240] and in 1973 [241]. Nine groups of 12 male dd mice were fed a commercial stock diet supplemented with 100, 250, or 500 ppm of Kanechlors 300, 400, or 500. A control group of eight mice was fed the stock diet. All mice were given water ad libitum. After 32 weeks, the animals were starved for 18' hours, killed, and examined macroseopieally for tumors. Seven of the 12 mice fed Kanechlor 500 at 500 ppm developed hyperplastic liver nodules and five had well-developed 103 905348 N 08034 hepatocellular carcinomas. None of the mice fed Kanechlor 500 at lower concentrations or Kanechlor 400 or 300 at any concentration developed hepatocarcinomas. In 1973, Kimura and Baba [242] described neoplastic changes in the livers of rats exposed to Kanechlor 400. Thirty 10-week-old rats were separated into an experimental group of 10 males and 10 females and a control group of 5 males and 5 females. The experimental group was fed a diet supplemented with olive oil containing various concentrations of Kanechlor 400. The control group received an olive oil-supplemented diet. The diet of the experimental group of rats contained 38.5 ppm of Kanechlor 400 for the first 4 weeks, followed by 77 ppm for 8 weeks, 154 ppm for 3 weeks, 308 ppm for 3 weeks, and 616 ppm for 8 weeks. Body weights were, checked weekly and showed rapid decreases during the 616-ppm feeding period; for this reason the Kanechlor 400 content of the diet was reduced to 462 ppm for the next 32 weeks. The total feeding period for the experimental and control animals was about 58 weeks (400 days). All rats that Ingested total doses of more than 700 mg of Kanechlor 400 developed hypertrophy of the liver [242]. Pale brown nodules were present on the parietal and cut surfaces of the livers of female rats that had Ingested more than 1,200 mg of PCBs. However, none of the male rats had such hepatic nodules, despite having ingested equal or greater amounts of Kanechlor 400. On microscopic examination, the livers of female rats were observed to have fatty degeneration and multiple adenomatous nodules that appeared to be benign neoplastic lesions. Males did not develop such neoplastic lesions; however, their livers did exhibit fatty degeneration. Lung abscesses, pneumonia, splenic atrophy, and Intracranial abscesses were 104 N 0 8 0 3 5 905349 found frequently in the experimental group. The authors [242] thought that resistance to infection was lowered in the rats fed Kanechlor 400. A formal rulemaking hearing was convened August 20, 1976 by the US Environmental Protection Agency on its proposed toxic pollutant water effluent standards for PCBs (Federal Register 42:6532-55, February 2, 1977). Part of the testimony concerned comparative studies in which groups of 100 male and female Charles River rats were fed 1, 10, and 100 ppm of Aroclors 1242, 1254, or 1260 for 24 months. The survival of the rats was poor and the experiment was said to have been Inconsistently reported. A rvaluation of the pathology slides revealed the occurrence of liver tumors (hepatomas and cholangiohepatomas) in the rats fed anyone of the three A r o d o r products. The incidence of liver tumors in the rats dosed at 100 ppm was 3/20 for Aroclor 1242, 6/27 for Aroelor 1254, and 7/27 for A r o d o r 1260, compared with 0/20 for the controls. In addition to the tumors there was a high frequency of nodular hyperplasia. The incidence of nodular hyperplasia at 100 ppm was 8/20 for Aroclor 1242, 13/27 for Aroclor 1254, and 7/27 for Aroclor 1260, comparedwith 1/23 for the controls. Nodular hyperplasia in the rats dosed at 10 ppm occurred in 2/10 for Aroclor 1242, 3/26 for Aroclor 1254, and 9/23 for A r o d o r 1260, and 1/23 for the controls. The Incidence of tumors of the pituitary gland also was elevated in each treated group. Correlation of Exposure and Effect (a) Absorption, Metabolism, Excretion, and Body Burdens It has been demonstrated in experimental animals that PCBs can be absorbed into the blood from Inhaled air [97] and from the digestive tract 105 905350 N 08036 [50,51,95,96]. Qualitatively, the effects in experimental animals from absorption by either route were similar [98,99,202-206]. When PCBs were applied to the skin, certain effects, such as those on the liver, were similar to those obtained when PCBs were ingested or Inhaled [205-208]. Thus, it appears that PCBs were also absorbed by this route. In experimental animals, most PCB Isomers were metabolized in varying degrees to more polar compounds such as hydroxylated derivatives [41,48,49,51-56,58-81,85,87]. The more highly chlorinated isomers were metabolized slowly and accumulate in the tissues [41,50,51,55,61-64,66,8284,96,103,107-110]. The hydroxylated derivatives were excreted in the bile, urine, and milk [41,48,50-56,58-61,63-66,69,71-80,85]. Unmetabolized compounds were excreted in feces, milk, and hair [41-44,50,51,53-56,100102], and traces were found in urine [42,51-55,57-62,103-105]. In man, the metabolism of PCBs has not been studied. However, finding that PCB isomers that are difficult to metabolize become concentrated in residual PCBs of tissues from the general population, from persons who have Ingested PCBs, and from those with occupational exposure suggests that man metabolizes, eliminates, and stores the compounds in ways similar to those of animals [7,36,136,168,171-175]. Determinations of PCBs or their metabolites in urine or feces of humans have not been reported. PCBs have been found in human hair [102,142]. Excretion in human milk of PCBs with compositions similar to those in blood, has been reported in association with general environmental exposures and following ingestion and occupational exposures [143,144,168,192]. These findings of PCBs in human hair and milk also suggest metabolism and excretion similar to those of animals. N 08037 905351 Because PCBs are widespread In the environment, detectable -V concentrations have been found in tissues and body fluids of a substantial portion of the US population [36,102,134,135,137,140,144]. Detectable concentrations have been found in up to 62Z of blood serum samples, with 3P 3. concentrations ranging up to 30 ppb [137]. In emaciated patients, blood PCB concentrations as high as 100 ppb have been found [140]. PCB concentrations in about three-fourths of adipose tissue samples from the general population were <1 ppm, and the remainder were mostly in the range of 1-2 ppm [36,136]. Usually the PGB isomers found in blood and adipose tissue have been penta-, hexa-, and heptachlorobiphenyls [7,135,136], and a high correlation was found between the concentrations in these two tissues [141]. PCB isomers in cord blood were qualitatively Identical to those in maternal blood [138]. PCB isomers excreted in human milk were similar or identical to those in blood [168], and the concentrations in milk were positively correlated with adipose tissue concentrations [143]. In human milk samples from the general US population, PCB concentrations up to 13 ppm (fat basis) have been reported (EP Savage, written communication, February 1977). These concentrations of PCBs in blood, adipose tissue, and milk of the general US population arise from dietary Intakes estimated to be of the order of 10-20 jtg/day [46] and from Inhalation of air that may contain up to 100 ng/cu m [26,38]. (b) Irritation Effects and Chloracne The first reports of adverse effects of PCBs on workers Included chloracne [120,123,130], digestive disturbances [123], irritation of mucous Bembranes [120,123,130], and impotence [123]. The exposures associated 107 905352 N 08038 with the effects were not well-defined either qualitatively or quantitatively. When PCBs were first being manufactured, (In mostly open systems) the exposures were to benzene and unidentified intermediates In addition to PCBs [120]. Jones and Alden [120] and Schwartz [123] did not report exposure concentrations In their studies. However, Drinker et al [125] Indicated that average concentrations of PCBs ranged from about 0.5 to 1.5 mg/cu m In 30 factories, which may have Included the factories studied by Schwartz [123]. On the basis of these reports [120,123,125], It would appear that chloracne and some other systemic effects occurred with early PCB preparations when their average concentrations in workroom air were below 1.5 mg/cu m. Elkins [130] found that airborne PCB concentrations approaching 10 mg/cu m In capacitor-impregnating operations in Massachusetts were "unbearably" Irritating to the workers, but there vere no appsrent toxic effects with concentrations that averaged up to 5.8 mg/cu m. Elkins [130] did not describe the processes or the PCBs used. Puccinelll [186] found that when capacitors were filled with A r o d o r 1254 heated to 70-80 C, PCB concentrations of about 5-7 mg/cu m resulted. The workers studied by Puccinelll [186] developed chloracne after 4-8 months of exposure. In studying similar processes, Hofmann and Meneghlni [187] found that chloracne developed after 2.5-4 months of exposure. These Investigators [187] also described the development of areas of brown skin on the foreheads of workers. They did not describe the PCBs used or the exposure concentrations. Reports of the development of chloracne In Americans, who worked In operations which used heated PCBs, appeared In 1964 and 1969 [188,189]. In one of the processes [188], an Aroclor with a chlorine content of 65Z and containing both PCBa and polychlorinated 108 N 0 8039 905353 terphenyls was used; the PCS used in the other process [189] was not described, but extensive skin exposure from wearing PCB-soiled clothing and from immersion of unprotected hands into the PCB mixture was described. A case of chloracne that developed in an Australian worker after exposure to Aroclor 1242 at concentrations of 1-2 mg/cu m was reported by Ouw et al [196]. The PCB preparation was heated during a capacitor-filling process. Complaints of process workers included irritation of the face, eyes, and skin. Eczematous rashes were also found on their hands and legs. In the reports of chloracne development in occupations involving PCBs (where environmental concentrations of PCBs were measured) [125,130,186189,196], the sampling and analytical methods did not distinguish between vapor and particulate forms of the PCBs. However, a common factor in many of these reports [186-189,196] was the use of heat in the process which would tend to generate PCB vapors. In their study of capacitor and PCB manufacturing plants in Japan, Hasegawa et al [191] found that concentrations of PCB vapors (or particles <0.1 m in diameter) exceeded the concentrations of PCBs in particles >0.1 im in diameter. The compositions of PCBs in the particulate were similar to those in the PCB preparations in use, but the less highly chlorinated compounds were concentrated in the vapors. In this study, where PCB vapors ranged from 0.026 to 0.965 mg/cu m and PCBs in the larger airborne particulates ranged from 0.19 to 0,650 mg/cu m (maximum total PCBs of 1.6 mg/cu m), dermal ailments Included a brown chromodermatosis of the hands and chloracne. The workers had been exposed to PCBs from <1 to 20 years. Meigs et al [190] described a process in which chloracne developed where the exposures had to have been to PCB vapors. The PCB which was used 109 905354 N 0 8 0 4 0 as a heat-cxchanga medium was not described, but PCB concentrations were reported to be about 0.1 og/cu m in the workroom air where the workers were exposed. Under these conditions, chloracne developed after a minimum of 5 months of exposure. Chloracne has also been studied in connection with determinations of PCB concentrations in blood. Hara et al [192,193] found whole blood PCB concentrations of 7 to 300 ppb in Japanese workers engaged in capacitor filling. About 40Z of these workers had chloracne and 13% had irritation of the skin. Kitamura et al [194] found PCBs at 320-820 ppb in blood samples from Japanese workers engaged in capacitor manufacture. Skin ailments, including chloracne, were found in 10 of 13 workers studied. Inoue et al [195] found chloracne in a man exposed to PCBs in a silkglossing factory who had a concentration of about 200 ppb of PCBs in his blood, but they [195] found what were described as relatively mild skin abnormalities in 28 other workers engaged in similar processes who had blood PCB concentrations mostly under 100 ppb (2 had concentrations >100 ppb). Ouw et al [196] concluded from their study of capacitor workers that no adverse effects were found in workers with blood PCB concentrations <200 ppb. Studies of PCB-exposed workers where chloracne has not been found Include those of Levy et al [197], Karppanen and Kolho [198], and Bumgarner et al [199]. In the study by Karppanen and Kolho [198], workers who had been exposed to PCBs for 4 years in a capacitor-impregnating operation had PCB concentrations of 74-1,000 ppb in samples of their blood. The environmental exposure concentrations of PCBs were reported to meet "internationally accepted standards." Other factors of the work situation, 110 905355 Hi 08041 such as the skin protection used, were not reported. In the study by Levy et al [197], workers who had been exposed to PCBs for 2.5-18 years had concentrations of PCBs in samples of their blood ranging from 36 to 286 ppb. PCB exposure concentrations at the time of the study were 0.013-0.264 mg/cu m. Although some of the workers complained of throat or eye irritation, and some skin rashes were found, no cases of chloracne were seen. From the description of the work situation, it is unlikely that skin exposure to liquid or solid PCBs was an Important factor in the total exposure of these workers. In their study of refuse workers, Bumgarner et al [199] found blood PCB concentrations to be 4-14 ppb. One poaslble source of exposure of these workers was airborne Incinerator effluents, and it is unlikely that additional exposure from skin contact occurred. Although skin exposure was unlikely in these two reports [197,199] where chloracne was not found, skin exposure is not necessary for chloracne to develop. Chloracne has been observed in Japanese people estimated to have ingested total PCB doses of 0,3-4 g [146,164-167], and chloracne-like lesions have been produced in experimental rhesus monkeys fed PCBs at 3 ppm in their diets [222]. Thus, although eliminating exposure of the skin through engineering controls and using appropriate protective clothing and work practices will reduce the total absorption of PCBs, these practices will not necessarily eliminate chloracne. The data indicate that chloracne may oeeur with exposures to PCB vapor concentrations as low as 0.1 mg/cu m for several months, and with PCB concentrations in the blood of about 200 ppb. 905356 111 K 0 8 0 4 2 (c) Effects Referable to the Liver Some clinical and autopsy findings in Yusho, the disease that occurred after ingestion of PCB-contamlnated rice oil by humans, were indicative of liver injury [155-158,179-181]. These findings included changes in liver cell anatomy considered consistent with microsomal enzyme stimulation and increased SAP activity. Effects that persisted for several years Included decreased concentrations of iron and bilirubin in the serum [155,179] and increased serum concentrations of triglycerides. The latter were found to Increase with residual concentrations of PCBs in the serum [180]. The maximum amounts of PCBs consumed by individuals manifesting these effects were estimated to have been of the order of 3-4 g total intake over several months [165]. For two Yusho patients a daily PCB consumption of 67 pg/kg for 3 months was estimated [167]. The maximum Intake would have been of the order of 50 ppm in the diet or 0.5-1 mg/kg/day. For comparative purposes, absorption of PCBs from Inhalation during maximum occupational exposures that have been reported (10 mg/cu m) probably did not exceed 0.15 ng/kg/day. The extent to which PCB consumption was responsible for the effects on the liver is not known since the contaminated oil also contained PCDFs [20,160] in quantities that could have resulted in a maximum PCDF consumption of 20-50 mg. Autopsy findings 1-3 years after the poisonings indicated unusually high concentrations of PCDFs (0.3-2.5 ig/g) relative to PCBs (3.5-5.6 jig/g) in liver fat [160]. Although most animal feeding experiments have been conducted with dietary levels of PCBs that are much higher than those ingested by Yusho 112 N 08043 905357 * patient*, other* have been conducted with dietary PCB level* that aeem to confirm the Yusho findings. Experiment* have been reported with various commercial PCB mixture* (Arodor* 1242, 1254, 1260, and Clophen A60) added to the diet at 1-10 ppm [101,209-212,215,228,233]. These experiment* demonstrated increased liver weight* at all concentrations, dose dependent stimulation of microsomal enzyme activities, detectable proliferation of the SER at concentrations of 10-100 ppm, and other microscopic changes including enlarged hepatocytes, hepatocytle vacuolization, and, with prolonged exposures, development of adenofibrosis. At high PCB concentrations C>1.5 mg/cu m), Inhalation experiments with animals have demonstrated Increased liver weights [98,99,202,203]. Microscopic changes similar to those seen from PCB ingestion were found in livers of rats after inhalation of A r o d o r 1254 at 1.5 mg/cu m or more [203], and from other commercial preparations (Decachlorodlphenyl and Solvol) at much higher concentrations (>4 mg/cu m) [99,202]. These data from the Yusho poisonings and from animal experiments indicate that hepatic effects seen in human are similar to those seen in animals. They also Indicate that some commercial preparations may be less severe liver poisons than others, but the data are not definitive in this regard. The ingestion experiments demonstrated Increased liver weights from feeding PCBs at 1 ppm, and Increasing evidence of liver injury as dietary PCB levels were Increased. A dietary level of 1 ppm may be considered roughly equivalent to a dally intake of the order of 0.01-0.02 mg/kg, which would be somewhat similar to the intake from inhaling PCBs at 1 mg/cu m. 905358 113 ,N 0 3 0 4 4 *y. Several reports of occupational exposures to PCBs have Involved the liver In various ways [123,125,127,186,190,191,197,198,200]. In the earliest reports of PCB toxicity [123,135,127], the PCBs were mixed with chlorinated naphthalenea. The mixtures caused many cases of chloracne and, in some cases, jaundice. Liver cirrhosis with superimposed yellow atrophy was found in at least one fatality [125]. Similar findings have not been reported where exposures were to only PCBs in the absence of chlorinated naphthalenes. Mention of nausea and digestive disturbances in some reports [123,197] may have indicated liver injury. In the study by Schwartz [123], neither liver function test findings nor exposure concentrations were reported. In the Levy et al report [197], liver function tests (SAP, SCOT, SGPT, total bilirubin) performed at the time of the study did not indicate current liver injury. The workers had been exposed to unidentified PCBs at 0.013-0.264 mg/cu m, and blood PCB concentrations were 36-286 ppb. Even though there were no findings of current liver injury, these investigators' [197] examination of past medical records showed occasional findings indicative of slight liver injury (elevated serum enzymes, triglycerides, and uric a d d ) . A report of a worker who was removed from further exposure after experiencing nausea on exposure to an askarel containing A r o d o r 1254 was not accompanied by liver function test results or