Document Qgz4e6OL3r2mEGkJ6gdzm9ZZ8

ASA Reg. U.S. Pat. Off. Z37.4-1960 Revision of 237.4-1941 UDC 613.63 American Standard Maximal Acceptable Concentration of Benzene Sponsor American Industrial Hygiene Association Approved October 28, 1960 AMERICAN STANDARDS ASSOCIATION INCORPORATED MCD 000004807 American Standard Registered United States Patent Office An American Standard implies a consensus of those substantially concerned with its scope and provisions. The consensus principle extends to the initiation of work under the procedure of the Association, to the method of work to be followed, and to the final approval of the standard. An American Standard is intended as a guide to aid the manufacturer, the con sumer, and the general public. The existence of an American Standard does not in any respect preclude any party who has approved of the standard from manufacturing, selling, or using products, processes, or procedures not conforming to the standard. An American Standard defines a product, process, or procedure with reference to- one or more of the following: nomenclature, composition, construction, dimensions, tolerances, safety, operating characteristics, performance, quality, rating, certification, testing, and the service for which designed. American Standards are subject to periodic review. They are reaffirmed or revised to meet changing economic conditions and technological progress. Users of American Standards are cautioned to secure the latest editions. Producers of goods made in conformity with an American Standard are encour aged to state on their own responsibility in advertising, promotion material, or on tags or labels, that the goods are produced in conformity with particular American Standards. The inclusion in such advertising and promotion media, or on tags or labels, of information concerning the characteristics covered by the standard to define its scope is also encouraged. Published by AMERICAN STANDARDS ASSOCIATION INCORPORATED 10 East 40th Street, New York 16, N. Y. Copyright 1961 by American Standards Association, Incorporated Universal Decimal Classification 613.63 Printed in U.S.A. D3M461/1 MCD 000004808 Foreword (This Foreword is not a part of American Standard Maximal Acceptable Concentration of Benzene, Z37.4-1960.) American Standard Maximal Acceptable Concentration of Benzene, Z37.4-1960, has been developed by a committee, national in scope, functioning under the procedure of the American Standards Association. This committee was organized to co-ordinate all available information on the various air contaminants and to establish acceptable concentrations which could be used in the development of means for controlling such contamination. This standard on the acceptable concentration of benzene is one of a series of standards which have been prepared by the committee and approved by the American Standards Association. The initial draft of this standard was prepared co-operatively with the United States Public Health Service. The first standard on this subject was approved January 15, 1941. The subcommittee which developed the pres ent revision of this standard was under the chairmanship of Hervey B. Elkins. For many years the need for standard acceptable concentrations of toxic dusts, gases, mists, vapors, and fumes in the air of work places has been recognized. A great deal of information on such concentrations has been published, but it frequently differs, due largely to the varying conditions under which observations and tests were made. While research on the toxic effects of many dusts, fumes, mists, vapors, and gases is continuing in indus try, governmental institutions, universities, and elsewhere, the concentration set forth in this standard reflects information obtained from all authoritative published data and the experience of the members of the committee. The ASA Sectional Committee on Acceptable Concentration of Toxic Dusts and Gases, Z37, which developed this standard, had the following personnel at the time of approval: H. H. Schrenk, Chairman Don D. Irish, Vice-Chairman Henry G. Lamb, Secretary Organization Represented Name of Representative and Business Affiliation American Conference of Governmental Industrial Hygienists.. .Dr Herbert E. Stokincer, U. S. Public Health Service American Industrial Hygiene Association .................................. Dr Robert A. Kehoe, University of Cincinnati Philip Drinker, Harvard University (Alt) Dr Carey P. McCord, University of Michigan (Alt) American Institute of Chemical Engineers.................................... R. C. Stratton, Travelers Insurance Company Prof. C. F. Gurnham, Michigan State University (Alt) American Petroleum Institute.......................................................Allan E. Dooley, The Texas Company Dr Lamson Blaney, Sun Oil Company (Alt) American Public Health Association ........................................... Dr Lewis J. Cralley, U. S. Public Health Service American Society of Safety Engineers..........................................Warren A. Cook, University of Michigan Association of Casualty and Surety Companies...........................Myron A. Snell, Hartford Accident and Indemnity Company E. E. Theurer, Hartford Accident and Indemnity Company (Alt) Canadian Standards Association (Liaison).................................. Dr Kingsley Kay, Department of National Health and Welfare Conference of State and Provincial Health Authorities of North America........................................Dr Stanley H. Osborn, State Department of Health (Connecticut) Industrial Medical Association .....................................................Dr Carey P. McCord, University of Michigan Dr A. J. Lanza, New York University (Alt) International Association of Governmental Labor Officials........Hervey B. Elkins, Massachusetts Department of Labor & Industries Manufacturing Chemists' Association ..........................................Dr John H. Foulcer, E. I. du Pont de Nemours and Company, Inc Frank S. Low, Food Machinery and Chemical Corporation (Alt) National Association of Mutual Casualty Companies................. Dr C. R. Williams, Liberty Mutual Insurance Company Charles S. Lai/bly, Lumbermens Mutual Casualty Company (Alt) National Safety Council ................................................................ Frederick W. Sands, United States Rubber Company K. A. Kelsen (Alt) U. S. Department of the Army (Liaison) ......................................Frederick M. Bishoff U. S. Department of Health, Education and Welfare, Public Health Service (Liaison) ............................................... Dr Herbert E. Stokincer Dr W. Clark Cooper (Alt) _ _,,,, MCD 000004809 Organization Represented, U. S. Department of the Interior, Bureau of Mines .... U. S. Department of Labor, Bureau of Labor Standards Members-at-Large ............................................................... Name of Representative and Business Affiliation Hylton R. Brown Lawrence B. Bercer (Alt) Wiluam G. Griffin Dr Anna M. Baetjer, The Johns Hopkins University Manfred Bowditch, Lead Industries Association Philip Drinker, Harvard University Theodore F. Hatch, University of Pittsburgh Dr Don D. Irish, Dow Chemical Company Eugene H. Krackow, Chemical Warfare Laboratories Dr A. J. Lanza, New York University Dr Willard Machle Dr Norton Nelson, New York University Dr Sherman S. Pinto, American Smelting and Refining Company Dr Frank Princi, University of Cincinnati Dr H, H. Schrenk, Industrial Hygiene Foundation of America F. W. Sehl Dr C. Boyd Shaffer, American Cyanamid Company Dr Thomas L. Shipman, University of California Dr Henry F. Smyth, Jr, Mellon Institute of Industrial Research Dr W. F. von Oettingen, National Institute of Health Dr B. L. Vosburch, General Electric Company Dr Wiluam P. Yant, Mine Safety Appliances Company Dr John A. Zapp, Jr, E. I. du Pont de Nemours and Company, Inc MOD 000004810 Contents Section Pace The Meaning of Maximal Acceptable Concentration............................................................................. 6 1. Scope and Purpose.............................................................................................................................. 7 2. Properties of Benzene.......................................................................................................................... 2.1 General Properties .................................................................................................................... 2.2 Physical-Chemical Properties.................................................................................................... 2.3 Toxic Properties ........................................................................................................................ 7 7 7 7 3. Maximal Acceptable Concentration............................. 7 4. Sampling Procedure and Analytical Methods.................................................................................... 4.1 Sampling Procedure .................................................................................................................. 4.2 Analytical Methods.................................................................................................................... 7 7 8 References to the Text................................................................................................................................ 9 General References................................................................................................................................... 