exposure concentration data (In the Matter of General Electric Company, File No. 2833, New York State Department of Environmental Conservation, 1975). iMore conclusive studies of liver function were reported by Meigs et al [190], Haaegawa et al [191], Hara et al [192,193], and Ouw et al [196]. Of the workers exposed to vapors of an undefined PCB at 0.1 mg/cu m in the 1 H 905359 X 03045 V %x* -= y study by Meigs et al [190], liver function tests were performed on seven. Findings In six of the workers were normal and, In the other one, cephalin flocculation and thymol turbidity tests were on the borderline of abnormality. Hasegawa et al [191] found some changes in liver function tests (increased SGOT, SGFT, and SAP, and decreased serum cholinesterase and lipids) of 99 workers exposed to Kanechlors but the investigators considered that only the decreased serum lipids were significant. PCB exposure concentrations at the time of the study were 0.045-1.6 mg/cu m. The workers had exposure histories of <1 to 20 years. PCB concentrations in blood samples of the workers averaged 370 ppb. Hara et al [192] did not find evidence of a correlation of serum triglyceride concentrations with blood PCB concentrations during the first year after the work with PCBs was discontinued. However, when the same workers were studied 2 years after stopping work with PCBs, the proportion of workers with elevated serum triglycerides increased as residual blood PCB levels Increased [193], The effect was particularly prominent in workers with residual blood PCB concentrations >50 ppb. In a study of 34 workers exposed to A r o d o r 1242 in capacitor manufacture, Ouw et al [196] found individual abnormalities in SGPT, SAP, and serum bilirubin, but average values for the group were normal. Bromsulphaleln retention tests were elevated in four workers. Ouw et al [196] considered that there were no adverse responses in workers with blood PCB concentrations below 200 ppb. The PCB exposure concentrations were 0.32-1.44 mg/cu m. No evidence of impaired liver function was found in other studies [186,194,195,198] where PCB exposures were reported as: Aroelor 1254 at 5-7 mg/cu m for 2-4 years [186]; Kanechlors at >0.25 mg/cu m [195]; and 115 905360 K 08046 unidentified PCBe et <1 mg/cu m for 4 years [198]. Evidence relating to impaired liver function from occupational exposures to PCBs is generally consistent with findings in Yusho patients and in animal studies that indicated some effects could be expected from PCB Intakes equivalent to PCB inhalation at about 1 mg/cu m. The occupational exposure studies show occasional evidence of liver injury in workers exposed at concentrations of 0.013-0.264 mg/cu m [197], 0.1 mg/cu m [190], 0.045-1.6 mg/cu m [191], and 0.32-1.44 mg/cu m [196], Whether the observed effects occurred with exposures at the lower end of all these ranges is not known. The occupational exposure studies also showed delayed recovery of normal serum triglycerides after exposures to PCBs stopped [193]. The elevated serum triglycerides were related to the higher residual blood PCB concentrations, and these in turn were related to the years of exposure. Residual PCBs have repeatedly been shown to be the more highly chlorinated isomers and those metabolized with greater difficulty [7,36,51,.83,103,110,135,136]. Summaries of effects of PCBs on humans and animals are presented in Tables III-9 and III-10, respectively. Carcinogenclty. Mutagenicity, Teratogenicity, and Effects on Reproduction (a) Carcinogenicity There is extensive evidence for formation of arene oxide intermediates during the metabolism of PCBs by several species ineluding rhesus monkeys [51,68,69,74,75,81,115,116,118]. Arene oxide formation was also proposed as a plausible intermediate in the metabolism of the slowly 116 N 08047 905361 metabolized 2,2',4,4',5,5'-hexachlorobiphenyl [70,79], Binding PCB metabolites to nuclear components of liver cells has been demonstrated on administration of PCBs to monkeys [51], and to rats [81], and by in vitro experiments [51,82,86,116,117], This information is sufficient to arouse suspicions that PCBs could have carcinogenic potential in humans. Hepatomas were produced in 170 of 184 examined female rats fed A r o d o r 1260 at 100 ppm from 3-4 to 23 months of age [218], and in .9 of 22 BALB/cj male mice fed Aroclor 1254 at 300 ppm for 11 months [221], The tumors found in the rats Included 26 hepatocarcinomas and 144 neoplastic nodules. Only one liver tumor, a hepatocarcinoma, was found in 173 control rats. In another report (Federal Register 42:6532-55, February 2, 1977), dose-related incidences of liver tumors were reported in rats fed A r o d o r s 1242, 1254, or 1260 at 1, 10, and 100 ppm in the diet for 24 months. No liver tumors were reported in rats fed the diets containing PCBs at 1 ppm. Only one tumor, a hyperplastic nodule (neoplastic nodule), was found in 23 controls. Neoplastic nodules were found in the livers of rats fed the diet containing 10 ppm of PCBs (2/10, 3/26, and 9/23 for A r o d o r 1242, 1234, and 1260, respectively). Higher tumor incidences were found when diets containing PCBs at 100 ppm were fed (11/20, 19/27, and 14/27 for A r o d o r s 1242, 1254, and 1260, respectively) and the tumors Included hepatomas and cholanglohepatomas (3, 6, and 7 for Aro d o r s 1242, 1254 and 1260, respectively). In this experiment the Incidence of pituitary tumors was high in PCB-fed rats. In a study sponsored by the National Cancer Institute, Aroclor 1254 was fed to groups of 24 rats at 25, 50, and 100 ppm in the diet. No liver 905362 r 08048 tumors were found In the controls* in the experimental females at any dose level, or in experimental males fed PCBs at 25 ppm. However, hepatocellular carcinomas were found in a male rat fedAroelor 1254 at 50 ppm and in two males fed the PCB at 100 ppm. The data also Indicated that the incidence of leukemias in.males was dose-related (3/24 in controls; 8/24 in rats fed 100 ppm). Kanechlors have also been found to produce liver tumors when fed to mice and rats [240,241,242], Of 12 miee fed Kanechlor 500 at 500 ppm for 32 weeks, 7 developed neoplastic liver nodules and 5 had well-developed hepatocellular carcinomas [240,241]. In this experiment which had only 12 miee/group and continued for only 32 weeks, liver tumors were not found with Kanechlors 300 and 400 or with lower dose levels of Kanechlor 500.However in another experiment [242], Kanechlor 400 fed to 10 male and 10 female rats for 58 weeks did produce liver tumors in the females. In this experiment the amounts fed (38-616 ppm) varied from time to time, but were in the 308-616 ppm range for the last 43 weeks. These findings from animal studies indicated to NIOSH that PCBs have potential carcinogenic activity ip humans. They indicate, but do not conclusively demonstrate, with the dietary levels used, that the less highly chlorinated mixtures (Arodor 1242 and Kanechlors 300 and 400) have less carcinogenic potential than the more highly chlorinated mixtures (Arodors 1254 and 1260 and Kanechlor 500). However, all PCB mixtures adequately tested in rats and mice have shown carcinogenic activity. The intakes of PCBs at the lowest dietary level that, has produced tumors in rats (10 ppm) would be somewhat comparable to intakee from occupational exposures at 5-10 mg/cu m. However PCBs are slowly eliminated from the U 8 905363 N 08049 body and Che higher chlorinated compounds may accumulate In the body for years. Thus animal experiments that are limited to 2 years by the life span of the animals may not be informative relative to workers exposed for up to 45 years. In humans, there are no adequate studies to confirm or deny carcinogenicity although preliminary data suggest that among Tusho patients, deaths due to cancers exceed expectations [160,161] and preliminary studies of two occupationally exposed groups in the US indicate that the occurrence of certain cancers may be excessive (HA Sindaire, written communication, June 1976; G Roush, written communication, September 1976). However, the two reports are not consistent as to the types of cancers found to occur more frequently than expected. (b) Mutagenicity Several PCBs and PCB mixtures, including the 4- end the 2,2',5,5'lsomers and A r o d o r s 1221, 1254, and 1260, were subjected to the "Ames" test for mutagenicity [116]. Although 4-chlorobiphenyl had mutagenic activity in this test, the more highly chlorinated PCBs showed very little activity. A r o d o r 1254 did not cause significant chromosomal changes in the testes of rats after it was administered for 7 days at 50 mg/kg/day [235]. In another experiment [236], neither A r o d o r 1254 administered at 300 mg/kg/day for 5 days nor A r o d o r 1242 administered at 500 mg/kg/day for 4 days produced chromosomal aberrations in spermatagonial or bone marrow cells of rats. These mixtures also did not produce any evidence of dominant lethal mutations in rats [237]. Although PCBs have little mutagenic potential, they may alter the mutagenicity and carcinogenicity of other compounds by stimulating microsomal enzyme activities [239]. 119 905364 K 08050 (c) Teratogenicity PCBs have been found In embryonic and fetal tissues of humans [139,168] and experimental animals [101] after introduction of PCBs Into the maternal body, demonstrating that the potential for direct teratogenic effects exists. Several experiments have been conducted with rats [101,228], rabbits [229], monkeys [232], and dogs and pigs (PL Earl et al, written communication, 1976) that are relevent to a discussion of PCB teratogenicity. In some of these experiments, the PCBs were administered by gavage and doses were reported In mg/kg; In other experiments, the PCBs were reported as ppm fed in the diet. For purposes of relative comparison, 50 ppm In the diet can be equated to 1 mg/kg/day. This is the order of magnitude of the maximum rate of PCB intake by Yusho patients. Animal experiments have used PCBs In dietary-equivalent amounts of 1-2,500 ppm. In most experiments with PCBs administered in amounts equivalent to dietary levels of 100 ppm or more, fetotoxicity (resorptions, absortlons) has been such that teratogenic effects may have been masked [101,228,229]. In the two-generation feeding study of rats by Linder et al [228], no terata were reported. This study covered Aroclor 1254 in the concentration range of 1100 ppm and Aroclor 1260 in the range of 5-100 ppm. Although terata were not reported, Aroclor 1254 concentrations of 20-100 ppm resulted In reduced litter sizes. In rhesus monkeys [232], feeding Aroclor 1248 at 2.5 and 5 ppm caused abortions In some cases and lower than normal birth weights, but no terata were reported. In dogs, terata were not found In pups born from dams fed the equivalent of 12 ppm in the diet, but were present when 48- or 200-ppm equivalents were fed. Sows fed the equivalent of 50 ppm in the same experiment had high rates of resorptions and, at 10-30 times this 120 N 0 8 0 5 .1 905365 level, tereta were definitely present in the piglets (FL Earl et al, written communication, 1976). Although there were retarded intrauterine growth and signs of PCB toxicity in Yusho babies at birth, no terata were reported [149,159,176,182,183]. A normal baby was bora to a woman exposed to PCBs in her work. The PCB exposure concentrations were not reported but the PCB concentration in her blood was 25 ppb at the time the baby was bora. These studies indicate that PCBs have teratogenic potential for humans. However, the terata observed in animals occurred at levels at or above doses equivalent to the maximum doses of the Yusho patients and at Intake rates 3-4 times greater than intakes expected from Inhalation at maximum reported occupational exposures. (d) Other Effects on Reproduction Feeding rats A r o d o r 1254 at 5 ppm or A r o d o r 1260 at 100 ppm had no effects on reproduction over two generations [228]. At higher dietary levels, reproductive effects included poor mating performances, fewer litters, reduced litter size, and high postnatal death rates in the litters. In rabbits, A r o d o r s 1221 and 1254 were not fetotoxlc when administered only during gestation in amounts equivalent to dietary levels of about 50-500 ppm [229], However, when administered during gestation at higher levels (600-2,500 ppm dietary equivalent), A r o d o r 1254 caused resorptions, abortions, maternal death, and, in two fetuses, asymmetric skulls [230]. Delaying administration of PCBs until after the first week of pregnancy did not eliminate the effects. Feeding rhesus monkeys A r o d o r 1248 at 25 ppm for 2 months resulted in a high degree of infertility that persisted for at least 8 months after 121 905366 N 03052 i the laet ingestion of PCBs [232]. In another experiment, rhesus monkeys fed Aroclor 1248 at 2.5 and 5 ppm for 6 months had irregular menstrual cycles with excessive and prolonged bleeding [233]. Even though these monkeys conceived well on mating, resorptions and abortions were frequent, and infertility was common in subsequent matings [233]. Nursing infants developed chloracne-like signs within 2 months and Infants frequently died during the nursing period. [234]. The milk contained PCBs at 0.154-0.397 ppm There are no reports of infertility or abortions attributed to human PCB consumption or exposure. There are reports of undesirable effects in children born to mothers exposed to PCBs in the diet and of undesirable effects developing from nursing such mothers. Babies born from mothers with Yusho were often dark colored and developed signs of Yusho after nursing [176,182,183]. In at least one case, Yusho developed in a baby who was only exposed to PCBs by nursing [182], Concentrations of PCBs in milk were not determined at the time of the Yusho poisoning. A milk sample obtained after birth of a normal baby from a woman exposed to PCBs at work contained PCBs at 0.25 ppm, and nursing was discontinued [195]. The woman's exposure history and time of last exposure were not given, but PCBs were present in her blood at 24 ppb. Based on the findings in monkeys [234] the decision to not nurse the baby seems entirely justified. 122 K 03053 905367 TABLE III-9 EFFECTS OF PCBa ON HUMANS PCB Intake Source Duration Exposure Index Environmental, Blood Amount/kind (ppb) Effects Ref. Ingeation Occupational ft ff ff ff ff ft ft Up to 8 non 0.3-4g Kanechlor 400 >50 Tusho Not known 10 mg/cu m - Unbearable irritation 4-8 non 5-7 mg/cu n Aroelor 1254 Chloracne, no liver injury 2,5-4 non Not reported .*" Chloracne, hyperpig mentation <1-20 yr 0.2-1.6 mg/cu m Kanechlora 370, ave. Chloracne, hyperpig mentation, liver injury 2.5 yr ave. Not reported Kanechlora 820, ave. Chloracne, no liver injury Not reported >0.25 mg/cu m Not reported 130-520 Chloracne, liver injury 2,5-18 yr 0.013-0.27 mg/cu m Not reported 36-286 Irritation, liver injury 14 non ave. 0.1 mg/cu m Not reported - Not reported <1-14 refuae workers Chloracne, liver injury No effects 145185 130 186 187 191 194 195 197 190 199 905368 123 N 08054 TABLE III-9 (CONTINUED) EFFECTS OF PCBa ON HUMANS PCB Intake Source Duration Exposure Index Environmental , Blood Amount /kind (ppb) Effects Ref. Occupational II II 2-23 yr 1-23 yr Up to 15 yr 0.32-1.44 mg/cu m Aroclor 1242 0.32-1.44 mg/cu m Aroclor 1242 Not reported Kanechlors If Not reported Not reported Kanechlors If General environment 4 years Continuous (>1 mg/cu m) Aroclor 1242 Air, 1-100 Food, 10-20 Mg/d >200 <200 Chloracne, liver injury 196 No effects 196 7-300 Chloracne, elevated triglycerides 192, 193 24 10-100 Normal baby Mild chlor acne 195 74-1,900 No effects 198 >1-30 No effects 137141 124 H 08055 905369 TABLE III-10 'J* EFFECTS OF PCB INHALATION ON ANIMALS Exposure Conditions Material mg/cu m Duration Species Effects Ref. Pydraul A 200 30,000 Solvol 10,000 If 250-500 Decaehlorodlphenyl ft 2,500 800 1 4 and 80 Aroclor 1242 8.6 If 6.8 If 1.9 Aroclor 1254 5.4 ft 1.5 2 hr 3 hr Rats If 8-69 3-hr exposures 6 hr 6 hr/d, 5 d/wk, 4 wk f ? If ? PCB in liver, 70 ppm 97 100Z mortality, liver necrosis 202 Liver necrosis, hyper 202 plasia of Kupffer cells Irritation, no gross effects 98 Irritation, increased liver weights, micro scopic liver changes blood cell changes 99 No irritation, Increased liver weights in females 99 7 hr/d, 5 d/wk, 3 wk 7 hr/d, 5 d/wk, 17 wk 7 hr/d, 5 d/wk, 31 wk 7 hr/d, 5 d/wk, 17 wk 7 hr/d, 5 d/wk, 31 wk Mouse, None rat, cat guinea pig* rabbit t II 1 Microscopic liver changes Microscopic liver changes; reversible 203 203 203 203 203 125 905370 !' 08 056 IV. ENVIRONMENTAL DATA AND BIOLOGIC EVALUATION Environmental Concentration Two reports of workroom air concentrations of PCBs appeared in 1954 [186,190], Puccinelli [186] studied the concentrations in air of a capacitor factory in Italy, using the methods of Elkins [130], and found concentrations in 500-liter air samples of 5.2-6.4 mg/cu m. Mlegs et al [190] did not report on the analytical methods they used to determine concentrations of PCBs in the breathing zones of workers exposed when a heat exchange unit in a Connecticut factory leaked. From the description of the factory, it is likely that the exposures were largely to vapors; the concentration found was 0.1 mg/cu m. In 1959, Elkins [130] reported that over a number of years, PCBs in some Massachusetts plants ranged up to 10.5 mg/cu m of air (Table IV-1). TABLE IV-1 PCB CONCENTRATIONS MEASURED IN MASSACHUSETTS FACTORIES Process Capacitor ttimpregnating If Capacitor soldering Oil mixing Regulator filling Adapted from reference 130 PCB Concentrations (mg/cu m) Maximum Average 10.5 5.5 0.3 5.8 4.5 0.2 0.9 1.1 0.8 0.6 0 . 2 0.1 905371 126 N 08057 Of 21 air samples collected in capacitor Impregnating operations Elkins considered that hazardous concentrations (>1 ppm for A r o d o r 1242; >0.5 ppm for A r o d o r 1254) existed in 15. While the sampling and analytical methods used were not documented Elkins [130] recommended sampling with either a fritted bubbler or two lmpingers in series, both r containing amyl acetate, and analyzing by the sulfur lamp method. 4. Occupational environmental studies were conducted in five Japanese *i plants by Hasegawa et al [191]. Kanechlors 200 (predominantly dlchloroblphenyl8>, 300 (mostly trichloroblphenyls), and 400 (mostly tetrachlorobiphenyls) were used or manufactured in the plants. Air samples were drawn through filter paper to collect particulate matter and normal hexane to collect vapors and analyzed by GLC. The data are summarized in Table III-7. In the paired samples, the vapor concentrations exceeded the particulate concentrations. One of the plants was a biphenyl recovery plant where PCBs were not used. In this plant, PCB concentrations were <0.02 mg/cu m. In the PCB manufacturing plant, PCB vapor concentrations were 0.026-0.163 mg/cu m, and particulate PCB concentrations were 0.0190.037 mg/cu m. Higher PCB concentrations were found in the capacitor plants: 0.095-0.965 mg/cu m of vapors, and 0.20-0.65 mg/cu m of particulates. In one particulate sample collected in a capacitor plant after a spill, the PCB concentration was 6.2 mg/cu m. Stalff et al [243] in a 1974 report were concerned about emissions from burned-out PCB-contalnlng ballasts in fluorescent fixtures in their laboratory. The investigators collected samples in two midget lmpingers, containing ethylene glycol and connected in series. The samples were analyzed by GLC. PCB concentrations in the air ranged from 0.012 to 0.166 127 905372 N 03058 mg/cu m when the ballasts burned out and were 0.002 mg/cu m 3 days later. In a 1976 report of a survey of Australian workers exposed to Aroclor 1242, Ouw et al [196] listed breathing zone concentrations ranging from 0.32 to 2.22 mg/cu m before corrective measures were taken, and from 0.08 to 0.75 mg/cu m after installing Improved ventilation. Breathing zone samples were collected at 30 llters/mlnute using Greenburg-Smith lmplngers containing 75 ml of Isopropanol. The concentrations found are shown in Table IV-2. TABLE IV-2 PCB CONCENTRATIONS IN THE AIR INSIDE A CAPACITOR PLANT BEFORE AND AFTER IMPROVEMENT OF EXHAUST VENTILATION SYSTEM Areas in the Impregnation Room PCB Concentrations mg/cu m Before After Area In the unloading tank In front of exhaust register from operator's breathing zone Area in the unloading tank not in front of exhaust register General atmosphere near tank Soldering area Adapted from reference 196 1.44 2.22 1.08 0.32 0.75 0.7 0.18 0.08 Exposures of electrical and materials technicians during 1976 to PCBs contained In materials they tested were evaluated by Levy et al [197]. Air samples were collected on magnesium silicate "Florlsil" at 50 ml/minute for 128 N 08059 905373 4-8 hours and analyzed by GLC utilizing electron capture detection. Breathing zone samples were collected on a single day from nine employees for 8 hours. The concentrations in the nine breathing zone samples, which would represent TWA exposure concentrations for the day, ranged from 0,014 to 0.073 mg/cu m. Concentrations of PCBs in nine point source samples collected over 4-8 hours on each of 3 days ranged from 0.013 to 0.264 mg/cu m, and in 19 room air samples collected over 4 hours on each of 3 days, from 0.08 to 0.16 mg/cu m. A plane manufacturing PCBs in the US was surveyed for worker exposure in July 1976 [244]. Three Aroclors (1016, 1242, and 1254) were made in the PCB production area. To begin the process, biphenyl and chlorine were piped into a chlorinator with a catalyst and allowed to react. Two separate group's of chlorinators were used for Aroclors 1242 and 1254. The product resulting from the reaction passed through a purifying operation, or to a distillation column as in the case of converting A r o d o r 1242 to A r o d o r 1016, and then on to the storage tanks. Mixing tanks were used to give the desired properties to the final product. 'v Although the operation was outdoors and theoretically a closed system, potential for employee exposure existed when samples were drawn or leaks occurred. Local exhaust ventilation was used in two operations: (1) while filling 55-gallon drums, hoses were placed near the openings, and (2) when employees tested samples drawn from the chlorinators, their work station was equipped with an exhaust fan and hood. Eleven personal and seven area air samples were taken in the PCB production area for 6-8 hours at a flow rate of 200 cc/minute [244], PCBs were collected on Florlsll, desorbed with hexane, and analyzed by GLC with 129 905374 N 03060 EC detection. Aroclor 1016 was the PCB produced on the sampling dates, and It was used as the standard for quantitating airborne PCBs. Personal air sample concentrations of PCBs reported as Aroclor 1016 ranged from 20 to 86 Mg/cu m, while PCBs In area samples ranged from 16 to 55 ug/cu m. The data are presented In Table TV-3. TABLE IV-3 PCB CONCENTRATIONS FOUND IN A PLANT MANUFACTURING PCBs ON 2 CONSECUTIVE DAYS Gig/cu m)* Personal Air Samples Job Title Premium operator Second operator Colimm operator Still operator Standard operator Distribution operator 7/21/76 47 46 64 40 54 7/22/76 20 43 51 86 61 36 ' 'V. Area Air Samples Location 7/21/76 2/22/76 Drumming 43 51 Temperature testing 25 52 Chlorlnators 55 36 Incinerator burner 16 - Total sampling time varied from 409 to 455 minutes and sample volumes varied from 67.6 to 201.6 liters. Adapted from reference 244 130 N 0306 905375 Sato and Hasegawa [32] studied concentrations of PCBs in factories that had discontinued their use in production of pressure-sensitive copying paper 2 years earlier. PCB concentrations in the factories had not been determined when PCBs were being used, but were considered [3] to have been similar to those found by Hasagawa et al [196] in capacitor manufacturing plants. The concentrations found by Sato and Haswgawa [32] at the time of sampling ranged from 0.13 to 4.4 Mg/cu m. The PCB concentrations in the outdoor air around the factories were 0.043-0.09 Mg/cu m [3]. Another study of contamination in factories after PCB use had been discontinued was reported by Fujlwara et al [33]. These investigators found 0.25 mg/cu m in air of a factory that had previously used PCBs in silk glossing. In addition to air contamination, PCBs were found in the dust around machinery and in the floor boards. PCB concentrations found in the air of some other factories and their surrounding environments in Japan were summarized in 1976 by Tatsukawa [245]. Concentrations found before 1957 in a factory producing transformers and capacitors ranged from 0.39 to 4.5 mg/cu m. The factory was said to have been old-fashioned with bad ventilation [245]. Concentrations found in warehouses for carbonless copying paper in 1972 ranged from 2 to 70 Mg/cu m. In the same year, concentrations of 0.04-0.05 Mg/cu m were found in a university laboratory where PCBs were used, and concentrations of 0.006-0.12 Mg/cu m were found in areas of mills that recycled paper. Background concentrations found in urban areas of Tokyo, Osaka, and Matsuyama City were <0.002-0.04 Mg/cu m. Background concentrations of PCBs in ambient air over the US have been reported in ng/cu m quantities [26,38]. 13l Average concentrations of 905376 N 03062 about 100 ng/cu m were found In Florida and Colorado In 1975 [38]. Control of Exposure Tha present primary use of FCBs Is as dielectric or insulating fluids for electrical capacitors and transformers. Potential hazards of PCBs in these industries result from inhalation and dermal exposures. It is here that engineering controls, such as local exhaust systems are necessary. Local exhaust systems should be designed and operated in conformance with American National Standard Z9.2-1971 Fundamentals Governing the Design and Operation of Local Exhaust Systems [246]. Guidelines for handling capacitor and transformer askarels include the following recommendations from the American National Standards Institute (ANSI) [4]: (1) Enclosed systems of sealed piping, properly gasketed joints, valves, containers, and processing chambers should be used for any portion of the operation where askarel temperatures may exceed 55 C; (2) Enclosure should preferably extend to all other portions of the system insofar as practicable; (3) Operations utilizing PCBs should be Isolated from other manufacturing areas to avoid cross contamination; (4) Provision should be made for adequate ventilation and regulation of manufacturing operations to avoid open exposure to askarels; (5) When askarels are used at elevated temperatures (especially 55 C or higher), engineering controls must be applied, either by the use of closed systems or by effective local exhaust ventilation with general workroom exhaust. Durfee et al [247] cited the following potential sources of air emissions of PCBs in transformer and capacitor manufacturing operations: (1) vapor exhaust from stream jet ejectors; (2) evaporation from accidental 132 -N 0 8 0 6 3 905377 spills; (3) evaporation from hot surfaces as part of flood-filling, inspection, or holding operations; (4) vacuum pump exhausts; (5) evaporation from plant waste water. There are currently no commercially available fluids which can be considered as totally acceptable substitutes for PCBs in the broad range of AC capacitors, nor are there substitute dielectric systems which would satisfy reliability and safety requirements in most applications [28]. Transformers containing PCBs represent only about 5 Z of the US transformer market, and are used only where safety and reliability are of prime Importance. For new installations, building and installation design provisions could be made to accommodate the use of filled, open dry-type, or sealed dry-type transformers. Major construction changes would be required to compensate for the fire resistance of askarel-fllled units if existing askarel-fllled transformers are to be replaced with oil-filled units of equivalent electrical ratings [4]. Environmental Sampling and Analytical Methods (a) Air Sampling Before discussing the various methods available for sampling airborne PCBs, it is pertinent to discuss the criteria for an ideal sampling device. NIOSH evaluated an Industrial worker's exposure and found that sampling in the breathing zone gives a truer picture of actual exposure than does area sampling. The first criterion for an ideal air sampling device then la that it be amenable to personal sampling. In addition, it should be light, compact, and small enough so that workers can pursue their daily activities without being aware of its presence. The second criterion is that the 133 905378 sampling device have a sufficient capacity for PCBs to enable the collection of an air sample representative of a typical workday. Thirdly, recovery of PCBs from the sampling device should be quantitative or, at the least, reproducible. Finally, the sample must be stable in or on the sampling device between the time of sampling and the time of analysis. This latter criterion is hardly of concern here due to the general stability of PCBs. An air sampling procedure using fritted bubblers or impingers filled with toluene was published by ANSI in 1974 [4]. Neither the sampler capacity nor the sampling efficiency had been experimentally evaluated. Where high sampling flow rates or high capacities were required, additional bubblers or impingers in series were recommended. Bidleman and Olney [248] used porous polyurethane foam for collecting samples of atmospheric PCBs. They found that the polyurethane foam showed excellent collection efficiency (99Z or better) for tri-, tetra-, and pentachlorobiphenyls. The authors [248] did not address the matter of sample recovery from the sorbent. In an environment where carbonless copy paper was being used, Nishiyama et al [249] collected PCBs by drawing the air through a cooled column filled with Shimalite, a gas chromatographic solid support similar to Chromosorb W. The collection efficiency of the device was 95% and the PCBs were eluted from the column with hexane. Other Investigators used 5% glycerol-coated Florlsil for collecting organochlorine pesticides and PCBs from air [250]. Collection efficiencies were 90-100Z for PCBs. Harvey and Stelnhauer [251] collected ambient air samples of PCBs using 0.25Z OV-17 silicone oil coated on ceramic saddles (distillation N 08065 905379 column packing). The collection efficiency of thie device was 702. More recently, Glam et al [252] found that sorbent tubes packed with deactivated Florisil could be used for collecting PCBs and phthalates from air [252], These compounds were found to be effectively retained by Florisil. The authors did not discuss efficiency of recovery. In 1976, Laveskog and Llndskog [253] deecribed a stack sampling device for chlorinated hydrocarbons which they used for PCB collection. This device utilized glass wool for the collection of particulates followed by a sorbent, 25-402 Apiezon M on Chromosorb W, to collect vapors. The collection efficiency of the column was 992, and desorption efficiency with absolute ethanol was 872. The authors investigated charcoal as a sorbent, but found it unsuitable for their purposes since the PCBs could only be recovered by extraction in a soxhlet apparatus with chloroform which In turn could not be used with electron captur'e detection. Occupational Safety and Health Administration (OSHA) workers have used charcoal tubes for personal air sampling for PCBs (RG Kupel, written conmunlcatlon, 1976). While the sampling device would be expected to have good capacity for PCBs, recovery from charcoal is not quantitative'. vLlttle other Information Is known about this method. A NIOSH Standards Cosipletlon Program Report [254] indicated that PCBs with 542 chlorine content were effectively trapped on a fibrous glass filter. However, the presence of PCB vapor either apparently was not addressed or was assumed to be negligible. This may not be a valid assumption, particularly since another report from the same program [255] showed that PCBs with 422 chlorine content have appreciable vapor pressure. 135 905380 f `J S O 66 NIOSH has also Investigated the method of Giam et al [252], using Florisil as a sampling medium, in Industrial environments. Florisil (30/48 mesh) was placed in a tube similar to that used in the charcoal tube method for solvents, 100 mg in the front section and 50 mg in the back. The retention capacity of this sampling device for PCBs was evaluated under laboratory and field conditions, using various vapor generation techniques. In laboratory experiments,. PCBs at 10 #g/llter and 75Z relative humidity were sampled through a 100-mg Florisil bed at 0.2 liter /minute with no evidence of breakthrough after 4 hours (48 liters). Of 21 samples collected on Florisil in a capacitor plant, only 6 had PCBs on the backup section and all 6 backup sections contained 1% or less of the total PCBs in the tube. The volumes of air sampled ranged up to 61 liters, and PCB concentrations in air as high as 1.5 jig/liter were measured. Other laboratory experiments showed that PCBs could be desorbed quantitatively from Florisil with hexane. Results from Florisil tube and lmpinger samples taken side by side in the capacitor plant and analyzed with a single commercial PCB product as a standard were statistically similar. Impingers are not suitable for personal sampling and are inconvenient to use because they must be recharged with the sampling solvent frequently and must be used in series. The handling of absorber solutions is difficult because of the potential for spillage and leakage of the solvent and samples during transport to and from the sampling site. Solid sorbent sampling devices are well suited for personal sampling since they are relatively small, and personnel wearing the devices quickly become unaware of their presence, enabling more representative sampling. Shipment of these devices is relatively simple. 136 V. 08067 905381 Of the solid sorbent sampling devices discussed, Florisil-ftiled tubes are deemed the most advantageous because Florisll has a high capacity for PCBs and can be quantitatively desorbed; field evaluations have shown that Florlsll-filled tubes are easier to handle and more convenient than lmpingers. Therefore, the Florlsil-filled tube method is recommended for collection of PCBs from air, as detailed in Appendix I. (b) Analytical The chemistry of PCBs was extensively reviewed by Hutzlnger et al [1], and PCB analytical chemistry has been reviewed by several authors [256-264] but only references pertinent to selection of an analytical method for determination of PCBs in industrial air samples will be discussed here. Of the analytical techniques available, the one most widely used for determining PCBs is GLC with EC detection. This technique is rapid, precise, and very sensitive. The far greater sensitivity of EC detection compared with that of the flame ionization detector (FID) is demonstrated by comparison of their relative reaponses to varloua PCB isomers, shown in Table IV-4 [1], 137 905382 08068 'N TABLE IV-4 RELATIVE MOLAR RESPONSES OF ELECTRON-CAPTURE AND FLAME-IONIZATION DETECTORS TO SOME PCBs Relative Molar Response PCB Electron Capture Flame Ionization 2-chloro 3-chloro 4-chloro 2,2'-dichloro 2,4-dichloro 2,6-dichloro 3,3'-dlchloro 3,4-dlchloro 4,4'-dlchloro 2,4,4'-trlchloro 2,2'4,4'-tetrachloro 2,2'6,6'-tetrachloro 3,3'4,4'-tetrachloro 3,3'5,5'-tetrachloro 2i 3,4,5-tetrachloro 2,3,5,6-tetrachloro 2,2'4,4'6,6'-hexachloro 3,3'4,4'5,5'-hexachloro 2,2'3,4,5,5'6,6'-octachloro 2 , 2 ,3 , 3 ,5 , 5 '6,6'-octachloro decachloro Adapted from reference 1 1.00 0.20 1.10 5.16 17.7 32.0 6.10 15.2 5.97 135 106 20.6 396 320 367 259 347 726 1,180 1,150 1,410 1.00 0.92 0.87 0.99 0.86 0.91 0.94 0.86 0.81 0.78 0.87 0.90 0.87 0.85 0.87 0.71 During the GLC-EC detection analysis of PCBs, multicomponent mixtures of various PCBs are almost always encountered. The samples analyzed may or may not resemble a commercial PCB mixture. If so, the appropriate commercial PCB mixture can be used as a standard for quantitation; If not, a commercial mixture should not be used. Quantitation cannot be accurate since It Is based on Incomplete resolution of PCB Isomers. Even if complete resolution were possible, all PCB Isomers are not available for standards and the specific EC detection response of each Isomer would need 138 N 0 8 0 6 9 905383 to be known. Many different methods have been used to "quantitate" or estimate PCBs. Heights or areas of one [263], two [264], three [265], or more [266,267], or of all chromatographic peaks [268-270] of a given sample have been used for comparison with standard commercial PCB mixtures. The chief disadvantage of such methods is that when the chromatogram of the sample does not closely resemble that of the standard the estimates are neither precise nor accurate. An improvement upon these methods is the use of mixed PCB standards, as described by Beezhold and Stout [271]. This procedure Involves mixing various proportions of different PCB commercial mixtures, such as A r o d o r 1242 and A r o d o r 1254, and obtaining sets of chromatograms. The chromatogram most closely resembling the sample is selected and the corresponding mixture is used as the standard. Sawyer [269], in a collaborative study, evaluated the quantitation of PCBs in chicken fat. He found that the use of the total peak area or the sum total of all peak heights gave better results than did the use of selected peaks. The use of mixed standards gave good results when the composition which best duplicated the response pattern of the sample was used. This was adopted as an official method by the Association of Official Analytical Chemists [272]. Using a different approach to standardization, Rote and Murphy [273] produced a standard response curve using A r o d o r s 1232, 1242, 1248, 1254, 1260, and 1262. This plot was of the total area responses on the GLC trace divided by the weights of the A r o d o r s Injected versus the average number of chlorine atoms in the molecule. The peaks in each chromatogram were identified as to chlorine content per chlorobiphenyl molecule, and 139 905384 N 08070 each sample could Chen be quantitated using the response curve. The accuracy of this method Is not greater than that of the methods previously mentioned, since it has been shown that the response of EC detection varies greatly with the degree of chlorine substitution and also with the relative position of the chlorine substitution [1]. Risebrough et al [274] and Collins et al [268] used dichlorodiphenyldichloroethylene (p,p'-DDE) as a standard and assumed that the response of each chlorobiphenyl Isomer was equal to that of p,p'-DDE. This method can only be grossly approximate, since the response of EC detection to individual FCB Isomers varies greatly [1], Risebrough et al [274] also reported the use of mlcrocoulometric detection to determine total chlorine content, using a commercial PCB mixture as a standard. Sawyer [269] compared the EC detection with the microcoulmetrlc and electrolytic conductivity detectors and found that the latter two detectors are subject to more operational problems than is the EC detection. An analytical method utilizing a computer for the quantitation of PCBs was described by Zobel [275]. This method would not be of value for routine sample analysis in industrial hygiene laboratories because of the expense or unavailability of a computer. The method of Webb and McCall [276] involves standardization of an Aroclor mixture whose peak-by-peak composition has been determined as weight percentages of the total. Since the response-to-welght factor is known for each peak, the actual weight equivalent of each peak in the sample can be calculated despite vast differences of overall GLC patterns. To utilize this method as a standard procedure, it is necessary that some 140 N 0 8 0 71 905385 agency serve ae a central repository for distribution of the reference materials. Presently, standards for A r o d o r s 1242, 1254, and 1260 as dilute solutions In lso-octane are available from Webb and McCall [276]. However, a fully characterized standard for the widely used A r o d o r 1016 is not available. Potential future sources for these types of standards may be either the Association of Official Analytical Chemists or the US Pood and Drug Administration. These organizations currently are interested In this method [277] and are planning to test it collaboratlvely. The US Environmental Protection Agency has adopted the method of Webb and McCall [276] as a recommended procedure for quantitation of PCBs in industrial effluents [278]. Other investigators have also concluded that this method is the best available method of quantitation [279]. Berg et al [280] investigated the quantitation of PCBs in terms of derivatives. PCBs could be quantitatively converted by catalytic dechlorination to bicyclohexyl. However the authors [280] found that the relatively low level of sensitivity, because bleyelohexyl had to be determined by GLC with FID, was a marked disadvantage. They [280] found that treatment of PCBs with anltmony pentachlorlde under elevated temperatures and anhydrous conditions gave good yields (85Z) of decachlorobiphenyl which could be determined by GLC with EC detection. Armour [281] evaluated the perchlorlnatlon procedure of Berg et al [280] to determine its utility as a routine method for the confirmatory quantitation' of PCBs. It was found necessary to modify that procedure because of observed inconsistencies in the efficiency of conversion of A r o d o r s 1254 (90-100Z) and 1242 (30-70Z) to decachlorobiphenyl. Armour [281] attributed this to volatilization of the lower molecular weight PCB 141 905386 K 98072 \ * component* during solvent evaporation before their reaction with antimony pentachloride. The remedy selected was to end evaporation while a small amount (0.1 ml) of solvent still remained, but this rendered the choice of solvents a more critical matter because of possible interferences during the perchlorinatlon step. Chloroform was the solvent chosen because it minimized volatility and reacted favorably at the selected conditions. The Increased pressure produced as a result of this substitution of chloroform required discontinuing use of flame-sealed Carlus tubes as recommended by Berg et al [280] for containing the elevated temperature-pressure perchlorinatlon reaction. The recommended substitute was a vacuum hydrolysis tube having the same volume specifications (10 mm O.D. X 150 mm), a tight Teflon sealing valve, and a side venting arm [281). Other modifications devised by Armour [281) Included the addition of methanol to the reaction mixture's extract to produce an azeotrope with the residual chloroform whleh could then be evaporated to a small volume before dilution, preparatory to determination of decachloroblphenyl. To determine the feasibility of a shortened reaction time, Armour et al tested iron as a catalyst, but decided that although a reaction time of 6 hours with iron catalyst resulted in quantitative (99Z average conversion for six Aroclors) and reproducible (83-110Z) conversions, the catalytic modification offered little advantage over the overnight procedure. Perchlorinatlon has been used for the quantitation of PCBs by others [282,283). While the sole perchlorinatlon product, was usually decachloroblphenyl, there have been reports of undesired byproducts resulting from contamination of the antimony pentachloride with bromide ions [284,285]. Results of NIOSH investigations Indicate that this i N 03072 905387 contamination problem can be eliminated by vacuum distillation of the antimony pentachlorlde. Factors for converting decachlorobiphenyl to A r o d o r s are presented in Table ZV-5. TABLE IV-5 FACTORS TO CONVERT DECACHLOROBIPHENYL TO AN EQUIVALENT AMOUNT OF AROCLOR Aroelor Average Molecular Weight Q* 1221 188.5 0.38 1232 223 0.45 1242 257.5 0.52 1016 257.5 0.52 1248 292 0.59 1254 326.4 0.65 1260 361 0.72 1262 395.3 0.79 ^Calculated by dividing the average molecular weight by 499, the molecular velght of decachlorobiphenyl Adapted from reference 281 From a review of the literature, NIOSH concludes that the simplest method of PCB quantitation involves standardization of samples with single commercial mixtures of PCBs. Should the composition of a sample not closely resemble that of a single commercial PCB mixture, the most accurate and precise method of quantitation available would be that of 905388 143 N 08074 perchlorination, which seems to offer the best approach for determining total PCB content in samples when the initial concentrations of individual PCBs are of little or no concern. NIOSH recommends desorption of PCBs from Florlsil with hexane, analysis by GLC, and quantitation of the sample by comparison with a standard PCB mixture of similar composition (Appendix II). If a PCB mixture with a composition similar to that of the sample is not available as a standard, NIOSH recommends converting the sample PCBs to decachloroblphenyl for quantitation. The methodology presented in Appendices I and II has been tested with Aroclor 1016 in the laboratory and in practice. Operating parsmeters found by NIOSH are presented in the Appendices. Biologic Evaluation While there is presently no adequate method for biologically monitoring industrial workers for exposure to PCBs, additional research may make feasible the routine measurement of residues of these compounds in blood or other body fluids. 08075 144 905389 V. WORK PRACTICES The employment of good work practices is required if hazardous occupational exposures to PCBs are to be prevented. The carcinogenic, teratogenic, dermatologic, and fetotoxic effects of PCBs largely determine the nature of necessary work practices. (a) All locations where occupational exposure to PCBs occurs should be established as regulated areas and posted with signs warning persons of the procedures necessary upon entering or leaving. When an otherwise closed PCB system is opened, eg, during the loading and unloading of storage tanks, the following work practices are desirable: (1) Only authorized personnel should be permitted in the area; (2) Adequate ventilation should be provided and the exhaust air should not be discharged into any environment until it has been adequately decontaminated; (3) To prevent skin contact with PCBs, workers should be required to wear and use PCB-reslstant protective clothing and equipment, including respirators. (4) Upon leaving regulated areas, workers should be required to remove such protective clothing and equipment and place it in impervious containers pending either decontamination or disposal; (5) After removing such protective clothing and equipment, workers should be required to wash their hands, forearms, and faces, and to shower after the last exposure of the day. 145 905390 Tr Whenever a worker muse come Into direct contact with PCBs, eg, during cleanup of spills or maintenance of vessels, PCB-resistant protective clothing and an appropriate respirator must be worn. (b) Leakage and Spill Procedures PCB spills are to be cleaned up promptly, either by the use of sorbent materials, such as sawdust, or by trapping and removal through pumping or other suitable means. In case of spillage of PCBs on clothing, the contaminated clothing should be removed as soon as practical, the skin should be thoroughly washed, and the clothing should be laundered or disposed of properly. Facilities and procedures for such cleanup must be provided at manufacturing facilities producing capacitors and transformers, because spills of PCBs are quite likely to occur during the filling and handling of such devices. Users of PCB-filled transformers should inspect them periodically for leakage. If leakage is found, the cause should be corrected and the spillage should be soaked up with sawdust or other absorbent material. The leak area should be cleaned finally with rags soaked with an appropriate safe solvent. Leaky transformer gaskets can be sealed temporarily by painting over the leaky area with epoxy cement. Refer to Transformer Askarel Inspection and Maintenance Guide [25], and Guidelines for Handling and Disposal of Capacitor and Transformer Grade Askarels Containing Polychlorinated Biphenyls [A] for further maintenance procedures. (c) Emergencies In emergencies, immediate measures must be taken to eliminate hazardous conditions. Non-essential workers must be evacuated until the emergency no longer exists. Any worker having visible contamination of the 146 905391 N 08077 skin with PCBs must shower immediately unless other action is warranted. (d) Respiratory Protection To ensure against inadvertent exposure to PCBs, workers' respirators must be properly selected, fitted, and maintained. A guide to industrial respiratory protection [286] has been developed which contains sufficient information to enable the establishment and maintenance of a respirator program that meets the requirements outlined in 29 CFR 1910.134. The guide [286] Includes information on respirator selection, use, maintenance, and inspection, as well as a complete description of various types of respirators and their advantages and limitations, respirator fitting procedures, wearer training instructions, and physiologic and psychologic constraints on respirator use. Several NIOSH studies [287-289] have shown that respiratory protection may be Inadequate in many occupational situations, eg, abrasive blasting, coal mining, and paint spraying. For this reason, respirators are generally regarded by NIOSH as a type of control to be used only where engineering controls cannot be used, made adequate, or provided. 905392 147 VI. DEVELOPMENT OF STANDARD Basis for Previous Standards In 1942, Che Subcommittee on Threshold Limits of the National Conference of Governmental Industrial Hygienists compiled a list of maximum permissible concentrations of atmospheric contaminants recommended by various state industrial hygiene units [290]. The eight states that made recommendations for PCBs (chlorodiphenyls) were unanimous in recommending 1 mg/cu m. No basis for the recommendations was given. Cook [291], in his 1945 listing of Maximum Allowable Concentrations of Industrial Atmospheric Contaminants, cited PCB standards for California and Utah of 1 mg/cu m and Oregon of 0.3 mg/cu m. He [291] also citedunofficial guidelines for Massachusetts of 5 mg/cu m and for New York of 1 mg/cu m and he recommended 1 mg/cu m, based on the report of Drinker [132], The American Conference of Governmental Industrial Hygienists (ACGIH) began listing PCBs (chloro di phenyl) with "toxic dusts, fumes and mists" in its recommendations of maximum allowable concentrations of air contaminants for 1946 [292], It compiled its 1946 list from its 1942 list [290] and from Cook's [291] list, and continued to recommend 1 mg/cu m for PCBs. The ACGIH continued to recommend 1 mg/cu m for PCBs (chlorodiphenyl) until 1956 when it specified 1 mg/cu m as the limit for PCBs with 422 chlorine and proposed a limit of 0.5 mg/cu m for PCBs with 542 chlorine a[293]. Each recommendation was clearly defined as threshold limit value (TLV) for an S-hour TWA concentration to which it was "felt" workers could be repeatedly exposed without adverse effect on their health. 148 n 08079 905393 In 1961, the ACGIH added the notation "skin" to the TLV of those substances, including PCBs, which in liquid form can penetrate the skin to cause systemic effects [294,295]. In 1962, the ACGIH published documentation of its TLV recommendations [296]. Based on information in the reports of Schwartz [123], Drinker et al [125], Meigs et al [190], and Treon et al [203], the ACGIH [296] concluded that for PCBs chlorinated to 42Z, 1 mg/cu m would seem to offer reasonably good protection against severe systemic toxicity but may not guarantee complete freedom from chloracne. They also cited the information [207] that PCBs could be absorbed through the skin, causing fatty degeneration of the liver. In documenting its recommendation for PCBs containing 54Z chlorine, the ACGIH [296] cited Drinker et al [125], Drinker [132], and Treon et al [203], and on the basis of these reports it [296] considered that 0.5 mg/cu m appeared to be reasonable for repeated occupational exposures. The American Industrial Hygiene Association's Hygienic Guide "Chlorodiphenyls (containing 42Z and 542 chlorine)" [297], published in 1965, adopted the ACGIH recommendations for time-weighted average exposures and suggested a short-exposure tolerance for PCBs of 10 mg/cu m to prevent unbearable irritation, based on the report of Elkins [130]. The Hygienic Guide [297] provided information that minimum lethal doses applied to the skin of rabbits for 24 hours were 1 g/kg for PCBs containing 42Z and 1.5 g/kg for PCBs containing 54Z chlorine. It also recommended avoiding prolonged or repeated skin contact, and it recommended laundering of contaminated clothing before reuse, protecting the eyes from liquid splashes, treatment of the eyes if PCBs were splashed into them, and 149 905394 * 03080 periodic examinations to detect early evidence of akin irritation or liver damage. In 1970, the International Labour Office published permissible levels of toxic substances for several nations [298]. The PCB standards for six nations are given in Table VI-1, TABLE VI-1 PERMISSIBLE LEVELS OF PCBs FOR SIX NATIONS Country Standard (mg/cu m) Type of Standard Czechoslovakia 42Z Chlorine 54Z Chlorine Finland 42Z Chlorine 54Z Chlorine Poland Romania 42Z Chlorine 54Z Chlorine USSR Tugoslavia 42Z Chlorine 54Z Chlorine Adapted from reference 298 1 .0 0.5 1 .0 0.5 0 .1 1 .0 0.5 1 .0 0.5 0.5 MAC 1 MAC 8-hour It MAC II I tt In 1975, Winell [299] compiled a list of international occupational hygienic standards for chemicals, including "chlorodiphenyl." She listed values for Sweden of 0.5 mg/cu m and for the German Democratic Republic of 1.0 mg/cu m. In both countries the standards were the same for PCBs containing 42Z and 54Z chlorine. The standards listed for the Federal Republic of Germany were 1.0 mg/cu m for PCBs containing 42Z chlorine and 150 ^ ,, N 08081 905395 0.5 mg/cu m for those with 54Z chlorine, respectively. The TLV documentations for PCBs published by the ACGIH In 1976 [300] did not differ significantly from the original documentations [296]. However, the ACGIH [300] recalled, citing von Wedel et al [205], that several deaths due to liver atrophy occurred among workers exposed to fumes of chloroblphenyls and chloronaphthalenes, but pointed out that relatively few, if any reports had appeared of sytemlc poisoning of workers exposed only to fumes of PCBs. The ACGIH has retained a TWA of 1 mg/cu m as the TLV for PCBs with 42Z chlorine concent and a TWA of 0.5 mg/cu m as the TLV for those with 54Z chlorine content (through 1976) [301]. However, a tentative short-term exposure limit (TLV-STEL) was added to the recommendations In 1976. STEL Is defined by ACGIH [299] as the maximum concentration to which workers can be exposed for up to 15 minutes continuously without suffering from irritation, chronic or Irreversible tissue change, or narcosis of sufficient degree to Increase accident proneness, impair self-rescue, or materially reduce work efficiency. According to the ACGIH [301], the STEL is to be considered a maximum allowable concentration, or absolute ceiling not to be exceeded at any time during the 15-mlnute excursion period; such excursions are not to occur more than 4 times a day and there must be at least 60 minutes between them. The STEL recommended for PCBs was 1 mg/cu m regardless of the degree of chlorination. This recommendation was made on the basis that the TLV documentation for PCBs [300] suggested that the values should be ceilings never to be exceeded, rather than TWA values for 8 hours of exposure [301]. 151 905396 w 08082 The 1968 ACGIH recommendations [302], adopted as the federal standards for PCBs (29 CFR 1910.1000, Table G-l) are TWA 8-hour exposure concentrations of 1.0 mg/cu m for mixtures containing 42% chlorine and 0.5 mg/cu m for mixtures containing 54% chlorine. Basis for the Recommended Standard (a) Permissible Environmental Limit The major effects that have been found in workers exposed to PCBs are chloracne [186-191,195,196], liver injury [190-193,196], and irritation of skin and mucous membranes [192,196,197], Exposures at peak PCB concentrations of 5-10 mg/cu m have been reported as "unbearably" irritating [130], Chloracne has been reported after occupational exposure to Aroclors 1242 [196] and 1254 [186], and to various Kanechlors [191,192,194,195], as well as after ingestion of Kanechlor 400 [146,153]. Chloracne has frequently been associated with processes where the PCBs were heated [186189,196], The methodology in most of the exposure studies did not differentiate between vapor and particulate forms of the PCBs [186,190,196]. In one study of Kanechlors in capacitor manufacturing plants where chloracne was common, vapor (or small particulate) concentrations (0.095-0.95 mg/cu m) exceeded particulate concentrations (0.02-0.65 mg/cu m) [191], In another capacitor plant where heated Aroclor 1254 was used, exposure concentrations were 5-7 mg/cu m, but the vapor components were not seperately determined [186]. In this plant, chloracne developed among workers after 4-8 months of exposure. A study of workers, in a plant where the work situation indicated the exposures were to PCB 152 N 0 8 0 8^ 3_ 905397 vapors, showed that chloracne developed after a minimum of 5 months and an average of 14 months of exposure [190], In this study, exposure concentrations of an undefined PCB were reported as 0.1 mg/cu m. In other studies where PCB concentrations were not measured, chloracne developed after 3-8 months of exposure [187,189]. These data show that chloracne can develop after prolonged exposures to PCBs In concentrations as low as 0.1 mg/cu m, and that as the PCB exposure concentrations Increase, the duration of exposure required for the development of chloracne decreases. The data also Indicate that PCBs in the vapor phase may contribute substantially to development of chloracne. However, they do not prove that only PCB vapors cause chloracne. Particulate PCBs have been shown to be absorbed from inhaled air by experimental animals [97], and ingested PCBs have caused chloracne [146,153], Occupational exposure to a variety of PCB mixtures (Aroclors 1242, and 1254, various Kanechlors, and others) has caused chloracne, and no commercial PCB mixture has been shown to have more or less chloracnegenic properties than others. There are some studies of PCB workers in which chloracne was not found [197-199]. In one of these studies, the A r o d o r 1242 concentrations were imprecisely reported [198] and In the others the PCB mixtures were undefined [199]. The report by Levy et al [197] gave possible