9 mod 000004811 The Meaning of Maximal Acceptable Concentration It is generally recognized that there are levels of concentration of atmospheric contaminants to which a person may be exposed without known ill effects or discomfort. Since it is not practical to maintain com pletely uncontaminated air in most industrial situa tions, it is necessary to establish maximal acceptable concentrations of atmospheric contaminants encoun tered in industrial operations. These concentrations in themselves do not represent a scale of relative toxicity; they represent the concentrations of con taminants below which ill effects are unlikely to be experienced by any but hypersusceptible individuals. These concentrations are usually based upon data obtained by one or more of the following procedures: (1) Laboratory tests on animals (2) Laboratory tests using human subjects (3) Environmental and medical investigations in plants A common feature of these procedures is that the experimental exposure shall correspond to the normal work pattern. This should be taken into consideration also in the application of maximal acceptable con centration values. Three criteria have governed the establishment of these concentrations: (1) Organic or other tissue changes (2) Functional reactions that have no discernible untoward effects on health but cause impairments, such as in-co-ordinations and increased proneness to accidents (3) Discomfort or adverse sensory effects In those cases in which the concentrations have been established on the basis of organic changes, it is logical to assume that repeated exposure to con centrations significantly in excess of the acceptable concentration probably would produce injury. When the level has been established on the basis of a func tional change or discomfort, it is logical to assume that exposure to concentrations not greatly exceeding the acceptable concentration would not produce materially injurious effects. Hence it is important to understand the criteria upon which any such maximal acceptable concentration has been established. Though the purpose of the acceptable concentration is to minimize health hazards, its immediate use is for guidance in establishing engineering procedures to prevent objectionable concentrations of toxic or noxious materials from being present in the air of work places. Comparison of the results of air analyses with maximal acceptable concentrations indicates acceptable conditions or otherwise the need, extent, and urgency of control measures. Sampling and analysis should be performed by competent personnel using an acceptable method that will provide a reliable measure of actual exposure. Air analyses in conjunction with acceptable con centrations of such atmospheric contaminants as are encountered in industrial operations serve as a measure of exposure, but not as a means of diagnosis of occupational disease. Diagnoses should be based on a consideration of all factors, including results from clinical and physical examination, as well as from air analyses, from means of assessing amounts of materials in the body, and a knowledge of toxico logical effects of the materials under consideration. In the application of the standards, it should be kept in mind that: (1) The acceptable concentrations serve as stand ards for good industrial hygiene practice. (2) They serve as engineering guides. Design and operation should aim at maintaining all concentra tions below the acceptable maximum. (3) They should be applied and interpreted by competent individuals with a full understanding of the basis and limitations of the information from which the standard has been developed. (4) It is advised that these standards are con sidered to be guides toward good industrial hygiene and are not intended as legal requirements. (5) The levels are applicable only for exposure to a single substance. In the case of exposure to mixtures, the effect may be increased or decreased, and controls should be based on the specific situation. MCD 000004812 6 American Standard Maximal Acceptable Concentration of Benzene 1. Scope and Purpose 1.1 The maximal acceptable concentration of ben zene applies to all places of employment. 1.2 The purpose of this standard is to prescribe the maximal acceptable concentration of benzene in the atmosphere of work places for guidance in design and operation, so as to protect the health of the workers. lating white blood cells, platelets, and red blood cells. Individual susceptibility varies greatly. Absorbed benzene is excreted partly as phenol con jugated with sulfate in the urine. Determination of the ratio of inorganic to total sulfates in the urine is a useful method of estimating benzene exposure [4], Medical control procedures should emphasize pe riodic blood examinations. 2. Properties of Benzene [1] * 2.1 General Properties. Benzene (benzol) is the lowest homologue of the aromatic hydrocarbons. It should not be confused with benzine (benzin), a mix ture mainly of aliphatic hydrocarbons. Benzene is a colorless liquid. Commercial benzeneisseldom pure and may be contaminatedwith xylene, toluene, phenol, thiophene, carbon disulfide, acetonitrile, and also by pyridine and other substances. 2.2 Physical-Chemical Properties Chemical formula: CsH6 Molecular weight: 78.11 [2] Specific gravity: 0.879 at2^n-C 4 Vapor density (air = 1.00): 2.7 Boiling point: 80.1 C Melting point: 5.5 C Vapor pressure at 26.1 C: 100 mm Hg (milli meters of mercury) Flash point (closed cup): --11C(12F) Explosive limits (percent by volume in air): 1.4-7.1 [3] Autoignition temperature: 562 C (1044 F) 2.3 Toxic Properties. Benzene absorption occurs mainly through inhalation of the vapor. Upon acute exposure, benzene acts predominantly as a narcotic, causing depression of the central nervous system. With chronic exposure, benzene may cause bonemarrow damage, resulting in a change in the circu- Numbers in brackets throughout the text refer to cor responding numbers in References on page 9. 3. Maximal Acceptable Concentration 3.1 The maximal acceptable concentration of ben zene (benzol) shall be 25 parts per 1,000,000 parts of air by volume, corresponding to 0.08 mg (milligram) per liter at 25 C and 760 mm pressure, for exposures not exceeding a total of 8 hours per day, with the understanding that variations in concentration should fluctuate below this level. 3.2 The maximal acceptable concentration of ben zene is based on field studies in plants where benzene poisoning has occurred. Serious cases of benzene pois oning have been reported where concentrations averaged 150 ppm (parts per million) [5], 105 ppm, [6], 100 ppm (3 cases) [7], and 60 ppm [8]. Blood changes were found in workers exposed to average concentrations of 100 ppm and 90 ppm [9], 80 ppm [5], 105 ppm [6], and 60 ppm [8]. The concentration of 25 ppm is intended to provide the average individual with a considerable margin of safety against serious benzene poisoning. A medical control program is recommended whenever workers are exposed to concentrations of benzene vapor ap proaching the maximal acceptable concentration. 4. Sampling Procedure and Analytical Methods 4.1 Sampling Procedure 4.1.1 The sampling procedure shall be in accord ance with what experience shows is necessary to secure a sample which is truly representative of the actual working conditions at the location tested and for the period of the employees' daily exposure. This implies that the volume of the sample and the rate at which it is drawn into the sampling apparatus shall 7 MCD 000004813 Z37.4 8 be such that the taking of the sample does not itself change appreciably the atmospheric conditions at the location tested. The volume of the sample shall be consistent with the sensitivity of the analytical method employed. 4.1.2 Samples of air should be taken wherever exposure to benzene in the atmosphere is known or suspected to be of hygienic significance. 4.1.3 Samples should be taken at the breathing level, close to the mouth or nose of the worker, with special attention to the locations near the source of the benzene and in the path of air currents carrying it towards the worker, if such condition exists. 4.1.4 Samples should be taken in sufficient num bers to indicate whatever differences in concentration of benzene exist during the working period. 4.2 Analytical Methods. The analytical methods recommended for use are based on the formation of dinitrobenzene by the action of fuming nitric acid and concentrated sulfuric acid. The sample may be taken originally by passing the air through such a nitrating mixture, in a suitable bubbler, at a rate of 0.02 to 0.25 liters per minute [10]; or grab samples may be taken in suitable receptacles and then shaken with nitrating acid [11]; or the air may be passed over silica gel, and the latter heated in the laboratory to drive off the benzene, which is passed through nitrating acid. The dinitrobenzene may be determined by the color produced by methyl ethyl ketone and alkali. Any other analytical method may be used, pro vided it is equivalent in applicability and reliability to those cited. Note: It is understood that the sampling and analysis of contaminated air as specified above, and the interpretation of the data in relation to the stated permissible concentration shall be done only by technically qualified and competent persons. 000004814 MCD * * References to the Text Z37.4 9 [1] Physical constants, unless otherwise referenced, are taken from or calculated from International Critical Tables of Numerical Data, Physics, Chemistry, and Technology. Published under the direction of National Research Council-- National Academy of Sciences. New York: Mc Graw-Hill Book Company, Inc, 1926-1929. [2] Calculated from International atomic weights, 1940. Journal of the American Chemical So ciety, vol 62, 1940, facing p 680. [3] Coward, H. F. and Jones, G. W. Limits of Flammability of Gases and Vapors. Revised and enlarged ed. Washington D. C.: Government Printing Office, 1952 (U.S. Bureau of Mines Bulletin No. 503). [4] Yant, W. P.; Schrenk, H. H.; Sayers, R. R.; Horvath, A. A.; and Reinhart, W. H. Urine sulfate determinations as a measure of ben zene exposure. Journal of Industrial Hygiene and Toxicology, vol 18, no. 1, 1936, pp 69-88. [5] Bowditch, Manfred and Elkins, Hervey, B. Chronic exposure to benzene (benzol); I. the industrial aspects. Journal of Industrial Hy giene and Toxicology, vol 21, 1939, p 321. [6] Heimann, H. and Ford, C. B. Chronic benzol poisoning in plastics industry; note on liver damage. Industrial Bulletin, vol 19, Nov 1940, p 224. [7] Wilson, Rex H. Benzene poisoning in industry. Journal of Laboratory and Clinical Medicine, vol 27, 1942, p 1517. [8] Hardy, Harriet L. and Elkins, Hervey B. Medical aspects of maximum allowable concen trations: benzene. Journal of Industrial Hy giene and Toxicology, vol 30, 1948, p 196. [9] Final Report of the Committee on Benzol. Chi cago: National Safety Council, May 1926, 128 pp. [10] Schrenk, H. H.; Pearce, S. J.; and Yant, W. P. A Microcolorimetric Method for the De termination of Benzene. Washington, D. C.: Government Printing Office, 1935 (U.S. Bureau of Mines Report of Investigations, No. 3287). [11] Siecel, J. and Burke, W. J. A modified method for the determination of benzol in air. Indus trial Bulletin, vol 18, no. 1,1939. General References Browning, Ethel. Toxicity of Industrial Organic Solvents. Revised American ed. New York: Chemical Publishing Company, Inc, 1953. Davis, P. A. Toxicity of benzene. Journal of the American Medical Association, vol 114, 1940, pp 553-557. Fairhall, Lawrence T. Industrial Toxicology. 2d ed. Baltimore: The Williams and Wilkins Com pany, 1957. Fire-Hazard Properties of Flammable Liquids, Gases and Volatile Solids. Boston: National Fire Pro tection Association, 1954 (NFPA No. 325). Flammable Liquids and Gases. (The National Fire Codes, vol I.) Boston: National Fire Protec tion Association, 1958. Greenberg, Leonard. Benzol Poisoning as an Indus trial Hazard. Washington, D. C.: Government Printing Office, 1926 (U.S. Public Health Re ports, Reprint No. 1096, pp 1357-1375, 14101431,1516-1539, July 2, 9, 23). Greenberg, Leonard; Mayers, May R.; Goldwater, Leonard; and Smith, Adelaide R. Benzene (benzol) poisoning in the rotogravure printing industry in New York City. Journal of Indus trial Hygiene and Toxicology, vol 21, 1939, p 395. Hamilton, Alice and Hardy, Harriet L. Industrial Toxicology. 2d ed. New York: Paul B. Hoeber, Inc, 1949. Henderson, Y. and Haggard, H. W. Noxious Gases and the Principles of Respiration Influencing Their Action. 2d ed. New York: Reinhold Pub lishing Corporation, 1943. Patty, Frank A., ed. Industrial Hygiene and Toxi cology, vol II. New York: Interscience Publish ers, Inc, 1949. von Oettincen, W. F. Toxicity and Potential Dangers of Aliphatic and Aromatic Hydrocarbons. Washington, D. C.: Government Printing Office, 1940 (U.S. Public Health Service Bulletin No. 255). Stull, D. H. Vapor pressure of pure substances-- organic compounds. Industrial and Engineering Chemistry, vol 39, 1947, p 517. MCD 000004815 American Standards The standard in this booklet is one of over 1950 standards approved to date by the American Standards Association, Incorporated. The ASA provides the machinery for creating voluntary standards. It serves to eliminate duplication of standards activities and to weld conflicting standards into single, nationally accepted standards under the designation "American Standard." Each standard represents general agreement among maker, seller, and user groups as to the best current practice with regard to some specific problem. Thus the completed standards cut across the whole fabric of production, distribution, and consumption of goods and services. Manufacturers, consumers, technical organizations, and governmental agencies -- all substantially interested and affected groups -- are represented on the committees which develop and regu larly revise American Standards. The completed standards are used widely by industry and commerce and often by municipal, state, and federal governments. The ASA, under whose auspices this work is being done, is the American clear inghouse for standards activity on the national level. Founded in 1918, it is a federation of more than 100 trade associations, technical societies, professional groups, and consumer organizations. Some 2200 companies are affiliated with the ASA as company members. ASA is the United States member of the International Organization for Stand ardization (ISO). Through this channel American industry makes its position felt on the international level. American Standards are on file in the libraries of the national standards bodies of more than 40 countries. For a free list of all American Standards or information about membership in the ASA write: AMERICAN STANDARDS ASSOCIATION INCORPORATED 10 EAST 40th STREET NEW YORK 16, NEW YORK MCD 000004816 On the job benzene vapor exposures of less than 5 ppm were measured concurrent with the 24 hour collection of urine from 52 employees. Urinary phenol levels of the collective study group, measured as either concentration or weight, showed a positive statistically significant correlation with benzene exposure. However, due to variances in individual baseline phenol levels, determination of benzene exposure at these low concentrations is relatively weak. Since baseline phenol concentrations exist over a range of values, adjustment fora single value ofeach individual's baseline did not improve correlation for the collective study group. A study of benzene exposure versus urinary phenol levels GORDON J. ROUSH and M. GERALD OTT HER Industrial Hygiene Laboratory, Corporate Medical Department, The Dow Chemical Corporation, Midland, Michigan 48640 introduction The 1974 N10SH proposed standard for benzene' requires the monitoring of urinary phenol levels of employees with time-weighted average (TWA) exposures exceeding 5 parts per million (v/v air). The correlation between benzene exposure and increased urinary phenol levels has been reported previously.2 A level of 75 mg phenol/ liter of urine (mg/1) is proposed as a signal of unacceptable benzene absorption requiring close medical surveillance. This study was designed to evaluate the proposed technique of "biological monitoring" in an industrial environment. It was also intended to determine if concentrations in the area of 75 mg phenol/liter of urine are indicative of unacceptable benzene exposure. mechanic, and material transfer operator. Usually, samples were obtained from two employees in each job. Participation was voluntary since the collection of urine depended on each person's willingness to cooperate. Urine samples and breathing zone air samples were collected on the same day. Increases in urinary phenol levels were expected to correlate directly w'ith inhalation of benzene vapors. Skin adsorption was assumed to be negligible since most jobs required the wearing of rubber gloves when handling benzene. Potential exposure to other chemicals should not have affected urinary phenol levels since none were known to interfere with, or contribute to the metabolism of benzene to phenol. benzene vapor sampling procedure Benzene is widely used as a raw material and solvent by The Dow Chemical Company. Five benzene-consuming production facilities were selected to represent industrial environments where benzene is handled along with other chemicals. Over a six month period, benzene exposures were studied for 52 employees from 25 job classifications, including laboratory technician, production operator, plant Actual TWA exposure to benzene was determined via personal samplers worn on each employee's collar throughout the course of his workday. Workdays varied from 8 to 12 hours in length. A small battery powered vacuum pump provided a low air flow rate, 100 to 250 milliliters per minute (ml/min), through charcoal packed stainless steel tubes. A few "extra large" commercially available sample tubes were used, but most of the sample collection tubes were custom-packed with Pittsburgh coconut base For more information about authors, see "this issue's authors . . w American industrial Hygiene Association JOURNAL (38) 2177 on page A-3 67 MCD 000004827 activated charcoal, 12-30 mesh. Charcoal was used because of its suitability for collection of a wide range of aromatic compounds which were likely to be encountered. The custom packed tubes were approximately .47 cm (3/16 in.) in diameter by 12.7cm (5 in.) in length and contained approximately one gram of charcoal. Efficiency of the total sampling system, including error of analysis, was determined by spiking sample tubes and submitting them for analysis with tubes used in monitoring. "Spiking" of the sample tubes was accomplished by preparing in a 100 liter SaranR bag a known concentration of benzene, both by itself and with a mixture of other chemicals found in the work place. Air from the bag was drawn through a sample tube at the same flow rate used in the plant studies. Collection of urine began when the employee started work, and continued for 24 hours. The "day" sample was collected in a hospital specimen container while the employee was at work. A second container for the "night" sample was taken home and used until he returned to work the following day. Thus, the two "combined" urine samples represented approximately 24 hours of urine. A baseline urine sample was collected by each employee after being away from work fora minimum of48 hours. No other restrictions were placed on the collection of the baseline urine sample. Information concerning consumption, within the last 24 hours, of any medication, tobacco, or alcohol was recorded by each employee for each urine sample. Anv known chemical exposure was also noted, hiiormation concerning previous or present health problems, particu larly of the liver, kidney, or heart, was requested for each volunteer. 10% SP 1000 5% FAPP 5% QF 1/8% SE 30 10% UCW 98 10-20% Carbowax 20,000 5% SP 1200/1.75% Bentone 34 10% LAC 2R446 15% Carbowax 4000 10% DC 200 Durapak OPN/Poracil C 80/100 The columns ranged in length from 1.83m (6 ft.) to 4.57m (15 ft.) and were prepared from .95cm (1/8 in.) inside diameter stainless steel tubing. Column temperatures ranged from 18.3 to 68.3"C (65 to 155F). Selection of a column depends on the combination of chemicals absorbed on the charcoal. A column packed with SP 1000, Durapak or SP 1200/Bentone would be suitable for benzene alone. urine samples Urine phenol analysis was based on the NIOSH proposed standard for benzene.1 The urine samples were hydrolyzed with perchloric acid at 95C for two hours, saturated with sodium chloride, and extracted with isopropyl ether. The ether extract was analyzed for total phenol using a flame ionization gas chromatograph. The only modification of the NIOSH method was the saturation of the hydrolyzed urine with sodium chloride. This step increased the extrac tion efficiency of the isopropyl ether. The chromatograph column consisted of a tube .95 cm (1/8 in.) in diameter, 1.83m (6 ft.) long and filled with 2% EGA CG-AW-DMCS (980-100 mesh) packing. The following temperatures were utilized: column at 160C, injection port at 230250C, and detector temperature at 290-300C. Maximum sensitivity under these conditions was about 2 mg phenol/liter urine. analysis of samples air samples The charcoal absorbent used in air monitoring was desorbed with cold carbon disulfide and analyzed by gas chromatography using a flame ionization detector. Specific chromatographic conditions varied over the several months of personnel sampling. Column packings included: 20-30% Carbowax 20,000 results data Table I lists data collected from air and urine sample analysis. TWA benzene vapor exposure concentrations are given as ppm (v/v) and they are grouped according to the length of the workday. Concentrations of phenol in urine are 'Registered trademark of The Dow Chemical Company abroad. 