PCB exposure concentrations of 0.013-0.264 mg/cu m and breathing zone concentrations of 0.014-0.073 mg/cu m. Thus the data Indicate that chloracne may be prevented by keeping PCB exposures below 0.1 mg/cu m (100 Mg/cu m). In some of the studies where chloracne developed, signs of liver Injury were not found [186,194,195], but in the majority of studies where 153 905398 f; 0 8 0 3 4 chloracne was found, there were alao indications of liver injury [190193,196]. Evidence of impaired liver function was found by other investigators [197] in a study where workers had not developed chloracne. Meigs et al [190] found evidence of slight liver injury in workers exposed to PCBs at 0.1 mg/cu m, and Levy et al [197] found historical evidence of liver Injury in the medical records of workers In the plant where they found exposures were <0.25 mg/cu m. Among the findings In these medical records were elevated serum triglycerides [197]. Abnormal serum triglycerides have been found In exposed workers by others [191-193], and In the Japanese people who accidentally consumed PCBs [155,157,158,175,179181]. The effect on serum triglycerides In workers was related to duration of exposure [193] and, in the workers and In the Yusho patients, to residual PCBs In the blood [175,180,193]. In the Japanese workers who were removed from exposure, the effect remained for at least 2 years [193]. Other indications of liver injury in exposed workers Included occasional findings of elevated serum enzyme activities, and abnormalities in various other liver function tests [190,191,196,197]. A level of exposure at which liver injury will not occur is not indicated by the occupational exposure studies, since evidence of liver injury has been found in the occupational studies with the lowest PCB concentrations. It is not possible to determine whether liver injury occurred with exposures at the lower levels of all the occupational exposure ranges reported, but to protect workers from any liver injury it seems that exposures should be maintained below 0.01 mg/cu m (10 jig/cu m). Animal experiments do not demonstrate a safe exposure level either. Although Treon et al [203] found no evidence of liver injury In 154 n 03035 905399 `11*fc experimental animals (rabbits guinea pigs* cats rats and mice) exposed to Aroelor 1242 at concentrations of 1.9-8.6 mg/cu m for up to 31 weeks Ouw et al [196] found evidence of liver injury in workers exposed to Aroelor 1242 at 0.32-1.44 mg/cu m. In their experiments with Aroelor 1254, Treon et al [203] found microscopic evidence of liver Injury in animals exposed at 1.5 mg/cu for 31 weeks. Linder et al [228] found Increased liver weights in rats fed Aroelor 1254 at 1 ppm for two generations. The Intake of FCBs at this dietary level can be compared to the intake from inhalation exposure at about 0.1-0.2 mg/cu m; thus the animal experiments appear to confirm indications of liver Injury in workers exposed to PCBs in this range. The combined studies of Levy et al [197], Meigs et al [190], Hasegawa et al [191], and Ouw et al [196], and the animal studies [203,228], provide further support to the conclusion that PCB exposures must be maintained at lower levels to prevent liver Injury than to prevent chloracne. Since Indications of liver Injury can be found in reports of both occupational studies [190,191,196] and animal experiments [203,228] with the lowest PCB exposure, there is no proof of an exposure level that is adequately low to prevent liver injury. The prevention of liver Injury is of particular concern because there is substantial evidence that arena oxides are formed during the metabolism of PCBs by animals [51,68,69,74,75,81,115,116,118], and the data offer no reason to suspect that humans metabolize PCBs differently from animals. PCB metabolites have been demonstrated to bind to nuclear components of hepatic cells of rhesus monkeys [51] and rats [81] and this is sufficient evidence to arouse suspicions that PCBs could be potential carcinogens in 155 905400 K 08086 the workplace. Commercial FCB preparations that have been adequately tested in rats [218,242] (Federal Register 42:6532-55, February 2, 1977) and mice [221,240,241] have been demonstrated to cause liver tumors. No liver tumors were found in rats fed A r o d o r s 1242, 1254, and 1260 at 1 ppm in the diet, but each of these mixtures produced tumors at 10 ppm (Federal Register 42;6532-55. February 2, 1977). In this same experiment a high incidence of pituitary tumors was found in PCB-fed rats. In Tusho patients [160,161], and in American workers (written communications, HA Slnclaire, June 1976; G Rouseh, September 1976), preliminary studies only indicate that the occurrence of certain cancers may be excessive. However, the findings in rats and mice demonstrate reproducible production of liver tumors after ingestion of various PCB mixtures, and NIOSH concludes that PCBs in workplace air are potential carcinogens. Additional concerns for the health of workers and their families are adverse reproductive effects [228,230,232,233], Including terete in animals fed various PCBs (FL Earl et al, written communication, 1976), and adverse effects in human and animal Infants nursed by PCB-exposed mothers [101,182,233]. PCBs resembling those in maternal blood both qualitatively and quantitatively have been found in human cord blood and in tissues of newborn humans and animals [101,138,139,168]. Fetal resorptions were common, and dose related incidences of terata were found in pups and piglets when bitches and sows were fed A r o d o r 1254 at 1 mg/kg/day or more. Terata were not found in babies of Tusho patients (maximum consumption of PCBs of about 0.15 mg/kg/day); however, many undesirable effects including low birth weights and chloracne-like lesions at birth and after nursing were found [176,182,183]. 156 n 0 80 37 905401 Based on the findings of adverse reproductive effects, on its conclusion that PCBs are potential carcinogens in humans and on its conclusion that occupational and animal studies have not demonstrated a level of exposure that will not subject the worker to possible liver Injury, N10SH recommends that the TWA concentrations of PCBs in the breathing zone of workers be maintained at or below the minimally detectable TWA concentration for up to a 10-hour workday, 40-hour workweek. NIOSH considers the minimally detectable concentration of PCBs for the monitoring of occupational exposures to be 1 yg/cu m, based on Its review of the literature and the methodology presented in Appendices I and II. Maintenance of exposures to PCBs at or below this concentration should reduce risks of reproductive and carcinogenic effects, and protect the employees from metabolic dysfunction, hepatic injury* and dermal effects due to PCB exposures during their working lifetimes. It is recognized that employees handling PCBs may have skin contact with these substances, potentially resulting In dermatologic and systemic effects. Consequently, appropriate work practices, training programs, and other measures should be required, regardless of the concentrations of airborne PCBs. Therefore, occupational exposure to PCBs has been defined as working with PCBs or with equipment containing PCBs that can become airborne or that can spill or splash on the skin or into the eyes, or the handling of any solid products that may result in exposure to PCBs by skin contact or by Inhalation. (b) Sampling and Analysis Based on an evaluation of the literature and on Its own studies, NIOSH recommends sampling and analysis for PCBs as detailed in Appendices I 157 905402 : 08088 and II. Florlsil has been selected as Che solid sorbent for PCBs because It will collect vapors as veil as particulates and PCBs can be quantitatively recovered from It. The recommended Florlsil sampling tubes have been shown to have an adequate sorption capacity (at least 100 u g ) for monitoring occupational exposures at the recommended limit for up to a 10hour workday. NIOSH has used the sampling method for monitoring TWA occupational exposures at 10-250 n g / c u m [197,244] by sampling at about 200 ml/mlnute for the entire workday. Total sample volumes of up to 100 liters were collected. At 1 pg/cu m, 100 liters of air would contain 100 ng of PCBs. The lower limit of PCB detection by GLC with EC detection was found to be 32 pg/4-yl Injection. Since the contents of the Florlsil tubes are dissolved In 5 ml of solvent, this represents a total of 40 ng of adsorbed PCBs. Although NIOSH recommends sampling at 200 ml/mlnute, It may be feasible to use pumps that sample at faster, rates if there are analytical difficulties with samples of about 100 liters due to low concentrations of PCBs. (c) Medical Surveillance Occupational exposure to PCBs has been shown to cause signs of liver injury and Impaired liver function. Ouw et al [196], Hasegawa et al [191], and Levy et al [197] all found occasional incidents of elevated serum enzymes; exposure conditions under which these will not occur are not known. Therefore, NIOSH recommends determination of SGOT and SGPT Initially and at annual Intervals. The responsible physician may also wish to determine serum triglyceride concentrations since these have been found to be abnormal in some workers chronically exposed to PCBs [191-193,197]. Especially, elevated serum triglyceride concentrations have been found to i ca 905403 N 08089 be related to duration of exposure and to the concentration of residual FCBs in the blood [193]. Although the data indicate that the recommended standard will prevent chloracne, it is not known that it will prevent other skin ailments. NIOSH recommends that in comprehensive physical examinations, special emphasis be given to the condition of the skin. PCBs fed to bitches and sows have been found to be teratogenic (FL Earl et al, written communication, 1976). Although terata have not been observed in human babies whose mothers had been exposed to PCBs [176,182,183], PCBs have been found in human embryos and fetuses [138,139,168], and undesirable effects (abnormal skin color and low birth weights) have been observed in neonates [176,182,183] born after their mothers had ingested PCBs. A woman who was occupationally exposed to PCBs had a blood PCB concentration of 25 ppb when her normal baby was b o m [195]. NIOSH considers that its recommended standard will protect unborn babies but recommends that women exposed to PCBs at work be advised of the potential hazards of PCB exposure to unborn children. PCBs have been found in milk of women who have been exposed tb PCBs [168,195] and babies have been adversely affected after being nursed by > PCB-exposed mothers [182]. A safe level of PCBs in the milk of mothers occupationally exposed to PCBs is not known. Human milk samples in the general US population usually contain detectable amounts of PCBs, and about one-third of the whole milk samples have been found to contain >50 ppb and up to about 350 ppb (EP Savage, written communication, February 1977). It is not known if all the mothers from whom these samples were taken nursed their babies without effect. Infant monkeys who were nursed by mothers 905404 159 X 0 8 0 9 0 in their milk et 150-350 ppb became sick and developed chloracne [23A], After conaultation, the woman who waa occupationally expoaed to PCBs and who had PCBa in her milk at about 250 ppb, stopped nursing her baby out of concern for its health [195], Based on these considerations, NIOSH recommends that women working with PCBs be counseled concerning the advisability of nursing their babies. (d) Personal Protective Equipment and Clothing PCBs applied to the skin or cornea of experimental animals have been shown to cause local lesions and liver and kidney injuries [205-208,225], One worker who developed chloracne after 3 months of exposure to PCBs was described as having frequently Immersed his hands in the PCB mixture and his clothes were described as often being impregnated with PCBs [189].Employees working with an askarel containing 60% Aroclor 125A frequently developed skin rashes which were considered by the company physician to be allergic or contact dermatitis from the askarel (In the Matter of General Electric Company, File No. 2833, New York State Department of Environmental Conservation, 1975). Other complaints of these workers that were ascribed to the askarel included irritation of the eyes, nose and throat. Levy et al [197] and Ouw et al [196] found that employees exposed to PCBs at 0.0130.26A mg/cu m and 0.32-l.AA mg/cu m, respectively, complained of similar irritations and, on examination, there were findings of skin rashes and nasal irritation. Ouw et al [196] considered that one reason the blood PCB concentrations in workers they studied did not decline (after improvements in the ventilation system had reduced the environmental concentrations of PCBs) was because the workers did not comply with the recommendations for protecting their skin from PCB contact. 160 905405 Based on those reports [189,196,197,205-208,225], NIOSH recommends that employees working In situations where skin contact may occur be provided with clothing that Is Impervious to PCBs and that will cover all body surfaces where contact may occur. To prevent splashing PCBs Into the eyes, NIOSH recommends that employees wear appropriate goggles or safety glasses In accordance with 29 CFR 1910.133 and ANSI Z87.1-1968. Since NIOSH has found PCBs to be potential carcinogens and recommends that exposures be maintained at or below 1 pg/cu m, It considers that only a self-contained breathing apparatus with a full facepiece operated In the positive-pressure mode will provide adequate protection when workers are In areas where higher concentrations exist. Based on NIOSH studies [287-289], other respiratory protective devices are not considered adequate to provide the needed protection. (e) Other Considerations Engineering controls are recommended to maintain PCBs In closed systems to reduce exposures to the extent feasible. Such a recommendation is consistent with the Toxic Substances Control Act (Public Lav 94-469) and with the need to protect employees from exposure to PCBs. However, there are situations, such as In accidental leakage from closed systems and in repair of equipment, when PCBs may not be confined. The recosmtended standard prescribes general work practices for PCBs as well as emergency work practices. Employees should be informed of the hazards of working with PCBs, and trained In the recommended general work practices and the procedures to follow In emergencies. The advantages to their health of complying with the work practices and medical monitoring requirements of the recommended standard should be explained to the employees. As Ouw et 161 905406 N 03092 al [196] pointed out, Improving air quality does not go far In alleviating the workers' body burdens of PCBs without their cooperation in Implementing the recommendations for protecting their skin from PCB contact. NIOSH also recommends certain sanitation practices to minimize intake of PCBs by employees. Among these practices Is the requirement that employees be provided with clean work clothing daily and that they change clothing before leaving work. The Importance of this measure to the employee and the employee's family Is exemplified In finding up to 180 ppm of PCBs in the dust of PCB-workers' homes [36]. PCBs may remain In contaminated premises for years [33]. Partly for the same reason, and because PCBs in contact with the skin can be irritating [196,197] and also because they have caused systemic effects in experimental animals [205208,225], NIOSH recommends that workers shower before leaving work. Toxic effects from Ingestion of PCBs have been well documented in humans [145-185] and experimental animals [101,209-224,226-237,240-248]. Workers may have an Intake of PCBs from their normal diet of 10-20 pg/day [46], and the maximum additional Intake expected from NIOSH'a recommended allowable work exposures might be of the order of 10 pg. NIOSH recommends that workers wash their hands before eating and that food, drinks, and smoking materials not be permitted in PCB work areas. The Importance of this recommendation may be evaluated by considering that one drop of PCBs spilled on food, in drinks, or otherwise conveyed into the mouth may contain about 50 jig of PCBs, compared to a total Intake of 20-30 n g from other sources, including allowable occupational exposures. Because the consequences of working with PCBs may be substantial, NIOSH recommends that entry Into PCB work areas be restricted to authorized 162 905407 employee* whoee entry 1* logged dally, and whose exposures are monitored at least annually to ensure that airborne exposures are at or below the recommended TWA limit. 905408 163 N 08094 VII. RESEARCH NEEDS There le e cleer need for lnforaeelon in the following ereee: (a) The effects of chronic exposure of animals and humans to PCBs at low concentrations require investigation. Epidemiologic studies of occupational groups and information on concentrations of PCBs in workroom air and any related clinical findings would be useful. (b) Chronic exposures of animals to PCBs at concentrations in the range of the recommended environmental limit. (c) Studies of the reproductive histories of women who have been exposed to PCBs in their occupational environments, Including studies of status and development of Infants b o m to these women. (d) The absorption efficiencies of various PCB mixtures by the dermal and respiratory routes. (e) The method of transport of PCBs in the blood and the partition between blood on the one hand, and fat stores and milk on the other. (f) A problem that confounds our understanding of the toxicity of PCBs is that of the toxic activity of contaminants associated with PCBs. The contaminants found in commercially important PCB products should be identified, prepared in pure form and studied toxieologically both as individual substances and as mixtures with other, related compounds. (g) Studies regarding methods of removing PCBs from the skin (cleansing). (h) Studies on the use of various barrier creams as a means of minimizing dermal exposure to PCBe. 164 905409 i s(1) There uncertainty regarding baseline values for PCBs In the blood of humans; research should be conducted to determine baseline values for the general population and for non-exposed Industrial populations. 165 905410 'f 0 8 0 9 6 VIII. REFERENCES 1. Hut Zinger 0, Safe S, Zltko V: The Chemistry of PCBs. Cleveland, The Chemical Rubber Co Press, 1974, pp 3,4,7-9,22,23,197-220,243-48 2. Mieure JP, Hicks 0, Kaley RG, Saeger VW: Characterization of Polychlorinated Biphenyls, In Proceedings of the National Conference on Polychlorinated Biphenyls, November 19-21, 1975, Chicago, EPA560/6-75-004. US Environmental Protection Agency, Office of Toxic Substances, 1976, pp 84-93 3. Kuratsune M (ed): Environmental Health Criteria for Polychlorinated Bi- and Terphenyls-- WHO Environmental Health Criteria Programme (Japanese document to World Health Organization). 