68 Am. Ind. Hyg. Assoc. J. (3d} February. 1977 MOD 000004828 Benzene TWA Range 40 2.5 2.0 1.5 1.3 12 1.1 1.0-0.6 <0.5 TABLE I Results of Air Sampling (ppm) and Urine Analysis (mg/I) Number of People 2 7 15 Hours Worked 12 12 12 12 12 12 12 12 12 ____________ Concentration Range of Phenol in Urine, mg/I _________ Unadjusted________ ________ NIOSH Adjusted Baseline Day Night Combined Day Night Combined 7 3 5 8 9 58 1-5 2-36 1-32 51 28 14 17 16 67 4-6 2-65 2-39 26 14 6 2 17 30 2-20 2-83 2 18 39 23 11 6 17 38 3-10 2-73 2-20 51 37 26 14 18 73 7-11 4-65 2-36 23 18 13 13 26 60 4-18 5-90 3-16 37 30 21 14 22 65 6-15 5 77 3-16 44 3.9 38 3.6 3.5 3.0 2.6 2.5 2.1 2.0 13 1.2 1.0-0.6 <C 5 1 2 T 1 1 4 5 8 6 27 51 35 27 51 35 8 2 41 22 25 55 29 34 8 4 49 22 32 51 22 33 8 2 39 6 7 17 13 8 37 46 45 45 61 64 63 8 4 24 21 22 36 28 32 8 3 14 12 13 22 17 19 8 6 10 5 7 10 5 6 8 4-5 11-23 9-10 9-15 18-20 11-15 15-16 8 75 40 64 57 34 55 49 8 2 62 5 74 6 8 11 46 25 30 37 18 21 8 2-6 3-21 4-24 4-23 4-18 4-19 4-18 8 3-80 2-16 4-12 4-13 8-15 5-11 6-17 expressed as milligrams of phenol per liter of urine (mg/1). The concentrations are listed as measured, and as adjusted according to the NIOSH proposed benzene criteria. The following equation was used to calculate the adjusted values. Adjusted nConcen.tr.a.tion Last 2 digits Measured of NIOSH aver- Concen- x age specific = --t-r-a--t-i-o--n------------- g--r-a--v-i-ty------------ Last 2 digits of measured specific gravity TABLE II Results of Air Sampling (ppm) and Urine Analysis (mg) Benzene TWA Range 4.0 2.5 2.0 15 1.3 1.2 1.1 1.0-0.6 <0.5 Number of People 1 i i 1 1 i 2 7 15 Hours Worked 12 12 12 12 12 12 12 12 12 Weight Renge of Phenol in Urine, mg Actual Adjusted for Baseline Day Night Day Night 32 21 22 8 12 16 6 3-65 2-28 16 7 7 3 18 25 2-11 4-77 2-9 28 19 14 4 5 2 1 to 4 -51 to 39 -10 to 23 12 5 1 -7 8 23 1 to 8 -20 to 52 -20 to 5 4.4 39 38 3.6 35 30 2.6 2.5 2.1 2.0 1.3 1.2 1 0-0.6 <0.5 1 1 1 1 1 1 7 1 2 1 1 1 4 5 8 21 20 17 18 8 13 31 12 28 8 76 7 4 8 5 17 8 32 82 2 13 6 15 . 8 17 17 14 14 8 12 18 9 13 8 4 3 2 -1 8 5-12 10-11 3 to 10 5 to 6 8 15 52 -13 -9 8 51 4= 1 8 8 16 6 8 8 2 6 2-8 0 to 5 1 to 7 8 2-6 5-10 -24 to 2 -56 to 3 American Industrial Hygiene Association JOURNAL (38) 2/77 69 0004829' TABLE 111 Coefficients from Correlation of Benzene TWA Exposures with Weight of Urinary Phenol and Urinary Phenol Concentrations TWA of 8 hour workday {22 men) Urine Segment Day Night Combined Phenol Weight Coefficients 0.66 0.46 0.53 Phenol Concentration Coefficients Measured 0.55 0.50 0.52 NIOSH Adjusted 0.66 0.63 0.64 TWA of 1 2 hour workday (30 men) Day Nighi Combined 0.44 0.18 0 32 0.42 0.18 0.34 0.51 0.23 0.41 TWA of combination of 8 and 12 hour workdays Day Night Combined 0.38 0.40 042 0.45 0.37 0.43 0.56 0.42 0.50 TWA of combination of 8 and 12 hour workdays. 5 cases of "unacceptable** phenol concentrations deleted Day Night Combined 0.57 0.69 0.72 0.56 0.55 0.61 0.69 0.69 0.77 TWA of combination of 8 and 12 hour workdays. 5 cases of "unacceptable'' phenol concentrations deleted. 12 hour workday data adjusted to an 8 hour workday Day 0.70 Note: A perfect correlation is 1.0. no correlation is 0.0. Each product moment correlation coeffecient above was calculated as follows: Coeff Xi Y> + X>Y> + . . . + XnYn _*(mean value of x) (mean value of y) (n-l)(Std. deviation of X) (Std. deviation of Y) Where n = number of observations X, Y = parameters being correlated The average specific gravity of urine used by NIOSH is 1.024. As a comparison, the respective average specific gravities of urine samples included in this report were 1.021, 1.021, and 1.022, for the day samples, night samples and baseline samples. These values are similar to the se recently reported for a large vvuix population. The weight of phenol measured in the urine samples is shown in Table II. Phenol weight was of interest as an alternative to concentration as a means of measuring benzene exposure. Measuring weight instead of concentration would eliminate the problem of low phenol concentration due to the intake of large volumes of liquid. This dilution of urinary phenol levels is handled in the NIOSH criteria by measuring .'oecific gravity, comparing it with a traditionally used average, and adjusting the measured concentration accordingly. correlation of data parameters Two main parameters, urinary phenol concentration and phenol weight, were correlated with measured employee TWA benzene exposures. The correlation coefficients and the equation used in calculating them are shown in Table III. A correlation coefficient is a measure of the strength of relationship between two variables. In Table III, most of the coefficients exce:d 0.3, a value representing the highest correlation which would be expected if random numbers were substituted for the reported sample values. This value assumes a sample size of 52 observations and a confidence level of 95% or p <0.05. Since most of the coefficients exceed 0.3, in most instances a positive significant correlation exists between TWA benzene exposure and the two different measures of urinary phenol levels. Figures 1 and 2 are plots of the strongest relationships for phenol concentration and phenol weight respectively. Besides comparing two methods of reporting urinary phenol levels. Table III indicates the different ways in which the experimental data was analyzed. Obvious subgroups exist in the total of 52 observations reported. Examination 70 Am. Ind. Hyg Assoc. J (33) February, 1977 MCD 000004830 Figure 1 - TWA benzene expsoure versus adjusted con centration of phenol in urine (.5 cases of high baseline concentrations deleted). of the data included analysis of these subgroups as well as the total group. Two of the sub-groups in Table III resulted from the sampling of employees with two different length, 8 and 12 hour, workdays. A third sub-group with the high baseline urinary phenol levels became evident after the data had been collected. High baseline levels are apparently normal for some individuals and these individuals may exceed the concentration of 75 mg/1, proposed in the NIOSH document as an unacceptable level of "absorption." The five individuals with high background phenol levels will be discussed in more detail later. They were deleted in the last two correlation groups in Table III in order to determine the degree of influence they exerted on the collective group. The last correlation in Table III was an effort to further examine the relationship between excreted phenol weight and benzene exposure. Since the data had been collected using two different length workdays, it was logical to expect a higher weight of phenol to be excreted in the "day" samples by persons working the longer day. This was assuming vapor exposures were fairly equal throughout the workday. The individual phenol weights collected during the 12 hour workdays were reduced by 1/3 to equalize them with the 8 hour workday. The correlation of this adjusted "day" weight of phenol is reported as the last section of Table III. This study agrees with previous studies showing a good correlation between benzene exposure and urinary phenol levels. The highest correlations in Table III occurred when the five persons with high background phenol levels were deleted from the data. These correlations are statistically significant at the critical level, p <0.005. If persons with high baselines are included in the data field, the best correlations are significant at 0.0005 <p <0.005. However Figures 1 and 2 show the unpredictability of this association at relatively low exposure levels. These figures are plots of data, excluding high baseline phenol levels, which generated the highest correlation between phenol concen tration/weight and TWA benzene exposure. Plots of data which included persons with high baseline phenol levels showed an even wider and more unpredictable scattering of points. The solid line in Figures 1 and 2 is a least-squares plot, or regression line. The broken lines represent plus or minus two residual standard deviations and should contain between them approximately 95% of the data points. Efforts to use the regression line to predict benzene exposure resulted in the equations shown in Figures 1 and 2. The ppm value for two standard deviations is given below each equation. Two standard deviations for these, the best two correlations, represent an unacceptable 35-40% of the experimental (0-5 ppm benzene) data range. For example, assume an employee's urine was monitored and it contained 25 mg/1 of phenol. Based on Figure 1, the best conclusion that can be drawn is that the employee is 95% sure his TWA benzene exposure was between 0.4 and 3.9 ppm. Or, if 100 employees were monitored for one day, and all of the urine Figure 2-TWA benzene exposure versus weight of phenol in urine (5 cases of high baseline concentrations deleted). American Industrial Hygiene Association JOURNAL (38) 2/77 71 mcd 0o004Q31 TABLE IV Correlation Coefficients for TWA Benzene Versus Urinary Phenol Weight. Adjusted and Unadjusted for Background Phenol Levels TWA of 8 hour workday (2 men) Urine Segment ay Night Combined TWA of 12 hour workday (30 men) Day Night Combined TWA of combination of 8 and 12 hour workday Day Night Combined TWA of combined 8 and 12 hour workdays, 5 cases of "unacceptable" phenol concentrations deleted Day Night Combined TWA of combination of 8 and 12 hour workdays. 5 cases of "unacceptable" phenol concentrations deleted. 12 hour workday data adjusted to an 8 hour workday Day Note: Perfect correlation is 1.0. no correlation is 0.0. Unadjusted for base 066 046 0.53 0.44 0.18 032 0.38 040 0.42 057 0.54 0.65 0.70 Adjusted for base 0.59 0 59 060 038 0.15 0.29 0.36 0.40 0.41 0.41 0.58 0.53 0.45 samples contained 25 mg/1 of phenol, one could assume that approximately 95 out of the 100 had had a TWA benzene exposure between 0.4 and 3.9 ppm. Less than 10% of the time will an employee's actual exposure fall on (within 0.1 ppm of) the regression line. Urinary phenol levels are not an accurate method of predicting TWA benzene exposures in the range of 5 ppm or less. Another observation exists. It is that NIOSH's recommended procedure for adjusting "spot" urine samples to a standard specific gravity slightly improved the correlation of the 24 hour urine samples. NIOSH recommends this TABLE V Summary of Employees* with High Baseline Urinary Phenol Levels Benzene, ppm TWA Age 0.2 57 0.8 0.8 48 1.2 23 2.0 33 3.5 27 MedK'**on used at time of survey Esidrex 2 Aspirin day of 1st base History o medical problems Hi blood pressure No Problems Diet medication during workday sample, Rolaids on 3rd base No Problems None No Problems 2 Aspirin day of 2nd base No Problems - Urinary Phenol Levels. mg/I V.ork hours per day 8 Measured Day Night Base 16 12 *- 80 12 NIOSH Adiusted Day Night Base 15 12 * 68 9 12 65 83 26 65 91 33 - -- 99 - 108 ", - 62 - 64 12 67 30 58 73 60 87 -- 44 51 -- 63 * 58 8 40 64 75 34 55 64 -- 59 - 64 * 36 * 32 8 46 45 37 61 64 47 -6 7 84 * 77 AM male employe-* 72 Am Ind. Hyg. Assoc. J (38) February. 1977 MCD 000004832 5.0 r 4.0 - a3 i -100 -50 0 50 Unadjusted Weight of Phenol in Urine, mg too 150 Figure 3-TWA benzene exposure versus unadjusted weight of phenol in urine. procedure a hen a single urination is sampled, to allow for dilution of phenol concentrations due to large volumes of liquid intake. When this adjustment was applied to the various urine segments. Table III, the resultant concentration correlated better with TWA benzene exposure. background phenol levels Table IV, and Figures 3 and 4 present the result of adjusting measured urinary phenol levels Volume of Urine Day Night Bata 375 850 '` 44 25 1000 . - 925 - - 73 140 225 235 - - . . 1450 235 255 Specific qravitv Day Night Bate 1.026 1.025 1.028 - - 1.031 1.024 - 1 022 - - 1.019 1.022 1.023 1.022 - - 1 012 - - 1.016 1.021 1 026 365 820 260 1 028 1.028 1.028 . 55 - 1.022 - 365 - 1.027 690 1825 695 1.018 1.017 1.019 - 13 - - 1.021 T- * * 445 - * 1.026 according to each individual's normal baseline level. A baseline urine sample was collected after each volunteer had been away from work or any known chemical vapor exposure for 48 hours. Each baseline phenol weight was calculated and subtracted from the total weight of phenol in their "day" and "night" urine segments. Theoretically, this adjustment should have compensated for persons with normally high urinary phenol levels, leaving the adjusted weights of phenol entirely related to benzene absorption. Figure 3 is a plot of unadjusted urinary phenol weight for all 52 observations. Figure 4 illustrates the effect of subtracting the baseline ground weights of these 52 individuals. Table IV compares group correlation coefficients for TWA benzene exposures versus both unadjusted and adjusted weights of urinary phenol. In most cases, the unadjusted measured weights have a higher group correlation than the adjusted weights. This finding indicates the difficulty in using a single value for baseline urinary phenol levels. For any individual, a baseline range should be determined to accurately assess what phenol level is "above" normal. The negative phenol weights in Figure 4 also indicate that unknown factors are causing greater fluctuations in baseline levels than those resulting from low benzene exposures. A study of non-exposed controls is underway and will be reported in a future publication. American industrial Hygiene Association JOURNAL (38) 2/77 73 000004833 MCD The benzene r ing will urf react with w-1Le* or hydroxyl ions unless it * 80 is substituted with a .number of; eIect''negative groups (Ayers and * 81 Muder, 1964) . Without this substitution, the hydrolysis of benzene * 82 will occur only under specialized condi* `on- of temperature and * 83 pressure. Oxidation v/i11 occur only in the pi esence of catalysts * 84 and/or elevated temperature (Howard arid Durkin, 19741. Benzene can be * 86 photo l.yzed at v/ave lengths less than ?9Q nm (Howard and Durkin, 1974); * 87 Kaplan e_t al_. (1971) demonstrated one of the photoproducts of aqueous * 88 benzene to be 1,3-cyc!opentadiene~1-cartoxaldshyde. B_enzene can be * 89 photolyzed in smoq or heavily polluted air. The long-term stability * 90 of benzene under atmosphere 'onditions. is unknown, but it is not * 91 completely inert (Howard md nijricjrij 1P7-1). * 91 Toxicology Data Plants * 93 * 95 Duns tan et al; ( 1975 ) exposed Skeltonema costalom (diatom), Amphidinium carterae (din0f1 age!late), Cricospaera carterae (cocrolithophorid) and Dunaliella terticlecta (green flagellate) cultures to various concentrations of spectro-grade benzene. In Amphidinium, growth was inhibited at concentrations from .001 to 100 mg/1, while the growth of Cricosphaera carterae was inhibited at benzene concentrations of ip mg/1 to loo mq/1; Dunaliella tertiolecta growth increased slightly at these r'oncnntrations. * 99 * 100 * 101 * 103 * 103 * 104 * 105 .* 106 4 Interim DPAFT Ho. I November 15, 1977 PV/KMIl - *3 *4 *5 *6 000004856 MOD Invertebrates * 110 Tigriopus californicus, a tide copepod, was exposed to four different * 114 concentrations of benzene (0.87, 0.44, 0.22 and 0.087 mg/1) by Barnett * 115 and Kontogiannis (1975). The two highest concentrations proved lethal * 116 to 40 percent of the copepods within the first two days of exposure. * 117 Of the copepods exposed to the lower benzene concentrations (0.22 and * 118 0.087 mg/1), 70 percent survived the 7 day observation period. * 119 Vertebrates * 122 In a acute toxicity study performed on striped bass (Morone saxatilis) * 125 in a continuous flow bioassay, the 72-hour and 96--hour LC50 values for * 126 benzene were identical - 10.9 + 0.2 ul/1, 9.6 mg/1 ^_Meyerhoff, 1975). * 128 Korn et al_. , (1976b) examined the effects of 3.5 ul/1 (3.07 mg/1) and 6.0 ul/1 _5.27 mg/1) benzene on the behavior of striped bass, Morone saxatilis, in a flow-thorugh bioassay. Fjsh were examined at 7 day intervals for 28 days. Benzene caused decreases in dry weight, wet weight and percent fat, but no differences was observed in kilocalories per gram weight between the two groups. Hyperactivity and changes in feeding habits were observed in fish exposed to 5.27 mg/1 benzene; fish at the lower concentration were only moderately affected. By one week after initial exposure, behavioral and feeding habits began to return to normal in both groups. * 130 * 131 * 133 * 134 * 135 * 137 * 138 * 138 * 140 * 141 5 Interim DRAFT No. I November 15, 1977 PV/KMM *3 *4 *5 *6 ' Flickering and Henderson (1966) studied f;'e acute toxicity of benzene * 143 to fresh water fish unde*' static bioassay conditions. In s0^t water * 145 (20 mg/1.; EDTA) 96-hour TLm values for fathead minnows (Pimephales * 145 promelas), bluegill (Lepom.s macrochirus'. goldfish, (Carassius * 146 auratus) and guppies (Lepistes reticulatus) weie 33.47, 22.49, 34.42, * 147 and 36.60, mg/1, respectively. In hardwai.ay (360 ma/1 hardness; EDTA) * 149 the 96 hour TLm was 32.00 my/1 for fatheads. * 150 Struhsaker et al_. (1974) examined the effects of benzene * 152 concentrations ranging from 5 to 55 ppm-vol/vol on egg and larval * 153 forms of Pacific herring, Clupea harengus pallasi (exposed for up to * 154 96 hours) and on the northern anchovy, Enqraulis mordax (exposed for * 155 up to 48 hours) in static, bioassnys. H_erring eggs exposed to an * 156 initial mean concentration of 35.2 to 39.6 mg/1 of benzene exhibited * 156 50 percent mortality after 95 hours, as well as delayed or abnormal * 157 development of the larval forms hatched from the exposed eggs. All of * 159 the larvae that survived longer than 33 days appeared normal. Initial * 160 mean concentrations of !7.5 to 22 mg/1 caused 50 percent mortality in * 161 herringlarvaeexposed for 43 hours and observed for 7 days. * 161 Mortality wasdue toclosure of the fore- andhindgut, resulting from * 162 changes in feeding habits. All concentrations greater than 8.8 mg/1 * 164 caused a delay in larval development, retarded growth, an increase in * 165 respiration and an interruption of normal behavior. The authors * 167 stated that the benzene concentration in the assay decreased over each * 168 24 hour exposure period (e.g., 39.6 mg/1 decreased to 10.6 mg/1 or * 169 6 Interim DRAFT No. I November 15, 1977 PV/KMM _ *3 *4 *5 *6 MCD 000004858 1 ass after 24 hours), due to '.'o i i til i 7-, L ' on. Anchovy larvae * 170 experienced 50 percent mortality at 17. to 22.0 mq/1 benzene after 48 * 171 hour exposure. At a concentration cf 4 \ mg/1 for a single 24 hour * 172 exposure, benzene caused a_ slight ac.ce1cration of larval development. * 173 Yolk utilization and effects on egg development were directly related * 174 to j^lte length of exposure to benzene. A 24 hour exposure to 4.1 and * 175 9.2 mg/1 increased yolk utilization, while 40 hours of exposure to the * 176 same concentrations delayed utilization; developmental rates declined * 177 with increasing concentrations and length of exposure. Anchovy and * 179 herring eggs were more '-esistant to benzene toxicosis than the larval * 180 forms of both species (Struhsaker, et aj_., 1974). * 180 Non-Human Mammals * 183 Sprague-Dawley rats of differnt ages received oral doses of undiluted * 186 benzene to determine the omnl IP 50(bimura et_ al_., 1970). Acute LD * 188 50's a -e: Immature rats; 3.-1 mg/kg; young adult rats, 3.8 mg/kg; old * 189 adulL rats, 5_.6 mg/kg. A concen tra tion of 0.87mg/kg body weight * 191 provedfatal to newborn rats. Deichman et_ a_L,(1963) exposed * 193 Sprague-Dawley rats to 15 to 831 ppm benzene vapor for 20 hours/week * 194 for 6 to 31 weeks. Rats exposed to a mean concentration of 65 ppm for * 195 26 out of 39 days shoved a_ decrease in v;hite blood cell count after * 196 tve weeks in males and after four 'weeks in female rats. Animals * 198 exposed to 47 ppm and .7! ppm exhibited abnormalities of the spleen and * 199 lungs. Rats exposed to 831 ppm fnr 32 or 46 days showed a decrease in * 200 7 Interim Cl'AFl No. I November !5. 