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Med d Lavoro 45:131-45, 1954 (Ita) 187. Hofmann MF, Meneghini CL: [Concerning folllculosls caused by chlorosubstituted hydrocarbons.] G Ital Dermatol Sifilol 103:42750, 1962 (Ita) 180 N 0 3 1 ' ' " ' 905425 188. Birmingham DJ: Occupational dermatology-- Current problme. Skin 3:38-42, 1964 189. Oliver NE: Chloracne. Arch Dermatol 99:127-28, 1969 190. Meiga JW, Albom JJ, Kartin BL: Chloracne from an unusual exposure to Arochlor. JAMA 154:1417-18, 1954 191. Hasegava H, Sato M, Tsuruta H: [Report on survey of work area environment where PCB is handled and of the health of workers handling PCB, in Special Research Report on Prevention of Environmental Pollution by PCB-llke Substances.] Japan, Research Co ordination Bureau, Science and Technology Agency, 1972, pp 141-99 (Jep) 192. Hara Z, Harada A, Kimura S, Endo T, Kawano K: [Follow-up study of condenser factory after use of PCB discontinued (Part I).] Jpn J Ind Health 16:365,366, 1974 (Jap) 193. Hara et al: [Follow-up study of condenser factory after use of PCB discontinued (Part III).] Jpn J Ind Health 17:371,372, 1975 (Jap) 194. Kitamura M, Tsukamoto T, Sumino R, Hayakawa K, Shibata T, Hirano I: [PCB in blood of workers employed in an electrical parts manufacturing plant.] Jpn J Ind Health 15:539, 1973 (Jap) 195. Inoue Y et al: [Discovery of PCB pollution in a textile factory-- I. PCB level in blood serum of laborers and results of physical examination.] Jpn J Public Health 22:461-63, 1975 (Jap) 196. Ouw HK, Simpson GR, Siyall DS: The use and health effects of A r o d o r 1242, a polychlorinated biphenyls in an electrical industry* Arch Environ Health 31:189-94, 1976 197. Levy BSB, Meyer CR, Lowry L, Smallwood A: Health Hazard Evaluation Determination Report No. 76-52-386, Hazard Evaluation Services Branch, Division of Technical Services, Westinghouse Electric Corporation, Bloomington, Indiana. Cincinnati, US Dept Health, Education, and Welfare, Center for Disease Control, -National Institute for Occupational Safety and Health, April 1977, 17 pp 198. Karppanen E, Kolho L: The concentration of PCB in human blood and adipose tissue in three different research groups, in PCB Conference II, Stockholm, 1972. Solna, Sweden, National Swedish Environment Protection Board/Publications 1973:4E, pp 124-28 199. Bumgarner JE, Hammer DI, Colucci AV, Creason JP, Flnklea JF: Polychlorinated biphenyl residues in refuse workers. Research Triangle Park, NC, US Dept Health, Education, and Welfare, Public Health Service, National Institute of Environmental Health Sciences, June 1973, 10 pp 181 N 03112 905426 200. Cutler SJ, Young JL Jr: Third National Cancer Survey-- Incidence Data, Monograph 41. US Dept Health, Education, Welfare, Public Health Service, National Institutes of Health, National Cancer Institute, March 1975, pp 10-24 201. Bahn AK, Rosenwaike I, Herrmann N, Grover P, Stellman J, O'Leary K: Melanoma after exposure to PCBs. N Engl J Med 295:450, 1976 " 202. Rozanova LF: [Toxicity of some chlorinated aromatic hydrocarbons.] Farmakol Tokslkol 6(6):48-53, 1943 (Rus) *"203. Treon JF, Cleveland FP, Cappel JW, Atchley RW: The toxicity of the vapors of A r o d o r 1242 and A r o d o r 1254. Am Ind Hyg Q 17:204-13, 1956 204. Hunter B, Batham F, Heywood R, Street AE, Cherry CP: Decachlorodlphenyl toxicity to rats-- Dietary administration for 4 weeks. Huntingdon, England, Huntingdon Research Centre, May 1974, 53 PP '205. Von Wedel 1^, Holla WA, Denton J: Observations on the toxic effects resulting from exposures to chlorinated naphthalene and chlorinated phenyls with suggestions for prevention. Rubber Age 54:419-26, 1943' '206. Miller JW: Pathologic changes In animals exposed to a commercial chlorinated diphenyl. Public Health Rep 59:1085-93, 1944 L207. Peribok VP: [Effects of chlorinated diphenyl (sovol) on the skin and Its resorption.] Farmakol Tokslkol 17:51-54, 1954 (Rue) 208. Vos JG, Beems RB: Dermal toxicity studies of technical polychlorinated biphenyls and fractions thereof In rabbits. Toxicol Appl Pharmacol 19:617-33, 1971 209. Vos JG, De Roij T: Immunosuppressive activity of a polychlorinated biphenyl preparation on the humoral immune response in guinea pigs. Toxicol Appl Pharmacol 21:549-55, 1972 210. Vos JG, Van Drlel-Grootenhuls L: PCB-induced suppression of the htsBoral and cell-mediated immunity In guinea pigs. Sel Total Environ 1:289-302, 1972 211. Bruckner JV, Khsnna KL, Cornish HH: Biological responses of the rat to polychlorinated biphenyls. Toxicol Appl Pharmacol 24:434-48, 1973 212. Bruckner JV, Khanna KL, Cornish HH: Effect of prolonged Ingestion of polychlorinated biphenyls on the rat. Pd Cosmet Toxicol 12:323-30, 1974 213. Bruckner JV, Khanna KL, Cornish HH: Polychlorinated biphenyl-induced alteration of biologic parameters In the rat. Toxicol Appl Pharmacol 28:189-99, 1974 182 K 0BV I3 905427 214. Litterst CL, Farber TM, Baker AM, Van Loon EJ: Effect of polychlorinated biphenyl* on hepatic microsomal enzymes in the rat. Toxicol Appl Pharmacol 23:112-22, 1972 215. Kimbrough RD, Linder RE, Gaines TB: Morphological changes in livers of rats fed polychlorinated biphenyls. Arch Environ Health 25:35464, 1972 216. Allen JR, Abrahamson U : Morphological and biochemical changes in the liver of rats fed polychlorinated biphenyls. Arch Environ Contam Toxicol 1:265-80, 1973 217. Hansell MM, Eeoblchon DJ: Effects of chemically pure chloroblphenyla on the morphology of rat liver. Toxicol Appl Pharmacol 28:418-27, 1974 218. Kimbrough RD, Squire RA, Linder RE, Strandberg JD, Montaill RJ, Burse VW: Induction of liver tumors In Sherman strain female rats by polychlorinated biphenyl A r o d o r 1260. J Natl Cancer Inst 55:145359, 1975 219. Kimbrough RD, Linder RE, Burse VW, Jennings RW: Adenofibrosis in the rat liver-- With perslstance of polychlorinated biphenyls In adipose tissue. Arch Environ Health 27:390-95, 1973 220. Kimbrough RD: Brief communication: Pancreatlc-type tissue In livers, of rats fed polychlorinated biphenyls. J Natl Cancer Inst 51:679-81, 1973 221. Kimbrough RD, Linder RE: Induction of adenofibrosis and hepatomas of the liver In BALB/cJ mice by polychlorinated biphenyls (Arodor 1254). J Natl Cancer Inst 53:547-52, 1974 222. Allen JR, Abrahamson LJ, Norback DH: Biological effects of polychlorinated biphenyls and triphenyls on the subhuman.'..primate. Environ Res 6:344-54, 1973 223. Bell M: Ultrastructural Features of Gastric Mueosa and Sebaceous Glands After Ingestion of A r o d o r 1242 by Rhesus Monkeys, In Proceedings of the National Conference on Polychlorinated Biphenyls, November 19-21, 1975, Chicago, EPA 560/6-75-004, US Environmental Protection Agency, Office of Toxic Substances, 1976, pp 350-58 224. Allen JR, Norback DH: Polychlorinated biphenyl-end trlphenylInduced gastric mucosal hyperplasia In primates. Science 179:498-99, 1973 225. Vos JG, Notenboom-Ram E: Comparative toxicity study of 2,4,5,2',4*,5'-hexachloroblphenyl and a polychlorinated biphenyl mixture in rabbits. Toxicol Appl Pharmacol 23:563-78, 1972 905428 183 N 03114 226. Allen JR, Cartens LA, Abrahamson LJ, Marlar RJ: Responses of rats and nonhuman primates to 2,5,2',5'-tetrachlorobiphenyl. Environ Res 9:265-73, 1975 227. Torok P: Delayed pregnancy in NMRI mice treated with PCB-- 2,2'dichloroblphenyl. Bull Environ Contam Toxicol 16:33-36, 1976 228. Linder RE, Gaines TB, Kimbrough RD: The effect of polychlorinated biphenyls on rat reproduction. Fd Cosmet Toxicol 12:63-77, 1974 229. VilleneuveDC, Grant DL, Phillips WEJ, Clark ML, Clegg DJ: of PCB administration on microsomal enzyme activity in rabbits. Bull Environ Contam Toxicol 6:120-28, 1971 Effects pregnant 230. Villeneuve DC, Grant DL, Khera K, Clegg DJ, Baer H, Phillips WEJ: The fetotoxldty of a polychlorinated biphenyl mixture (Aroclor 1254) in the rabbit and in the rat. Environ Phys 1:67-71, 1971 231. Grant DL, Villeneuve DC, McCully KA, Phillips WEJ: Placental transfer of polychlorinated biphenylsin the rabbit. Environ Physiol 1:61-66, 1971 232. Allen JR, Carstens LA, Barsotti DA: Residual effects of short-term, low-level exposure of nonhuman primates to polychlorinated biphenyls. Toxicol Appl Pharmacol 30:440-51, 1974 233. Barsotti DA, Marlar RJ, Allen JR: Reproductive dysfunction in Rhesus monkeys exposed to low levels of polychlorinated biphenyls (Aroclor 1248). Fd Cosmet Toxicol 14:99-103, 1976 234. Allen JR, Barsotti DA: The effects of transplacental and mammary movement of PCBs on infant rhesus monkeys. Toxicology 6:331-40, 1976 235. Dikshith TSS, Rockwood W, Abraham R, Coulston F: Effects of a polychlorinated biphenyl (Aroclor 1254) on rat testis. Exp Mol Pathol 22:376-85, 1975 236. Green S,Carr JV, Palmer KA, Oswald EJ: Lack of cytogenetic effects in bone marrow and spermatagonialcells in rats treated with polychlorinated biphenyls (Aroclor 1242 and 1254). Bull Environ Contam Toxicol 13:14-22, 1975 237. Green S, Sauro FM, Friedman L: Lack of dominant lethality in rats treated with polychlorinated biphenyls (Aroclors 1242 and 1254). Fd Cosmet Toxicol 13:507-10, 1975 238. Hoopingarner R, Samuel A, Krause D: Polychlorinated biphenyl interactions with tissue culture cells. Environ Health Perspect, Experimental Issue No. 1, April 1972, pp 155-58 (4 08115 184 905429 239. Popper H, Czygan P, Grain H, Schaffner F, Garro AJs Mutagenicity of prlnary and secondary carcinogens altered by normal and Induced hepatic microsones (37103). Proc Soc Exp Biol Med 142:727-29 1973 240. Nagasaki H, Tomll S, Mega T, Marugaml M, Ito N: Hepatocarcinogenicity of polychlorinated biphenyls In mice. Gann 63:805, 1972 241. Ito N, Nagasaki H, Aral M, Makiura S, Suglhara S, Hlrao K: Histopathologic studies on liver tumorlgenesls Induced in mice by technical polychlorinated biphenyls and its promoting effect on liver tumors Induced by benzene hexaehlorlde. J Natl Cancer Inst 51:163746, 1973 242. Klmura NT, Baba T: Neoplastic changes In the rat liver Induced by polychlorinated biphenyl. Gann 64:105-08, 1973 243. Stalff DC, Qulnby GE, Spencer DL, Starr HG Jr: Polychlorinated biphenyl emission from fluorescent lamp ballasts. Bull Environ Contam and Toxicol 12:455-63, 1974 244. Jones M, Becker J: Industrial Hygiene Survey of the Polychlorinated Biphenyl Production Operation, Monsanto Industrial Chemicals Company, Sauget, Illinois. Cincinnati, Dept of Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, May 1977, 10 pp 245. Tatsukava R: PCB pollution of the Japanese environment, in Higuchl K (ed): PCB Poisoning and Pollution. New York Academic Press, 1976, pp 147-79 246. American National Standard: Fundamentals Governing the Design and Operation of Local Exhaust Systems, ANSI Z9.2-1971. New York, American National Standards Institute, 1972, 63 pp 247. Durfee RL, Contos G, Whitmore FC, Barden JD, Hackman EE III, Westln RA: PCBs in the United States-- Industrial Use and Environmental Distribution, EPA 560/6-76-005, US Environmental Protection Agency, Office of Toxic Substances (PB-252 012) 1976, pp 10,15,16,18,19, 74,75,88,147 248. Bldleman TF, Olney CE: High-volume collection of atmospheric polychlorinated biphenyls. Bull Environ Contam Toxicol 11:442-50, 1974 249. Nlahiyama K, Yano H, Kavano M: [Determination of polychloroblphenyl in air and its vaporization from noncarbon copy paper.] Shikoku Acta Med 29:305-10, 1974 (Jap) (Abst.) 185 905430 N 08116 250. Waklmoto T, Tatsukawa R, Ogava T, Watanabe I: Determination of organochlorine pesticides and PCB (polychlorinated biphenyl) in air by the dry column collection method. Bunseki Kagaku 23: 790-93, 1974 (Abet.) 251. Harvey GR, Steinhauer WG: Atmospheric transport of polychlorobiphenyls to the North Atlantic. Atmos Environ 8:777-82, 1974 252. Glam CS, Chan HS, Neff GS: Rapid and inexpensive method for detection of polychlorinated biphenyls and phthalates in air. Anal Chem 47:2319-20, 1975 253. Laveskog A, Lindskog A: Chlorinated hydrocarbons in the atmosphere. Chem Ing Tech 48:65, 1976 (Synopsis) 254. NIOSH Standards Completion Program: Chlorodlphenyl (542 Chlorine), Method No. SI21. Cincinnati, US Dept Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, 1976, 15 pp 255. NIOSH Standards Completion Program: Chlorodlphenyl (422 Chlorine), Method No. S120, Failure Report. Cincinnati, US Dept Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, 1976, 7 pp 256. Fishbeln L: Chromatographic and biological aspects of polychlorinated biphenyls. J Chromatogr 68:345-426, 1972 257. Fishbeln L: Chromatography of Environmental Hazards, Vol II. New York, Elsevier Scientific Publishing Co, pp 529-77, 1973 258. Interdepartmental Task Force on PCBs: Polychlorinated Biphenyls and the Environment, Report No. ITF-PCB-72-1, Springfield, Va, US Dept of Commerce, National Technical Information Service, CGM-72-10419, 1972, pp 23-40 259. Oswald EOj Albro PW, McKinney JD: Utilization of gas-liquid chromatography coupled with chemical lonizatron and electron impact mass spectrometry for the investigation of potentially hazardous environmental agents and their metabolites. J Chromatogr 98:363-448, 1974 260. Cook JW: Some chemical aspects of polychlorinated biphenyls (PCBs). Environ Health Perspect, Experimental issue No* 1, April 1972, pp 3- 13 261. Saroflm AF: PCBs-- Environmental Impact-- Analytical Methods. Environ Res 5:338-62, 1972 N 03117 186 905431 262. Sherma J: Gas-chromatography analyfis of polychlorinated biphenyls and other nonpesticide organic pollutants. Adv Chromatogr 12:141-76, 1975 263. Koeman JH, Ten Noever De Brauw MC, De Vos RH: Chlorinated biphenyls in fish, mussels and birds from the river Rhine and the Netherlands coastal area. Nature 221:1126-28, 1969 264. Skrentny RF, Hemken RW, Dorough HW: Silo sealants as a source of polychlorobiphenyl (PCB) contamination of animal feed. Bull Environ Contain Toxicol 6:409-16, 1971 265. Zitko V: Polychlorinated biphenyls and organochlorine pesticides in some freshwater and marine fishes. Bull Environ Contam Toxicol 6:464-70, 1971 266. Kell JE, Prleater LE, Sandlfer SB: Polychlorinated biphenyl (Arodor 1242)-- Effect of uptake on growth, nucleic acids, and chlorophyll of a marine diatom. Bull Environ Contam Toxicol 6:156-59, 1971 267. Hansen DJ, Parrish PR, Lowe JI, Wilson AJ Jr, Wilson PD: Chronic toxicity, uptake, and retention of A r o d o r 1254 in two estuarine fishes. Bull Environ Contam Toxicol 6:113-19, 1971 268. Collins 6B, Holmes DC, Jackson FJ: The estimation of polychlorobiphenyla. J Chromatogr 71:443-49, 1972 269. Sawyer LD: Collaborative study of tha recovery and gas chromatographic quantitation of biphenyl-DDT combinations in fish. J Assoc Off Anal Chem 56:1015-23, 1973 270. Flnsterwalder CE: Collaborative study of the determination of polychlorinated biphenyls in paperboard. J Assoc Off Anal Chem 57:518-21, 1974 271. Beezhold FL, Stout VF: The use and effect of mixed standards on the quantitation of polychlorinated biphenyls. Bull Environ Contam Toxicol 10:10-15, 1973 272. Pesticide Residues, in Horvitz W, Senzel A, Reynolds H, Park DL (ads): Official Methods of Analysis of the Association of Analytical Chemists, ed 12. Association of Official Analytical Chemists, 1975, pp 518-28 273. Rote JW, Murphy PG: A method for the quantitation of polychlorinated biphenyl (PCB) isomers. Bull Environ Contam Toxicol 6:377-84, 1971 274. Rlsebrough RW, Relche P, Olcott HS: Current progress in the determination of polychlorinated biphenyls. Bull Environ Contam Toxicol 4:192-201, 1969 905432 187 N 08118 275. Zobel MGR: Quantitative biphenyls-- A computer approach. 1974 determination of J Assoc Off Anal polychlorinated Cham 57:791-95, 276. Webb RG, McCall AC: Quantitative PCB standards for electron capture gas chromatography. J Chromatogr Sci 11:366-73, 1973 277. Burke JA: Report on chlorinated pesticides. J Assoc Off Anal Chem 59:338-40, 1976 278. Method for Polychlorinated Biphenyls (PCBs) in Industrial Effluents. Cincinnati, Environmental Protection Agency, Environmental Monitoring Support Laboratory, 1976, 40 pp 279. Chau AST, Sampson RCJ: Electron capture chromatographic methodology for the quantitation of polychlorinated biphenyls-- Survey and compromise. Environ Lett 8:89-101, 1975 280. Berg OW, Dlosady PL, Rees GAV: Column chromatographic separation of polychlorinated biphenyls from chlorinated hydrocarbon pesticides, and their subsequent gas chromatographic quantitation in terms of derivatives. Bull Environ Contam Toxicol 7:338-47, 1972 281. Armour JA: Quantitative perehlorlnatlon of polychlorinated biphenyls as a method for confirmatory residue measurement and identification. J Assoc Off Anal Chem 56:987-93, 1973 282. Hutzlnger 0, Safe S, Zitko V: Analysis of chlorinated aromatic hydrocarbons by exhaustive chlorination-- Qualitative and structural aspects of the perchloro-derlvatives of biphenyl, naphthalene, terphenyl, dlbenzofuran, dlbenzodioxin and DDE. Int J Environ Anal Chem 2:95-106, 1972 283. Mizutanl T, Matsumoto M: Determination of polychlorinated biphenyls by an exhaustive chlorination method. Shokuhln Elselgaku Zasshi 13:398-404, 1972 (Abst.) 284. Huckins JN, Swanson JE, Stalling DL: Perehlorlnatlon of polychlorinated biphenyls. J Assoc Off Anal Chem 57: 416-17, 1974 285. Trotter WJ, Young SJV: Limitation on the use of antimony pentachloride for perehlorlnatlon of polychlorinated biphenyls. J Assoc Off Anal Chem 58:466-68, 1975 286. Pritchard JA: A Guide to Industrial Respiratory Protection, No. NIOSH 76-189. Cincinnati, US Dept Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, 1976, 150 pp N 03119 188 905433 287. Blair A: Abraaive Blasting Respiratory Protective Practices, No. NIOSH 74-104. Cincinnati, US Dept Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, 1974, 116 pp 288. Harris HE: Coal Mine Dust Respiratory Protective Devices, Final Report Prepared by the Eastern Associated Coal Corporation for NIOSH Contract No. CPE 70-127. Cincinnati, US Dept Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, 1974, 221 pp 289. Toney CR, Barnhart WL: Performance Evaluation of Respiratory Protective Equipment Used in Paint Spraying Operations, NIOSH No. 76-177. Cincinnati, US Dept Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, 1976, 110 pp '290. National Conference of Governmental Industrial Hygienists: Report of the Subcommittee on Threshold Limits, in Transactions of the 5th Annual Meeting, NCGIH, Washington, April 9, 10, 1942, pp 163,164 *291. Cook WA: Maximum allowable concentrations of industrial atmospheric contaminants. Ind Med 14:936-46, 1945 '292. American Conference of Governmental Industrial Hygienists: Report of the Sub Committee on Threshold Limits, in Proceedings of the 8th Annual Meeting, ACGIH, Chicago, April 7-13, 1946, pp 54-56 ' 293. American Conference of Governmental Industrial Hygienists: Report of the Committee on Threshold Limits, in Transactions of the 18th Annual Meeting, ACGIH, Philadelphia, April 21-24, 1956, pp 70,72,73,76,78 ` 294. American Conference of Governmental Industrial Hygienists: Report of Committee on Threshold Limits, in Transactions of the 23rd Annual Meeting, ACGIH, Detroit, April 9-12, 1961, pp 120-22 * 295. American Conference of Governmental Industrial Hygienists: Threshold Limit Values for 1961, Adopted at the 23rd Annual Meeting, ACGIH, Detroit, April 9-12, 1961. Cincinnati, ACGIH, 1961, p 8 .296. American Conference of Governmental Industrial Hygienists, Committee on Threshold Limit Values: Documentation of Threshold Limit Values, ed 1. Cincinnati, ACGIH, 1962, pp 26,27 297. Chlorodlphenyls (containing 42Z and 54% chlorine), in Hygienic Guide Series. Am Ind Hyg Assoc J 26:92-94, 1965 298. Permissible levels of Toxic Substances in the Working Environment-- 6th Session of the Joint ILO/WHO Committee on Occupational Health, Geneva, June 4-10, 1968, Occupational Safety and Health Series No. 20. Geneva, International Labour Office, 1970, pp 182-87, 197,204,223,231,331,346 189 ' 905434 N 03120 299. Wlnell M: An International comparison of hygienic standards for chemicals in the work environment. Ambio 4:34-36t 1975 300. American Conference of Governmental Industrial Hygienists: Documentation of the Threshold Limits of Substances in Workroom Air, ed 3. Cincinnati, ACGIH, 3rd printing 1976, pp 51,52 