1977 PV/KMM -- *3 *4 *5 *6 MCD 000004859 white blood cell count i1'**- remainod r<'--stant throughout the period of exposure. * 201 * 201 Hjraki e_t a_L ( 1963) injected 5 female mi 5 male mice with 0.1 ml of * 204 a 1 percent solution (0.87 mg) earl) w^ek . fy.o mice died in 8 weeks; * 205 the remaining 8 mice wrs treated for K1 weeks. Of these, 2 males and * 206 3 femalesdeveloped subcutaneous sarcomas. Threeof thesetumors were * 207 transplantable into syngeneic mice. No controlswere reported. * 208 Humans * 211 Dobashi (1974) measured the cell renewal rate as well as the rate of * 214 DMA synthesis in ml tu- "d human_ leukocytes and Hela cells exposed to * 215 benzene. Both cel1 tvrm p/bibitn'1 5D percent inhibition of growth at * 216 2.2x10~3M {_171.6 mg/1), lhe rate nf DflA synthesis was 50 percent * 218 inhibited in leukocytes at 2.2xl()-3f1 (171.6 mg/1), while this * 219 phenomenon occurred at 1.1x10-311 (95.8 mg/1) benzene in HeLa cells. * 220 In man, acute benzene poisoning is characterized by nausea, vomiting, * 221 ataxia and excitement, ``oilowed by depression and coma. Death is * 223 usually the result of respi'story or cardiac failure j[Holvey, 1972). * 224 Aksoy e_t al_. (1976) reported that, of 34 patients, six patients having * 226 been exposed to 150 to 210 ppm benzene vapor for up to 28 years (mean * 227 exposure: 11 years) wore diagnosed as having Hodgkin's disease. * 228 Twenty other patients, also exposed to benzene, were later diagnosed .* 229 8 interim DRAFT No. I November 15, 1977 PV/KNM _ *3 *4 *5 *6 wcc ooooo^60 as leukemics. Based on case studies, the authors stated that benzene, because of its toxicity to both the hernat^ooietic and reticuloendothelial system, is etiologically related to the onset of Hodgkin's disease. Alternatively, the au^'mrs croposed that benzene may act with other unknown factors contributing to the onset of this proliferative disorder. *231 * 232 * 233 * 234 * 235 * 23b Aksoy e_t aj_. (1974) determined the distribution of types of leukemia * 237 in 34 patients (shoe workers exposed on the job) with chronic benzene * 238 poisoning. The incidence of leukemia was determined to be 13.5 in * 240 100,000, which is greater than the incidence of leukemia in the * 241 general population in 100,000). P_ati^r fs were chronically exposed * 243 to 210 to 640 ppm benzene vapor for up to T) years and most frequently * 244 exhibited acute myeloblastic leukemia. P_rn]evkemia, erythroleukemia * 245 and acute lymphoblastic leukemia were alsn diagnosed. The authors * 247 "Oted that the number of cases of leukemia among shoe workers declined * 2A8 in 1974; benzene usage was prohibited In Me factory in 1969. The * 250 authors also stated that, in 3 of the workers, genetic predisposition * 25C to leukemia by virtue of a past family rmuHr.al history of leukemia was * 231 contributory to the onset of the disease. * 252 Thorpe (1974) reported the results of a ton year study of workers * 254 chronically exposed to benzene vapors. In a population of 38,000 * 256 workers exposed to low levels of benzene, the numbers of leukemics was * 257 not abnormal when compared to the genera1 population. * 258 9 Interim DRAFT Do. \ November 15, 19'* PV/KNM _ *3 *4 *5 *6 MCD 000004861 Environmental Fate and Effects. * 260 Benzene is susceptible to breakdown by microorganisir?, While this has * 263 been proven under laboratory conditions, the extrapolations to * 264 environmental situations are difficult to make. Studies indicating * 265 that benzene can be degraded, with degradation rates depending on * 266 acclimation and incubation of the organisms, have been performed * 267 (Bogan and Sawyer, 1955; Malariey, 1960; Marion and Malaney, 1963; * 267 Chambers et. a]_., 1963), but these studies with mixed cultures indicate * 268 only the possibility of degradation, and at a very slow rate. * 269 Atlas and Bartha (1973) indicated that the biodegradabi iity of b_enzene * 272 in the marine environment is severely hampered by the limiting * 272 concentrations of nitrogen and phosphorus It must also be considered * 274 that the possibility of microbes using benzene as the sole or * 275 predominant carbon soruce is rare. * 275 Korn et. al.. (1976a) investigated the uptake, distribution and * 277 depuration of 14C-benzene in the northern anchovy, Engrauiis mordax, * 278 and the striped bass, Morone saxatilis. Anchovies were exposed to * 280 initial concentrations of .00069 ul/1 00061 mg/1) t.o 3.7 ul/1 (3.3 * 281 mg/1). Bass were exposed to an initial concentration of JD88 ul/1 * 283 (.08 mg/1). Exposure to 14C-benzene was static for 48 hours, followed * 284 by resumption of water flow for the duration of the experiment (to 9 * 285 10 Interim DfAFT No. I November 15, 1977 PV/KMM *3 *4 *5 *6 AS6*2, 0000 days). Benzene concentrators 'r rh* w"::er decreased exponentially throughout the experiment. * 286 * 287 The authors reported no deaths dur-g the tests. Accumulation in the * 290 bass was greatest in the gall bladder, collowed by the colon, liver, * 291 intestine, brain, gill, heart, stomach, and muscle. The gallbladder * 293 accumulated up to 53.4 and 8,450 times the initial water concentration * 293 and the muscle accumulated up to 111 and 135 times the water * 294 concentration in the bass and arohT.'y espectively. Maximum * 295 concentrations were attained from 0.35 to 4 days after exposure. Gall * 296 bladder, fat, and gill tissue retained labeled residue the longest. * 296 Depuration in the bass began on day 2 up to day 4 or 5 after cessation * 298 of exposure. Residues were undetectable in muscle tissue within 24 * 299 hours after exposure enled, * 300 Anchovies showed greate " retake than dH the bass, with maximum levels 303 maintained the longest 1-n brain, mscle and intestine. The liver * 304 accumulated up to 309 Hmps the Inti tel '-ater concentration. * 305 Benzene appears to accumulate in his sues that exhibit a high lipid content (Korn et_ ah . 1976a) or t present major metabolic sites. The major route of depuration in the 'v.o species of fish appears to be ]_iver, gall bladder, intestines and through the colon. In bass, most residues were not detectable beyond 7_days. * 307 * 309 * 309 * 311 * 312 11 Interim L),:AFT No. I Uovemter 15, 3 '377 PY/KMM *3 *4 *5 *6 MCD 000004863 Oeichman et a]_. (135?) exposed rat" to " average nf 'I7 ppm benzene * 314 vapor. Bjood benzene 1 r- n 1 s tanged fcr`.-an to 8.70 mg/1 (mean = * 315 4.2 mg/1) aftf?'' 180 days of o;'r.n;.<>-.- f-t. `-`<8 vanov exposed to 44 * 317 ppm for up tr 58 . 7- bo nr : orio is a airta * ed ablood benzene level range of 3.2 to 6.7 iug/1 fn.rnn = 4, p 1 mg/ i) . Summary * 318 * 318 3_enzene has bean demonstrated to: * 320 1_. Bicaccumulate up to 3150 times ;n the gall bladder of the northern arvhovv. * 322 * 322 2. to be a significant environmental pollutant because of its presence i_n n^soi'ies- * 324 * 325 3_- to cause changes in feeding habits in fish at 5_.27 mg/1. * 328 4. to cause 40 percent lethality in copepods at a concentration as low as .44mq/1 in 43 hours * 330 * 331 5_. to befatal to ?|p>./ horn tats a' anoral dose of J37 mg/kg body weight. * 334 * 334 6. have a 96 hou* 1.050 for striped Hass of 9.6 mg/1. * 336 7_.. to be implicated as a cans i five '-gent for leukemia in humans. * 339 12 Interim PPAFT No. I November 15, !77 PV/KOM *3 *4 *5 *6 Criterion Formulation * 341 8ased on the bioaccumulation properties of benzene an application * 343 factor of 0.01 is used. When the 0.01 application factor is * 344 multiplied by the 96-hour LC50 of 9600 ug/1 for the striped bass, * 345 Morone saxatilis, an economically important food organism, a criterion * 345 of TOO ug/1 Is derived. Sjnce benzene is considered to be a suspected * 347 carcinogen, all human exposure should be avoided. * 347 13 Interim DRAFT No. I November 15, 1977 PV/KMM _ *3 *4 *5 *6 ooooo^66 Vic REFERENCES * 350 1. Aksoy, M., e_taj_., 1974. Leukemia in shoe-workers exposed chronically to benzene. Blood 44: 837 * 353 * 354 2. Aksoy, M., et_ al_., 1976. Types of leukemia in chronic benzene poisoning. A. study in thirty-four patients. Acta. Haematologla, 55:65. * 357 * 359 * 359 3_. Atlas, R.M. and R. Bartha, 1973. Stimulated biodegradation of oil * 362 slicks using oleophilic fertilizers. Environ. Sci. Technol., 7: * 364 5.18. * 364 4. Ayers, G.W. and R.F. Muder, 196/>. ^Benzene", in Kirk-Othner Encyclopedia of Chemical Technology, A. Stanton ed. 2nd Ed. John Wiley and Sons, [nc., N.Y., Vol. 3, p_. 367. * 367 * 368 * 369 5_. Barnett, C.J. and J.E. Kontogiannis, 1975. The effect of crude oil fractions on the survival of a tidepool copepod, Tiqriopus californicus. Environ. Pollut. 8: 45. * 372 * 373 * 374 6_. Bogan, R.H. and C.M Savfyer, 1955. Biochemical Degradation of Synthetic Detergents, II. Studies on the reaction between chemical structure and biochemical oxidation. Sew. and Ind. Waste, 27:97. * 376 * 377 * 378 * 378 14 Interim DRAFT November 15, PV./KMM No. I 1977 " *3 *4 *5 *6 MCD 000004866 7. Deichmann, W.B., et aj ., 1963, The h^cpoietic tissue toxicity of * 381 benzene vapors. Toxicol. ApdI . Pharmacol. 5: 201. * 382 8. Dobashi, Y., 1974. Effects of benzene and its metabolites on the mitosis of cultures human cells. Sangyo Igaku 16: 453. * 385 * 387 9_. Dunstan, W.M., et_ aj_., 1975 . Stimulation and inhibition of * 390 phytoplankton growth by low molecular weight hydrocarbons. Marine * 392 Biol. 31: 305. * 392 10. Environmental Protection Agency, 197^. Health Effects of benzene: * 395 A Review. EPA 560/5-7S-0C3, Washington, O.C. Federal Register, * 397 27 May 1977. Part Vi Occupational Exposure to Benzene p. 27458. * 397 11. Hiraki, K., et_ a]_. . 1963. Development, of subcutaneous sarcomas in * 400 Swiss mice given related injections of benzene in olive oil * 401 Gann 54: 427. * 402 12. Holvey, D.N., ed. 1972. Hie Merck Manual of Diagnosis and Therapy. Merck and Company, P.ahway, Mew Jersey, p. 1697. * 405 * 406 13. Howard, P.H. and P.R. Ourkin, 1374. Sources of Contamination, Ambient Levels, and Fate of Benzene in the Environment, prepared for Office of Toxic Substances, IMS. Environmental Protection Agency, EPA 560/5-75-005,Washington, D.C. * 409 * 410 * 411 * 411 15 Interim DRAFTNo. I November 15, 1 077 PV/KMM _ *3 *4 *5 *6 000004867 tfCD K.ip Inn . L ?i: a I. , ' ' Fhefcrov.'d'1':1': of Aq'/eou^ Benzene. I. Identification of the -f nr'-tct as ' ' 'openta-liare - 1-carboxalclpiv/^0 . ,!nur . <'< . CItti. !>c. 92 3-3 I * 414 * 415 * 416 16. Kay, K , 19 76. Tox i co ! 'g i e and roncer scenic evaluation of chemicals used in the graphic art: industries. Clin Toxicol., 9: 359. * 419 * 420 * 420 16. Klnuira, E.T., et_ al_. . 1 Acute tux rity and limits of solvent residue for sixteen r-vg-nic solvents [oxiocol. Appl. Pharmacol. 19-699. * 423 * 425 * 425 17. Korn, 3. et_ a1_., 1975c Uptake, disir ibvtion and depuration of 14C-benzene in nor the--, r. ruv-ncry. ergraul is mordax, and striped bass, Morone saxati 1 is tr-.h. puH. 7 515. * 427 * 428 * 428 IP. Korn, 5., ejt a]_., 1976b. T ? fe r;4 r content and caloric 'T-t'-m!- -> r ?t> Fish, Bull. 7A: 694. benzene on growth, fat hiss, Moron,.: - -ratal is. * 431 * 432 * 433 1. MaTaney, G.W. , I960. 0 -'dative Ah * I< ty of Aniline Acclimated Activated Sludge. Jour, "-tor I'^lit. Cnntr. Fed., 32:1300. * 436 * 438 16 Interim DP AT1 Mo. 1 November 1 fj, 1977 PV/KMM "I *3 *4 *5 *6 000004868 mod 20. Marion, C.V. and G.W. Malaney, 1963. Ability of Activated Sludge Microorganisms to Oxidize Aromatic Organic Compounds. Purdue, Univ., Eng. Bull. Ext. Ser. 115, 297. * 441 * 443 * 443 21. Meyerhoff, R.D., 1975. Acute toxicity of benzene, a component of crude oil to juvenile striped bass (Morone saxatilis) Jour. Fish Res. Board Can. 32: 1864. * 446 * 447 * 447 22. National Academy of Sciences, National Academy of Engineering, 1974. Water quality criteria, 1972; U_.S. Government Printing Office, Washington, D.C. * 449 * 451 * 451 23. National Academy of Sciences, 1976, A Review of Health Effects of Benzene, National Academy of Sciences, Washington, D.C. June.. * 454 * 454 24. Pickering, Q.H., 1966. Acute toxicity of some important * 457 petrochemicals to fish. Jour. Water Pollut. Cont. Fed., 38: 1419. * 458 2_5. Stecher, P. ed. 1968. The Merck Index, Merck and Co., Rahway, New * 462 Jersey. * 462 26. Struhsaker, J.U., e_t aJL , 1974.Effects of benzene ( a water * 465 solublecomponent of crude oil) on eggs and larvae of Pacific * 466 herring and northern anchovy. _In Pollut. Physiol. Mar. Org., J.F. * 467 Vernberg and W.B. Vernberg, eds. Academic Press N.Y. p. 253. * 468 17 Interim DRAFT No. I November 15, 1977 PV/KMM _ _ *3 *4 *5 *6 0 ' mcD 000004869 Thorne, J.J. , 1974. epidemiologic survey of leukemia in persons potentially exposed to benzene. dour. Cccup. Med. 15: 375. * 471 * 472 18 interim UflAFr rio. f November 15, l''77 _ *3 *4 *5 *6 MCD 000004870 CRITERION DOCUMENT POLYNUCLEAR aromatic hydrocarbons' 8 S' * Criterion An interim vaLuet of 0.2 wt/1 total polycyclic aromatic f 14 hyi rocarbons is recommended for ambient waters. I 15 Because many polynuclear aromatic hydrocarbons are 16 carcinogenic in animals, human exposure should be 17 minimized. V 17 I Introduction 19 Polynuclear aromatic hydrocarbons (RAM's) represent a large class of compounds, many of which are tumorigenic in animals. PAH'S are formed as a result of incomplete* combustion of organic compounds without sufficient oxygen This leads to the formation of C-H tree radicals which cin polymerize to form various PAH'S (Groll, 1933; Ellis, 1937) . Domestic and industrial soots are^ 21 23 2425 * 26 27 the products of incomplete combusti on of carbonaceous materials such as wood, coal, and oil. The an relation of exposure to 300ts and. disease was first reported by the British surgeon, Percival Pott (1775), who observed a high Incidence of scrotal cancer in chimney sweeps. Three yea*. 3 later, as a result of Pott's finding, the Danish chimney c.feeps Guild suggested that its members remove soot from their 'lathing and bathe daily. A century later, Butlin ( 1392) revealed that, as a result of hese 28 30 31 32 33 34 35 36 1 INTERIM DRAFT NO. I December 1C, 1977 - PV/KMM : 3 4 |5 6 MCD 000004871 precautions, scrotal shin cancer became relatively rare- Thus, *h'* first example of 'll cease pr. event ion by reduction in direct exposure to the carcinogenic agent-, fs) -./as revealed. 37 38 38 Butlin (1892) observed greater incidences of skin cancer among workers in contact with coal-tar and pitch, which are residual products of coal distillation. Naturally formed oil in shale and petroleum, formed by heat and pressure in the earth's crust from decomposed animal and vegetable matter, contain PAH (Berenblum and Schoental, 1943; Cntchpole et ajl. , 1971). 41 42 43 44 45 45 The first case of skin carcinoma as ca result of exposure to shale 47 oil was reported by Bell (1876) and I.he carcinogenicity of shale 48 oil was later shown bv redtoh (1922) . . -49 The following list- shews pahs that have been identified from various sources (IARC- 1973)- - 52 52 2 INTERIM P.NAFT December IQ pv^'-yi NO. I 1977 3 4 |5 6 WCD OOOo04872 Table 1 Some Sources of Polycyclic Aromatic Hydrocarbons 55 56 57 MPOUND COAL-TAP PITCH SOOT SHALE OIL CRUDE OIL CRACKED OIL G E E nzo(a) pyrene 'iz(a) anthracene uzo (hi fluoranthene benz (a,h)anthracene ` enzo (a,e)pyrene ^nza(afh) pyrene 1 'enzo (a, i) py rene 'ysene "zo (j) fluoranthene leno(Le2r 3-cd)pyrene j > + i 4- 4- + + 69 70. .L 4- 3 INTERIM DP.APT December 10, rv/kmm HO. r i?77 3 4 I5 ooooo 4873 VIC'D <' jnncntra tions of .* e nton-hi nek ^not h;ve been reported as b i oh as 70640 inq/ko i <>r b ~uro (e) pyrne -nd bcnzo(a) pyrene (Falk 0 k a L .. 1959) . All 'r,`iiip,.nu`',-r l 1 -i d Lp V ib i.e l have been shown fo be carcinogenic i n 1 ihor - `-vy animal. h c?n ks . These components alone or in combine f.i o> are held ho be responsible for the rarernogenic effects of these pyrolytic products- Pyrene and f luorene, which are * n active o^rcinolens , hav e been found in coal Pars (T7indholz, 1970),, 76 77 78 79 80 82 82 82 Polynuclear aroma hi'* hydrocarbons find their way to waterways B4 adsorbed, onto aerosol ' v b 'C-eria. (Andelman and Suess, 1970). 35 Although their 90 l.ubi l.i. ty in cater is essentially zero, they may 87 euist in water in association *ith organic matter or colloids 89 (mi cel Les) as formed ty nynfh'tic detergents. Andelman and Suess 89 (T 970) reported that ''sc'-inoqon i.c t'd! concent rations, in 89 groundwater wore, Q.OOl `-o P.ni uq .1 ; treated river and lake | Ql cater as, 0.01 to ^0.070 uq/l; and surface water asr 0.025 to | 92 0.100 uq/1. In highly contaninatf'd surface water level3 qreater | 93 whan 0.1 uq/1 were- found... gorneff and Kunte (1969) have examined | 94 qround '.rater concentr:ntions of sir asily detected polycyclic ( 95 aromatic hydrocarbons, fluoranthene, 11r12-benzfluoranthene, and ', 12-benzoerylene, which have not been shown to be carcinogenic | 96 | 97 and 3 .4-benzf luoran **h`-n , 1, :< -benzpyrene and j 97 f ndorio (1 > 2,3-od) pyreu-*, which h.:2'.,r` been shown to be carcinogenic. | 98 ? .136 ug/1, from 48 samplings. Since these levels would be difficult to remove for drinking water purposes, the authors recommended that a maximum concentration of total olycyclic aromatic hydrocarbons be limited to a level not to exceed 0.2 Ug/1 for human consumption. The world Health Organization (1970) has also recommended 0.2 ug/1 in drinking water as a maximum level for the safety of consumers. 101 | 102 | 103 | 103 | 104 | 105 | 105 Contaminated waters can have seriously large PAH concentrations. Andelman and Suess (1970) have also quoted benz (a)anthracene concentrations of 0.025 to 10 ug/1 and benzo(a) pyrene concentrations of 0.001 to 1.84- ug/1 in industrial and bitumen contaminated effluents. Waste water from households, trades. aads, and industrial sources had up > i 31.4 ug/1 benzo (a)anthracene and 34.5 ug/1 benn (a)pyrene. 107 108 109 110 111 112 112 Physical and Chemical Properties- 114 Polynuclear aromatic hydrocarbons are a diverse class of compounds consisting of substituted and unsubstituted polycyclic and heterocyclic aromatic rings. They vary in color from white to yellow crystals with diverse melting points (e.g., benzo (c)acridine 108degrees (Beilstein's handbook) r dibenzo(h,rst)pentaphene 320-321 degrees(Beilstein's handbook)). PAHs are not very soluble in water. A few compounds in which. 117 117 119 120 120 121 123 5 INTERIM DRAFT December 10, PV/KMM MO J97 00o0 ' 0<?<9?5 3 4 j5 6 iproduced eritb^J !ni pro i f--rn* on but no tumors. >-h. rr r d3 benzanthracene *: *'' r>r : t potent. Of the 276 276 Application, of 1, 2,5.6-d ' b'tiTanthracene nr 3, n -benzopyrene to the amputated tail of the newt, Triturns vi.ridescens, failed to produce tumors; however:,- the rate of tail regeneration was markedly reduced by these compounds (Fir v.arel! o, and Wolsky, 3.9^6) . Lecamp and Deisol reported aJ.so that 3, 'v-benzopyrene did not 4 uduce tumors in regenerating limbs of the toad but inhibited the rate of regeneration and appearance of the formed limb. Sinm 5 a.r rest < ft "". e observed by Prada (1946) in Triton vulgaris. 279 280 281 282 283 284 285 286 286 Matoltsky (19-7) reported no tumor formation in the amphibians, 288 Rana esculenta and Triton cristatus injected with a 0.3 percent 289 solution of 3,4-ben7.opy'one. However, lie observed hemorrhaging 291 in the kidney and liver, parenchymal, degeneration, fatty 292 degeneration, and necrosis. in the frog (R. esculenta) he 293 observedpilmonary edema, ceJ.3ularinfiltration, and edematous 294 swellina of the alveolar w.-vUs as well as edema of the skin and 295 abdomen. Bonte (1950) also bailed to induce tumors in frogs with 297 3,.4-benzopyrene, implanted or painted on the skin; however, the 298 compound produced atrophy and ^oar?ssion of the mucous glands of 299 the skin and increased i to permeghU i.ty of the skin to water. 299 12 3 INTERIM DRAFT NO. I 4 hecember 10 . 3.977 |5 knh ~ 6 r MCD 000004882 Oont.enwi.il (1953) observed inhibition of cleavage and disturbances in the formation of biastomeres and neurolation in Triton and Axototl eggs exposed to unspecified concentrations of 3,4-benzopyrene. Colombo (1948), however, found that benzo(a)pyrene concentrations of l:2.n00 to 1:20,000 had no effect on the development of the ova, morula, or gastrula of the frog, Rana esculenta. Ruhland and Weiss (1954) observed that 1:1,000 to 1:10,000 solutions of benzo(a)pyrene reduced the motility of the sperm of Rana fusca; however, eggs fertilized by these sperm developed normally. , 301 302 303 304 305 306 307 303 309 309 Birds 312 'ntratracheal administration of 3-me+- ''ylcholanthrene (dose not specified) to ducks produces acute an'1 chronic inf lamination, and prolonged administration of the compound produced a variety of pulmonary tumors. Administration of ),4-benzopyrene also produceschronic pulmonary inflammation,but no tumor3 (Rigdon and Meal, 1965). Benzopyrene does not appear to be acutely toxic to ducks or chickens given a single val dose of 250 mg (Rigdon, and Neal, 1963). 