301. American Conference of Governmental Industrial Hygienists: Report of the ACGIH Committee on Threshold Limits for the Air of Workplaces, in Transactions of the 38th Annual Meeting, ACGIH, Atlanta, May 17-21, 1976, pp 27,28,30-36,158-60,164,184 * 302. American Conference of Governmental Industrial Hygienists: Threshold Limit Values for 1968-- Recommended and Intended Values, Adopted at the 30th Annual Meeting, ACGIH, St. Louis, May 13, 1968, pp 1,3,5,7 'v N 03121 190 905435 IX. APPENDIX I SAMPLING PROCEDURE FOR COLLECTION OF POLYCHLORINATED BIPHENYLS General Requirements (a) Air samples representative of the breathing zones of workers must be collected to determine the exposure from each job or from the specific operation in each work area. (b) Suggested records: (1) Date and time of sample collection; (2) Pump model and serial number; (3) Sample tube type and number; (A) Sampling duration; (5) Total sample volume; (6) Location of sampling; (7) Temperature, pressure, and relative humidity at time of sampling; (8) Other pertinent information. Calibration Since the accuracy of environmental sampling can be no greater than the accuracy of the air volume measurement, the accurate calibration of the sampling pump is essential to the correct estimation of the volume of the sample thet is collected. The required frequency of calibration is dependent on the use, care, and handling to which the pump is subjected. Pumps should be calibrated initially and recalibrated if misused or 191 905436 N 08122 repaired. If pumps receive hard usage more frequent calibration may be necessary. Regardless of use, maintenance and calibration should be performed on a regular schedule and records of these should be kept. The accuracy of calibration depends on the type of instrument used as a reference. The choice of calibration instrument will depend largely upon where the calibration is to be performed. Ordinarily, pumps should be calibrated in the laboratory. For laboratory testing, primary standards, such as a spirometer or a soapbubble meter, are recommended, although other standard calibration instruments, such as a vet-test meter or dry gas meter, can be used. The calibration setups will be similar for all instruments. Instructions for calibration with the soapbubble meter follow. If another calibration device is selected, equivalent procedures should be used. Since thezflowrate of a pump depends on the pressure drop across the sampling device, in this case a "Florisil" tube, the pump must be calibrated while operating with a representative tube in line. The calibration system should be assembled in series following this order: soapbubble meter, water manometer, Florisil tube, and pump. (a) Check the voltage of the pump battery with a voltmeter to ensure adequate voltage for calibration, and change or charge the battery if necessary. (b) Turn on the pump and moisten the inside of the soapbubble meter by immersing the buret in the soap solution and drawing bubbles up the inside until they travel the entire buret length without bursting. (c) Adjust the pump rotameter to provide the desired flowrate. N 08123 192 905437 *4-. (d) Cheek the water manometer to ensure that the pressure drop across the sampling train does not exceed 2.5 inches of water at 0.2 liter/minute. (e) Start a soapbubble up the buret and measure with a stopwatch the time required for it to move between calibration marks. (f) Repeat procedure (e) at least twice, average the results, and calculate the flowrate from the volume between the preselected marks divided by the time required for the soapbubble to traverse the distance. (g) Record the volume measured, elapsed time, pressure drop, air temperature, atmospheric pressure, serial number of pump, date, time, and name of person performing the calibration. (h) The rotameter reading should be corrected for temperature and pressure, if necessary. Sampling (a) Samples should be collected as near as practicable to the faces of workers without Interfering with freedom of movement. (b) Samples should be collected to permit determination of TWA exposures for every job involving exposure to PCBs and in sufficient numbers to express the variability of the exposures in the work situation. (c) Apparatus for Breathing Zone Sampling (1) Pump, battery-operated, with clip for attachment to the worker's clothing. Airflow through the pump should be controlled within 5% of the desired rate during the entire sampling period. (2) Sorbent Tubea Glees tubes at least 7 cm long with 4 mm I.D. and containing 1,3 905438 n 08124 two sections of 30/A8 mesh deactivated Florisil. (Florisil, 30/60 mesh, is sieved to the proper mesh size.) The front section, preceded by a glass wool plug, contains 100 mg adsorbent, and the backup section contains 50 mg. A urethane foam plug is placed between these sections and also behind the backup section. The ends of the tube are flame-sealed to prevent contamination before use. Deactivate the Florisil before packing the tubes by drying a weighed amount at 105 C for 45 minutes. After cooling to room temperature, add the Florisil to a round bottom flask which can be attached to a rotary evaporator. Add water at 3 ml/100 g of Florisil (le, 3% W/W water) and turn the mixture in the rotary evaporator for 1 hour or until it is uniformly mixed (free-flowing). (d) Collection and Shipping of Samples (1) Immediately before sampling, break each end of the sorbent tube to provide an opening at least one-half the Internal diameter of the tube (2 mm). (2) The smaller, or backup, section of Florisil should be positioned nearest the sampling pump. (3) The sorbent tube must be vertical during sampling. Tubes should not be placed in a horizontal position since this may lead to "channeling" of the sorbent bed. (4) Do not pass air being sampled through any hose or tubing before it enters the tube. (5) Collect the air sample at a flow rate of 200 cc/minute or less to obtain the total sample volume required. The recommended maximum sampling volume for this method is 50 liters. >: 38125 905439 (6) Cap the sorbent tubes with Inert plastic caps Immediately after sasipllng. Under no circumstances are rubber caps to be used. Label tubes and note precise location assignments. (7) Handle one additional tube in the same manner as the semple tubes except that no air is to be drawn through it. Label this tube as a blank. (8) If the tubes are to be shipped, pack them tightly to minimize breakage in transit. (9) Do not subject the tubes to extremes of temperatures or to low pressures. (10) Provide bulk samples of the PCB preparation whose presence in the environment is suspected to the analytical laboratory. Do not transport these bulk materials in the same container as the samples or blank tubes. If possible, also provide a bulk air sample to use for qualitative identification. *v 905440 195 N 08126 X. APPENDIX II ANALYTICAL METHOD FOR POLYCHLORINATED BIPHENYLS Principle of the Method A known volume of air is drawn through a tube containing Florisll to adsorb the PCBs present in the air sample. The collected PCBs are desorbed with hexane, and the resulting solutions are analyzed using gas-liquid chromatography with electron capture detection. The concentration of PCBs relative to a standard PCB preparation is read from a standard curve. If the air sample is found to differ significantly in composition from available PCB standards, then use the alternate procedure of perchlorinatlon described in paragraph (b)7 of Procedure. Range and Sensitivity of the Standard Analysis NIOSH has found with Aroclor 1016, that the minimum detectable amount of PCB is 32 pg/4 pi. With a total desorption volume were 5 ml, this would represent a total sample of 40 ng of Aroclor 1016. Thus the method is capable of detecting a concentration of 40 ng in a 1 cu m air sample, or a concentration of about 1 pg/eu m in an air sample of 50 liters. The upper range of the analytical method is apparently limitless depending only upon the degree of dilution needed to maintain the concentration of the sample within the linear range of the electron capture detector (32 pg to 3 ng/injection). In practice, concentrations in workplace air have been found to be as high as 1.5 mg/cu m. 'N 03127 905441 Interferences (a) Strict measures to avoid contamination are required when using the electron capture detector. Foremost, the syringe must be thoroughly cleaned after each injection. Hexane to be used in the analytical procedure should be periodically analyzed by GLC for purity. It should show no chromatographic peaks later than 45 seconds, if less than 5 jtl have been injected. (b) Any compound which has nearly the same retention time on the GLC column as one of the FCBs is an interfrent. This type of interference can often be overcome by changing the GLC operating conditions or by selecting another column. Retention time data on a single column, or even on a number of columns, cannot be considered as proof of chemical Identity. It is important, therefore, that a sample of the bulk mixture of FCBs be analyzed at the same time as the contents of the sample tubes so that chemical identification of possible Interferences can be made. (c) The interferences which have been reported in the literature in the GLC analysis of PCBs are not expected to be .Important for this method. Chlorinated pesticides, such as DDT, DDE, etc, have been reported as Interferences due to coextraction with PCBs during workup of samples such as water, tissue, soil, or biologic fluids. In the case of personal air sampling in an industrial environment, these interferences would not be present in amounts that would significantly interfere unless they were manufactured in the same area. Thus, unless these chlorinated pesticides are specifically known as potential lnterferents, extra cleanup or separation steps for these materials are not necessary. is? :N 08128 905442 (d) Sulfur-containing compounds in petroleum products have been reported as interferences. (e) If present in the FCB mixture, biphenyl will be an Interference when samples are analyzed by perchlorination; however, PCBs for the purpose of this recommended standard Include biphenyl. (f) Bromlnated impurities in antimony pentachloride have also been found to lead to interferences in perchlorination procedures. Results from NIOSH laboratories Indicate, however, that these bromlnated impurities may be removed byzvaeuum distillation of the antimony pentachloride. Precision and Accuracy The performance characteristics of the method as found by NIOSH are presented below. (a) The volume of air sampled can be measured to ilZ if a pump with a calibrated volume indicator is used. Volumes calculated from initial flow rate settings may be less accurate (5Z) because of changes in flow rate during sampling. (b) At airborne PCB concentrations of up to 10 mg/cu m, the front section of the Florlsll tube has a 100Z collection efficiency for 50-liter air samples.' (c) Recovery of known amounts of PCBs adsorbed on Florlsll is quantitative (100Z). (d) Sealed tubes or desorbed sample solutions can be stored for 2 months without PCB loss. (e) The precision of the analysis is dependent upon the precision and sensitivity of the technique used to quantitate the GLC peaks of the 198 n 08129 905443 samples and standards. The precision of the standard analytical procedure has a relative standard deviation of 4.4Z. (f) The average conversion of FCBs to decachlorobiphenyl is about 100Z with a relative standard deviation of about 2Z. (g) Recovery of decachlorobiphenyl subjected to the decachlorinatlon procedure Is >99Z with a relative standard deviation of 1.8Z. (h) The accuracy of these procedures Is not known; accuracy depends on the ability to separate and Identify each compound in the PCB mixture and to compare each with a known standard. Many of the Isomers In commercial PCB mixtures have not been separated or Identified, and standards for many of the Isomers are not available. Advantages of the Sampling and Analytical Methods (a) The sampling device is small, portable, and involves no liquids. (b) The capacity of the solid sorbent sampling device for PCBs is large and recovery of PCBs from the sorbent Is quantitative. (c) The contents of the sample collection tubes are analyzed by means of a rapid instrumental method. (d) Interferences are minimal, and most of those which do occur can be eliminated by altering chromatographic conditions. (e) The perchlorlnatlon procedure provides qualitative confirmation and quantitative measure of PCBs, since It Is based on measurement of the single GLC-EC detection response of decachlorobiphenyl. 905444 199 N 03130 Disadvantage of the Sampling and Analytical Methods (a) The precision of the sampling method is limited by the reproducibility of the pressure drop across the tubes. Pressure drop changes will result in variability in the flow rate and cause the sampling volume to be imprecisely known because the pump is usually calibrated for only one tube. (b) A substantial difference between the composition of PCBs in the air sample and that of the commercial PCB mixture being used as a standard will result in a large error in accuracy when the standard analytical procedure is used, since estimation of the PCB content of the sample is based on comparison with such a PCB mixture. Apparatus (a) Gas liquid chromatograph equipped with an electron capture detector capable of maintaining a detector testperature of 350 C. (b) Glass column (6 feet x 2 mm I.D.) packed with 1.5Z OV-17/1.95Z QF-1 on 80/100 mesh Supelcoport. (c) Vials (20-ml), with aluminum-lined caps. (d) Microliter syringe (10-^1). (e) Volumetric flasks (10-ml for standards) with glass stoppers. (f) Method for determining peak areas. (g) Culture tubes, 13 x 100 mm,with unlined screw top caps. (h) Oven, capableofmaintaining 160 C 5 C. (1) Sand bath. ^4 (j) Vortex mixer. N 08131 200 905445 Reagents (a) (b) (c) (d) (e) (f) (g) Hexane, pesticide-grade quality. Nitrogen carrier gas, prepurified. PCB mixture under study. Antimony.pentachlorlde, distilled under vacuum. Decachloroblphenyl. Sodium sulfate, anhydrous. Hydrochloric acid, 20Z aqueous. Calibration and Standards (a) Standardization Procedure Uae the particular PCB mixture ae the standard that was being used in the work area in which air samples were taken. Prepare standards in hexane at concentrations ranging from 8 to 500 ng'/ml. Calibration curves should be established daily since the electron capture detector response may vary from day to day. Plot the standard curve in terms of concentration (ng/ml) versus area. Since the injection volumes of the standard and the sample are Identical, the concentration of the sample can be read directly from the standard curve. (b) Alternate Standardization Procedure (Perchlorinatlon) The product of the perchlorinatlon of the PCB mixture with antimony pentachlorlde is decachloroblphenyl. Standards of decachloroblphenyl are prepared in hexane at concentrations ranging from 70 to 460 ng/ul. Calibration curves are established daily since the electron capture detector response may vary from day to day. The standard curve is plotted in terms of concentration (ng/ml) versus peak area. Since the injection 201 N 08132 905446 volume of the etenderd and the sample are Identical, the concentration of the sample can be read directly from this curve. Procedure (a) Cleaning of Equipment All glassware used for the laboratory analysis should be washed with a detergent, throughly rinsed with tap water, distilled water, pesticide- grade acetone, and finally pesticide-grade hexane and then dried. (b) Analysis of Samples (1) Preparation of Samples Score each tube with a file and place the glass wool and front section In a clean, dry vial. Place the separating urethane foam plug, the back section of the sorbent, and the retaining urethane foam plug In a second clean, dry vial. The front and back sections are analyzed separately. (2) Desorption of Samples Prior to analysis, pipet 5.0 ml of hexane into each vial. V. Florisil particles should not be allowed to d i n g to the glass above the solvent. A minimum desorption time of 10 minutes Is required before analysis. (3) Gas-liquid chromatographic conditions for PCB determination by this procedure are: (A) Nitrogen carrier gas flow rate, 60 ml/minute. (B) Injector temperature, 300 C. (C) Interface and detector temperatures, both 325 C. (D) Column temperature, 180 C. 202 \\ QB133 905447 (6) Staple Injection The solvent-flush technique Is recommended for Injection of materials Into the GLC apparatus. With this method, the following procedure would be used to Inject 4 pi of sample. Three mlcrollters of hexane would be drawn Into the syringe, followed by 1 ( il of air, followed by 4 jil of sample solution. After the needle Is removed from the sample solution, 1 additional <1 of air is drawn Into the syringe to minimize evaporation at the tip of the needle. The plunger now rests at the 9-pl mark. Inject at least 7 t il of the syringe contents into the gas chromatogram. Not less than 1 t il of flush-solvent should be used. Larger volumes of flush may give a solvent peak which interferes with sample component peaks. The syringe must be cleaned with hexane after each Injection. (5) Preliminary Analysis Using the solvent-flush method of subsection b(4), inject 1 pi of sample and 1 pi of flush-solvent at the conditions specified under subsection b(3). If the sample Is too concentrated, further dilutions will be necessary to bring the concentration of the sample solution Into the linear range of the electron capture detector. Ones the concentration of the sample is appropriately adjusted, its chromatogram should be compared to that of a standard to determine If the air sample la qualitatively different In composition from the standard. If there la little difference between the two chromatograms, then proceed with the standard analysis using the PCB mixture for standardization, subsection b(6). On tha other hand, should there be a significant difference between the two chromatograms (such that comparison with the PCB mixture could result la 203 905448 'N 08134 grots error), then use the alternate procedure for standardization, subsection b (7). (6) Standard Analysis Select at least five prominent peaks in the sample chromatogram and compare their heights or areas with those of the standard. Calculate the concentration of PCBs by comparing the heights or areas of the selected peaks in the sastple chromatogram of those in the standard chromatograms of known amounts of material. (7) Alternate Standardization Procedure A 200-/il aliquot of the sample is placed in a 13-ram x 100-ram culture tube and the hexane is slowly evaporated with dry nitrogen until 10 u l or less remain. Do not allow hexane to climb the tube during evaporation and do not allow the sample to evaporate to dryness. Immediately add 0.2-0.5 ad of distilled antimony pentachloride with a disposable plpet as rapidly as possible (antimony pentachloride decomposes rapidly la air) and cap the tube. The sample should remain light yellow after this addition, but if the sample turns dark brown or black, it must be discarded and another aliquot of that sample must be used. All samples are placed together in a sand bath. There should be no liner in the cap of the tube, since most liners are attacked by antimony pentachloride. A sample of decaehlorobiphenyl is treated in a manner similar to the samples. The sand bath containing all of the treated samples is placed in a preheated oven at 160 C for at least 3 hours. Samples may also be treated overnight. After perehlorinatlon, the sand bath is removed from the oven and the samples are removed from the sand and allowed to cool to room temperature. To each saaiple is added dropwlse 0.5 ml of 20% hydrochloric acid. This mixture is 204 N 08135 905449 l m i then extracted four tinea with 1-2 ml of hexane each time Each extract la paased through a funnel containing approximately 0.5 g of anhydrous sodium sulfate (retained by a glass wool plug) Into a 10-ml volumetric flask. The volume of the sample is brought to 10 ml by rinsing the pipet, sodium sulfate, and funnel tip with hexane. The funnel should not rest on thezllp of the flask during filtration. The glass wool plug and sodium sulfate in the funnel are replaced after each sample. An aliquot of the sample solution is Injected under the GLC conditions described above. The solvents flush technique is recommended using 2 y l of solvent back flush and 6 *il of standard or sample solution. The syringe must be cleaned with hexane after eech injection. The height or area of the decachlorobiphenyl peak is compared to that of the decachlorobiphenyl standard and the weight of decachlorobiphenyl present is calculated. (8) Gas-liquid chromatographic conditions for decachlorobiphenyl determination: (A) Nitrogen carrier gas flow rate, 90 ml/minute. (B) Injector temperature, 300 C. (C) Interface and detector temperature, 323 C. (0) Column temperature, 220 C. (c) Determination of Desorption Efficiency NI0SH has found average deeorption efficiency Is >99.32, thus, results of sample analyses need not be corrected for desorption efficiency. Calculations (a) Standard Analytical Procedure The following are the steps in the calculation of concentrations of 203 905450 N 08136 PCBs in air when determined with a PCB mixture as the standard. (1) Add the heights or areas of several selected prominent peaks (at least five) in the chromatogram, compare with the total heights or areas of those same peaks in the standard, and read the concentration of the sample solution (ng/ml) from the standard curve. (2) Multiply the concentration, in ng/ml, of the sample solution by the total volume, in ml, of the sample solution and calculate the weight of PCBs in the sample. Make corrections for the blanks if necessary. (3) Add the weights found on thefront and the back sections ofthe tube to find the total weight of PCBs in the air sample. (4) Divide the total weight of the PCBs in the air sample by the volume, in liters, of air sampled and report the PCB concentration in ng/liter or its equivalent in jig/cu m. (b) Alternate Standardization Procedure The following are the steps in the calculation of concentrations of PCBs in air using the perchlorlnation method. (1) The height or area of thedecachloroblphenyl peak in the chromatogram of the sample aliquot is compared to the height or area of the decachloroblphenyl peak in the chromatograms of the standard. The concentration of decachloroblphenyl in the sastple aliquot is read from the standard curve. (2) The concentration of decachloroblphenyl in this aliquot (ng/ml) is multiplied by the total volume (ml) of the sample solution to give the total weight of PCBs in the sample as decachloroblphenyl. 206 N 0 3 1 3 7 905451 (3) The weights of PCBs, as decachlorobiphenyl, found on the front and back sections of the tube are summed, corrections for blanks are made, and the total weight of PCB, as decachlorobiphenyl, In the air sample Is calculated. (4) The total weight of PCB Is divided by the volume of air sampled and the air concentration Is reported In ng/llter or Its equivalent In jug/cu m. 207 '>' 08130 905452 XI. APPENDIX III MATERIAL SAFETY DATA SHEET General Instructions for preparing a Material Safety Data Sheet (MSDS) are presented in this chapter. The examples used in the text are for illustrative purposes and are not intended to apply to any specific compound or product. Applicable information about a specific product or material shall be supplied in the appropriate block of the MSDS. The product designation is inserted in the block in the upper left corner of the first page to facilitate filing and retrieval. Print in upper case letters as large as possible. It should be printed to read upright with the sheet turned sideways. The product designation is that name or code designation which appears on the label, or by which the product is sold or known by employees. The relative numerical hazard ratings and key statements are those determined by the guidelines in Chapter V, Part B, of the NIOSH publication, An Identification System for Occupationally Hazardous Materials. The company identification may be printed in the upper right corner if desired. (a) Section I. Product Identification The manufacturer's name, address, and regular and emergency telephone numbers (including area code) are Inserted in the appropriate blocks of Section I. The company listed should be a source of detailed backup information on the hazards of the material(s) covered by the MSDS. The listing of suppliers or wholesale distributors is discouraged. The trade name should be the product designation or common name associated with the material. The synonyms are those commonly used for the product, especially 208 -N 03139 905453 formal chemical nomenclature. Every known chemical designation or competitor's trade name need not be listed. (b) Section II. Hazardous Ingredients The "materials" listed In Section II shall be those substances which are part of the hazardous product covered by the MSDS and individually meet any of the criteria defining a hazardous material. Thus, one component of a multicomponent product might be listed because of its toxicity, another component because of its flammability, while a third component could be included both for its toxicity and its reactivity. Note that a MSDS for a single component product must have the name of the material repeated in this section to avoid giving the impression that there are no hazardous ingredients. Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature. Where possible, avoid using common names and general class names such as "aromatic amine," "safety solvent," or "aliphatic hydrocarbon" when the specific name is known. The "Z" may be the approximate percentage by weight or volume (indicate basis) which each hazardous ingredient of the mixture bears to the whole mixture. This may be indicated as a range or maximum amount, ie, "10-40Z vol" or "10Z max wt" to avoid disclosure of trade secrets. Toxic hazard data shall be stated in terms of concentration, mode of exposure or test, and animal used, eg, "100 ppm LC50-rat," "25 mg/kg LD50skin-rabbit," "75 ppm LC man," or "permissible exposure from 29 CFR 1910.1000," or, if not available, from other sources of publications such as the American Conference of Governmental Industrial Hygienists or the 905454 209 N 08140 American National Standards Institute Inc. Flashpoint, shock sensitivity or similar descriptive data may be used to Indicate flammability, reactivity, or similar hazardous properties of the material. (c) Section III. Physical Data The data in Section III should be for the total mixture and should Include the boiling point and melting point in degrees Fahrenheit (Celsius in parentheses); vapor pressure, in conventional millimeters of mercury (mm Hg); vapor density of gas or vapor (air I); solubility in water, in parts/hundred parts of water by weight; specific gravity (water 1); percent volatiles (indicate if by weight or volume) at 70 degrees Fahrenheit (21.1 degrees Celsius); evaporation rate for liquids or sublimable solids, relative to butyl acetate; and appearance and odor. These data are useful for the control of toxic substances. Bolling point, vepor density, percent volatiles, vapor pressure, and evaporation are useful for designing proper ventilation equipment. Thie Information is also useful for design and deployment of adequate fire and spill containment equipment. The appearance and odor may facilitate identification of substancee stored in Improperly marked containers, or when spilled. (d) Section IV. Fire and Explosion Data Section IV should contain complete fire and exploalon data for the product, including flashpoint and autoignition testperature in degrees Fahrenheit (Celsius in parentheses); flammable limits, in percent by volume in air; suitable extinguishing media or materials; special firefighting procedures; and unusual fire and explosion hazard information. If the product presents no fire hazard, Insert "NO FIRE HAZARD" on the line K 08141 210 905455 labeled "Extinguishing Media." (e) Section V. Health Hazard Information The "Health Hazard Data" should be a combined estimate of the hazard of the total product. This can be expressed as a TWA concentration, as a permissible exposure, or by some other Indication of an acceptable limit. Other data are acceptable, such as lowest LD50, If multiple components are involved. Under "Routes of Exposure," consents In each category should reflect the potential hazard from absorption by the route in question. Comments should indicate the severity of the effect and the basis for the statement, If possible. The basis might be animal studies, analogy with similar products, or human experiences. Comments such as "yes" or "possible" are not helpful. Typical comments might be: Skin Contact-- single short contact, no adverse effects likely; prolonged or repeated contact, Irritation, and cracking. Readily absorbed through the skin with severe systemic effects. Eye Contact-- some pain and mild transient Irritation; no corneal scarring. ' V. "Emergency and First Aid Procedures" should be written In lay language and should primarily represent first-aid treatment that could be provided by paramedical personnel or individuals trained In first aid. Information In the "Notes to Physician" section should Include any special medical information which would be of assistance to an attending physician Including required or recommended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed workers. 211 N 03142 905456 (f) Section VI. Reactivity Date The comments in Section VI relate to safe storage and handling of hazardous, unstable substances. It is particularly important to highlight instability or incompatibility to common substances or circumstances such as water, direct sunlight, steel or copper piping, acids, alkalies, etc. "Hazardous Decomposition Products" shall include those products released under fire conditions. It must also include dangerous products produced by aging, such as peroxides in the case of some ethers. Where applicable, shelf life should also be indicated. (g) Section VII. Spill or Leak Procedures Detailed procedures for cleanup and disposal should be listed with emphasis on precautions to be taken to protect workers assigned to cleanup detail. Specific neutralizing chemicals or procedures should be described in detail. Disposal methods should be explicit including proper labeling of containers holding residues and ultimate disposal methods such as "sanitary landfill," or "incineration." Warnings' such as "comply with local, state, and federal antipollution ordinances" are proper but not sufficient. Specific procedures should be identified. (h) Section VIII. Special Protection Information Section VIII requiree specific information. Statements such as "Yes," "Ho," or "If Necessary" are not informative. Ventilation requirements should be specific as to type and preferred methods. Specify respirators as to type and NIOSH or US Bureau of Mines approval class, le, "Supplied air," "Organic vapor canister," "Suitable for dusts not more toxic than lead," etc. Protective equipment must be specified as to type and materials of construction. 212 -K 0 3 1 4 3 905457 W S *1 ! (i) Section IX. Special Precautions "Precautionary Statements" shall consist of the label statements selected for use on the container or placard. Additional information on any aspect of safety or health not covered in other sections should be inserted in Section IX. The lover block can contain references to published guides or in-house procedures for handling and storage. Department of Transportation markings and classifications and other freight, handling, or storage requirements and environmental controls can be noted. (j) Signature and Filing Finally, the name and address of the responsible person who completed the MSDS and the date of completion are entered. This will facilitate correction of errors and identify a source of additional information. The MSDS shall be filed in a location readily accessible to workers potentially exposed to the hazardous material. The MSDS can be used as a training aid and basis for discussion during safety meetings and training of new employees. It should assist management by directing attention to the need for specific control engineering, work practices, and protective measures to ensure safe handling and use of the material. It will aid the safety and health staff in planning a safe and healthful work environment and in suggesting appropriate emergency procedures and sources of help in the event of harmful exposure of esiployees. 213 905458 *K 08144 MATERIAL SAFETY DATA SHEET MANUFACTURER'S NAME AOORESS TRADE NAME 1 PRODUCT IDENTIFICATION REGULAR TELEPHONE NO. EM ERGENCY TELEPHONE NO. SYNONYMS II HAZARDOUS INGREDIENTS M ATERIAL OR COMPONENT % HAZARO OATA OILIN G POINT. 7EOMM HQ SPECIFIC GRAVITY (HtO-11 VAPOR OENSITV IAIR1) % VOLATILES 9Y VOL appearan ce ano odor III PHYSICAL DATA MELTING POINT VAPOR PRESSURE SO LU EILITY IN HjO. % Y WT EVAPORATION RATE (BUTYL ACETATE* II 214 N 0 314 5 905459 fla s h point (TEST METHOOI IV FIRE AND EXPLOSION OATA AUTOIGNITION TEMPERATURE FLAMMABLE LIMITS IN AIR. % EV VOL. EXTINGUISHING MEDIA LOWER UPPER SPECIAL FIRE FIGHTING PROCEDURES UNUSUAL FIRE ANO EXPLOSION HA2ARO HEALTH HA2ARO OATA V HEALTH HAZARD INFORMATION ROUTES OF EXPOSURE INHALATION SKIN CONTACT SKIN ABSORPTION EVE CONTACT INGESTION EFFECTS OF OVEREXPOSURE ACUTE OVEREXPOSURE CHRONIC OVEREXPOSURE EMERGENCY ANO FIRST AIO PROCEOURES EVES SKIN. INHALATION: INGESTION NOTES TO PHYSICIAN 215 905460 . F.* 387 46 VI REACTIVITY DATA CONDITIONS CONTRIBUTING TO INSTABILITY INCOMBAI BILITY HAZARDOUS DECOMPOSITION PROOUCTS CONDITIONS CONTRIBUTING TO NAZAR0 0 US POLYMERIZATION __________________ VII SPILL OR LEAK PROCEDURES STEPS TO BE TAKEN IP MATERIAL IS R ELEA SED OR SPILLEO NEUTRALIZING CHEMICALS WASTE DISPOSAL METHOO _____________ Vili SPECIAL PROTECTION INFORMATION VENTILATION REQUIREMENTS SPECIFIC PERSONAL PROTECTIVE EQUIPMENT RESPIRATORY ISPECIPY IN O ETA IU EYE GLOVES OTHER CLOTHING ANO EQUIPMENT 905461 N 08147 p r ec a u tio n a r y STATEM EN TS IX SPECIAL PRECAUTIONS o t h e r HANOCINO ANO s t o r a g e r e q u ir e m e n t s PREPAREO Y AOORESS. OATE 905462 217 0 814g TABLE XII-1 CHEMICAL AND PHYSICAL PROPERTIES OP SOME AROCLORS Dlatlllatlon Density Flash Fire- Aroclor Chlorine Range C g/ml point* Point* X w/w (corrected) 25 C P P Appearance 1221 1212 1242 1248 1254 1260 1262 1268 20.5-21.5 31.4-32.5 42 48 54 60 62 68 275-320 290-325 325-366 340-375 365-390 385-420 390-425 435-450 1.18 1.26 1.38 1.44 1.54 1.62 1.64 1.82 286-302 349 Clear mobile oil 305-310 460 1 384-356 none** I 379-384 I f none** 1 Light-yellow vlsous liquid II 1 Light-yellow soft sticky resin II II Light-yellow sticky viscous resin II I White to off-white powder Cleveland Open Cup ( 3 **None to boiling point Ci -- a Adapted from reference I -PaVO 905463 TABLE Xll-l QUALITATIVE AND PERCENT CHLOROBIPHENYL AND BIPHENYL COMPOSITIONS OF COMMERCIAL PCB PREPARATIONS (Q ualitatively m ajor peaks = M. m inor peaks m, am biguous identities = ?; quantitatively, percentages rounded) CL-Substltuted Positions Commercisi Preparation Designations (trade names omitted) to to L/ MCsVO_v Cn O co o Ul c4n^ 1221 1221 1221 1221 1232 1016 1242 1242 1242 1241 1248 1254 1254 1254 850 1240 1240 0 13 14 m 14 SI 05 SI SI SI 2 21 32 SI 35 SI 1 IS 08 IS SI 3 3m3 4 19 19 m 20 SI 2 2.3 04 2.4 4 3 2 1 < 0.7 IS <01 2.S 0.2 li IS St 2.4 03 04 tr SI 2.2* 9 5 SI 5 SI 7 SI <10 M SI 2.3* 3 ' SI 2 SI 1 SI IS M SI 2.4* 14 10 IS 11 IS 11 SI <5 M SI 05 3.4 1 SI SI 3.S tr 3.3* 3.4* 1 IS <3 4.4* 4 4 IS 4 SI 2 1M <3 2.3.4 2.3.5 2.3.4 2.r.3 IS 5 SI M? SI 2.33* 01 tr m 2,3,4* tr 2.4.5 2.4,4 2.2*4 03 SI SI SI 4 SI II M IS 8 2.3*.4 SI SI 4 IS - <15 M SI <13 2.4.4* 02 IS IS 4 IS 7 M? SI 3 2.2\5 2.3.5 2.4.5 04 02 02 06 IS SI SI 12 SI 9 10 SI 2 M SI 0.1 SI M SI <13 SI SI 2.2.4 SI 1 IS SI SI 2.3.4 03 M? 2.4.4 2 M 3.4.5 r.3.4 01 ti IS 16 M SI 21 3.3*.4 IS 3.4 4* 2M SI SI SI SI IS SI SI SI IS m SI SI SI SI 03 SI SI SI SI SI IS SI IS m IS SI SI SI SI SI TABLE Xll-2 (Continued) QUALITATIVE AND PERCENT CHLOROB1PHENYL AND BIPHENYL COMPOSITIONS OF COMMERICAL PCB PREPARATIONS (Qualitatively major peaka M, minor peaks =* m, ambiguous identities ?; quantitatively, percentages rounded) CL-Substituted Positions Commercial Preparation Designations (trai KKo>) O OC cn --* 1121 1221 1221 rU3..34S..5S 23.4.5 2.3.46 2.3,5.6 2.T.3.4 2.3..4 2.3.4.T 2.2\3.5 2.3.3\5 2,3.4*.5 2.2\3.6 2.3.Y.6 23.4.6 2.2\4,5 2.3\4,5 2.4,4*.5 2.2*.4,6 2.3.46 2.4.T.6 2\3,4.5 33.4.5 3.4,4'.5 2.2\3.3* 2.2*.3.4* 2.2*.3.5* 22.73..33.'6,4** 2.3.3*.5' 2.2\4.l* 2.2\4,5* 2.r.4.6* 2,3*.4,4* 2.3'.4,5* 2.3*.5.5* 2.2*.5.5* 014 1221 1232 IS 1016 1242 ii tr 3 04 02 <2 tr <tr2 tr 1m 1 1 IS 3 IS 0t1r SI 2 IS 1242 1242 M SI M? 6 M? M? M? M? 4 is 12 M? SI tr M? M? 7 m 16 m m M 2 <04 07 905465 e* -- . -- 3 E EE EEE E E S SB h m t r i * M M * . V t r i ia W i tKoi wto*' ftoi' nto ' t o tioj' h I Nto ' ^! S N w. w^ . * w* . * * T**'im. `Wt t- o t o It om t! o*t! otU^o m' tbion't ow*t o<7**toi*ito*m7t otjpo u'imttpo,''it ow t ow *t _o t orit oipl,i"tpoi ton t or-t oW i W W 221 905466 N 08152 TABLE Xll-a (Continued) QUALITATIVE AND PERCENT CHLOROBIPHENYL AND BIPHENYL COMPOSITIONS OF COMMERCIAL PCB PREPARATIONS (Qualitatively major peaks *= M, minor peaks = m, am biguous Identities - ?; quantitatively, percentages rounded) CL-Substltuted Positions Commercial Preparation Designations (trade names omitted) 1221 1221 1221 1221 1232 10K 1242 1242 1242 1241 1241 1254 1254 1254 A50 12M 12(1 12(0 AM AM OPS 2.2\4.5\( 2. r .4 .i.r 2,3\4.4\ 2.3'.4.5'.( 2,3.3\4'.5a 2.3',4,4'.5' 2.3'.4'.5.5` 2.3'.4\5'.( 3.3'.4.4\5 3. Y.4.W 2.2'.3.4.5.( 2.3.3*.4.5.( 2.3.4.4'.5.( 2.2*.3.3'.4.5 K> K) K> 2.2\3.4,4\5 2,2'.3.4.5.5* 2.2*.3.4.5.C 2,3.3*.4.4'.5 2.3.3*.4.5.5* 2.2'.3.3\4,6 2.2'.3.4.4',( 2.2*.3.4.5'.( 2.2'.3.4.(.6* 2.3.3*.4,4'.6 m 2.3.3*.4.5'.( 2.2'.3.3'.5.( 2.2'.3.4'.5.( O 2.2'.3.5.5*.( m 0 3 2.2'.3.5.(.6I 2.3.3\4'.5.( cn OJ 2.3.3'.S.5\6 2.2\3.3\4.4' 2.2',3.3'.4.5' 22.3.4.4.5' m 2.3.3.4.4'.5' m 2 2'.3.3'.4.C m 2.2'.3.4.4',(' m 0.8 <9 m 2 1 2m1 <1 12 M 5 M2 m 3 M2 2 M m II M3 905467 *e 3E 3- 3 3 2S 2 2 2 e 3V EE EE EE E E E EE E EE ES a s as 8 VV V S- es 8 V s se E E 8 EE E SS jvm' nvi ^ ^ rfn S ES '\ S S N 08154 223 905468 TABLE XII-2 (Continued) QUALITATIVE AND PERCENT CHLOROBIPHENYL AND BIPHENYL COMPOSITIONS OP COMMERCIAL PCB PREPARATIONS (Qualitatively major peaka ~ M, minor peaka = m, ambiguoua identitiea ?; quantitatively, percentagea rounded) CL-Hubatituted Poaitiona Commercial Preparation Dcaignationa (trade name omitted) 1221 1221 1221 1221 1232 1016 1242 1242 1242 1241 1241 1254 1254 1254 650 1260 1260 1260 660 2.3.3\4.4\5.5\6 2.2222\...3222222222......*\.\2223223r3.**\.\3\...3..3433333.3..3...3\.*33.4334\a***4.*\\.4.54.r.4..44554...\.4.,...545455554\*\\..5.\''5566r6,...66*6...5.,66..66.,u66\66****6**a`' m m 04 0III1rrI 2 m5 04 m mmm mMmmmm 07 07 Ir Reference Ko. 17 * 16 * 16 * 16 * 14 16 * 16 * 14 7 * 14 8 7 16 * PWIJbr). wrilteocommuMcalioa. November 1976 to K> O0 3 eenn CO O <CJO>