315 316 317 319 320 321 322 322 Administration of up to 2,5 mg benzopyrene/g of food for 24 days does not affect the growth or survive) of chicks, nor does a diet of 0.1 mg/g of food have any effect on the sperm, ova, egg 324 .326 326' 13 INTERIM DRAFT December 10, FV/EMM t'0. I 1977 _ ; MCD 000004883 3 4 |5 6 fertility, or chicks from eggs obtained from treated hens (Pigdon, and Neal 1963) . Hatchahi'ity of fertilized chicken eggs was determined after injection of 1-1 ug/egg of different PAH (Feno, 1968). The hate liability was reduced to 51 percent of the controls for benzo (a)pyrene, 73 percent for benzo(k)fluoranthene, 70 percent dibenzo (a, h) anthracene, !55 percent dibenzo (a, jj acridine and 76 percent ben -o (r,s , c.) pentaphene. Different combinations cf these PAH led to a greater than additive effect. 327 328 329 330 331 332 332 333 333 MammaIs 336 In an in vitro study on the effect of' 5 PAH compounds on the activity of selected enzymes, demant (1967) observed that the activity of catalase, an enzyme that acts on hydrogen peroxide and thus regulates the amount of this compound in tissues, was reduced by up to 50 percent by the FAH compounds. In order.of decreasing inhibition potency, the compounds were 3-methylcholanthrene, 3,4-benzopyrane, 1,2-benzanthracene, 9,10-dimethyl-l,2~benzanthrocens, and anthracene, which suggests that the catalase-inhibiting potency of the PAH compounds is related to their carcinogenic potency. None of these compounds had any effect on the activity of peroxidase. 339 340 341 342 344 345 345 347 348 349 349 14 INTERIM DRAFT HO. I December 10r 1977_ - FV/KMM 3 4 |5 6 MCD 000004884 _L -'v.:tivity of lipoxygena another < xidor^ductase, was only 'tii percent of the control level in the presence of 1,a-henzopyrene, the most potent inhibitor, and only46 and `51 percent of the control value in the presence of methylcholanthrene and dimethylbenzanthracene. Ofthe three carcinogens, dimethylbenzanthracene inhibited that activity of ribonuclease most and benzopyrene was least effective. None of the carcinogens had any effect on the activity of trypsin. 352 352 353 354 355 356 357 357 In mice injected with 1.25 ng of 3,4-bsnzopyrene or 2.5 mg of 3-methylcholanthrene (Dra.ganov, 1966), a significant increase occurred in succinic dehydrogenase activity in lung tissue 60 days after injection but not at 30 days after the injections. He i orted that enhanced succinic dehydrogenase activity occurred at the same time that pathological changes in the long tissue were observed. Z_innari (1.764) observed that same effect, in liver tissue, but enhanced succinic dehydrogenase activity occurred much more rapidly. In mice injected with a 2 percent solution of 3,4-benzo (a)pyrene, the activity of succinic dehydrogenase increased about 3-fold above the control level on the second day and gradually decreased to near control levels by the 30th day. However, the degree of morphological changes in the liver mitrqchondriaincreased with time, rather than with enhancement of succinicdehydrogenase activity. 360 360 362 363 363 364 365 366 367 367 368 369 370 371 371 15 INTERIM DRAFT NO. I December 10, 1977 FV/KMM ` MCD 000004885 3 4 |5 6 The effect of PAH compounds on the ' -t Lvit y of cat heps in from n* cellular fractions f ' at 13 vr- ' 'mogen:' -^*3 was investigated L'V Lomsadze and cov/ori or s(196) '"hey found that dime tJhylbenzanthr scene . .3 ~mt. hvlcho 1 anthrene, 1,2-benzo (a) pyrene, and anthracene lowered the activrty of the enzyme at a concentration of 0.005M. Anthracene -'as lease effective. These investigators also found a reduction In cathepsin activity in the rat liver 2 to 5 months aftar a single .injection of 5 mg of dimethylbenzantbracene to rats. 373 3 75 376 376 377 379 380 3 90 380 Deluca (1969) reported no chanuen in liver glutamic-oxalacetic transaminase (GOT) or g lucose- 6-phosptiate activity in rats injected with 0.1 mg 3, -banco (a) pyrene; hovjever, at a dose of 0.5 mg, the activity of got ca.e enhanced', ' 382 383 384 384 Intravenous injectio" of 0.5 mu of anthracene, pyrene, perylene, 3,4-benzopyrene, or 1 ..?,5.6'dlbeuzanthracene caused an increase in liver SH levels in "doe ''-`.hhin 1~ minutes to 1.5 hours. Subsequently, the SH levels dropped to below normal. 387 388 3 88 189 A. list of several PA.Hu are given in Table I with carcinogenic data for different animal species. This tab3.e represents only a few of the PAHs tested arid r- :c included in the list of PAHs selected by the international Agency for Research on Cancer working Group (197.3) b'c t -n HvdrcarcinogenLcity in animals. 391 393 394 394 396 16 INTERIM DRAFT pecomber in, r.'/FHrq NO. I 1977 _ MCD 000004886 3 4 |5 6 e PAHs were administered orally, in the diet or applied on the skin 397 397 17 INTERIM DRAFT December 10, PV/KMM NO. I 1977 - MCD 000004887 'impound -enzo (a) anthracene >enzo(b) fluoranthene ienzo (j) fluoranthene enzo(a)pyrene 'enzo(a)pyrene :hrysene 'ihenz (a,h) anthracene 'icenzc (a,e)pyrene tibenzo(a,h)pyrene ' ibenao (a, i) pyrene ndeno, (1,2,3, cd) pyrene Table ?. An i me?. mice rr ice mice mice rats hamsters rabbits mice mice mice mice mice mice mi ce 400 Adninistered Effect 403 oral cutaneous cutaneous diet oral oral cutaneous cutaneous cutaneous diet cutaneous cutaneous cutaneous cutaneous papillomas 1hepatomas. papillomas. carciuom carcinomas 407 stomach tumors 40 mammary tumors 40 papillomas. carcinom carcinomas 411 papillomas. carcinom papillomas. carcinom carcinomas 414 papillomas. carcinom papillomas. epithel.-i papillomas. epitheli papillomas. carcinom 18 INTERIM CRAFT December 10, P7/F71M NO. I 1977 OOqq 48a8 3 4 5 6 1_<*. Borneff, J. and H. Punts, 1969, Carcinogenic substances in soil and water. Arch.. Hyg. 15: 220. | 591 J 592 _15. Boyland, E., and r, Sims, 1967, The carcinogenic activities in mice of compounds related to benz (a) anthracene. Int. Jour. Cancer 2: 500. 594 596 596 J_6. Breedis, C. 195 0, Induction of accessory limbs in salamanders with mixtures containing carcinogens. Cancer Res. 10: 205. 599 600 17. Brown, E.R. , et al. , 1975. Tumors in Fish Caught in Polluted Waters: Possible Explanations. Comp. Leukemia Research, Leukemogenesis, Bibl. Haemat. 40 ed. Y. Ito and R.M. Dutcher, Univ. of Tokyo Fress, Tokyo. 47-57. 603 604 605 606 1_8. Butlin, T.C. 1892, Cancer of the Scrotum in Chimney Sweeps and Others. Brit. fled. Jour. 1: 134; 2: 1,66. 609 610 1_9. Catchpole, w. M., et al,, 1971. Specifications for cutting oils with special references to carcinogenicity. Ann Occup. Hyg, 14: 171. | 6 13 | 615 615 20. Cavalieri, E., and R. Auerbach, 1974, Reactionsbetween activated benzo (a)pyrene and nucleophiliccompounds, with 618 618 26 INTERIM DRAFT December 10, PV/KMM NO. I 1977 _ 3 4 |5 6 ooo,a96 possible implications on the mechanism of tumor initiation. Jour. Natl. Cancer Inst. 53:393. 619 620 21. Colombo, G. 1948, Effect of Testosterone, benzopyrene, and cholesterol on the ova of tailless amphibians. Atti ist, Veneto sci. Pt. 2. 106, 114. 622 623 624 22. Conney, A.H., and W. Levin, 1966, Induction of hepatic 7,12-dimethylbenz (a)anthracene metabolism by polycyclic aromatic hydrocarbons and aromatic azo derivatives. Life Sci. j>: 465. 626 627 629 629 23. Conney, A.H. 1967. Fharmaculogical implications of microsomal enzyme induction. Pharmacol. Rev. 19: 317. | 631 | 632 24. Cookson, M.J. , et al. , 1971, Mutagenicity of epoxides of polycyclic hydrocarbons correlates with carcinogenicity of parent hydrocarbons. Nature (London) New Biol 234: 186. 635 636 636 25. Davis, W.W., et al., 1942. Solubility of carcinogenic and related hydrocarbons in water. Jour. Amer. Chem. Soc., 64: 108. 639 640 640 26. deLima-Zanghi, G. 1968, Marine plankton fatty acids and pollution with benzo (a)pyrene. Cah. Oceanog. 20: 203. 643 644 27 INTERIM DRAFT December 10, PV/KMM NO. I 1977 6>Oo 489? 3 4 I5 6 27. Pe Luca, T., ami n. i:n Luca, 19 fc ' , Determination of glumatic-oxalacetic |_"g ansaminri r-`- and. g lucose-6-phosphatase in rat liver homogenate? after stir". 5 at ion vcith 3 f4-benzopyrene. Rass- Med. sper. 15: 79. 6'4 6 6 47 648 649 23. De Lustig, E. S., anti e,,t,., Matos, .1971, Teratogenic effects induced in tail, of Bnfo arenarum tadpoles following treatment with carcinogens. Experientia ?7: 555. 651 6 52 653 29. Diamond, L., and H.F. Clark, 1970, comparative studies on the interactions of berro (a) pyrene with cells derived from poikilothermic and homeothermic vertebrates. I. Metabolism of beuzo (a) pyrene. Jour. Nat. cancer Inst. 45: 1005. 6 55 656 65 8 659 j.0. Dontenwill, w. 1953, Effect of benzopyrene on the development of triton and axolotl eggs. Z. Krebsforsch. 59: 56. 662 663 31. Draganov, iv. 1966, ,;'nccinic dehydrogenase activity in the respiratory organs of mice after the intravenous injection of 3,4-benzopyrene and 70-me+hylcholanthrene. onkologiya 3: 135. 665 667 668 660 32 Duncan, M.,, and P. Brookes, 1..'HO, Relation of metabolism to macromolecular bind!no of the carcinogen benzo (a) pyrene, by mouse embryo cells ui culture.Tnt. Jour. Cancer (>; 496. 6 70 .671 673 28 INTERIM DRAFT December 10, PV/I'MM MO. I 1977 _ 3 4 |5 6 MCD 000004898 Ellis, C. 1937, The chemistry of petroleum derivatives, Vol. 2, Reinhold, New York. 675 676 24. Environmental Protection Agency 1970, water Quality Criteria Data Book, organic Chemical Pollution of Fresh WAter, Vol. 1. EPA Water Pollution Control Research Series 18010 DPV. U. S. Govt. Print. Office, Wash. D.C. 678 679 680 680 35. Environmental Protection Agency 1976, The environmental fate of selected golynuclear aromatic hydrocarbons, 560/5-75-009. 682 683 36. Epstein, S.S., et a_l- , 1963, Fhotodynamic effect of the carcinogen, 3,4-benzopyrene, on Paramecium caudatum. Cancer Res. 23: 35. 686 687 687 37. Evans, W.C., et al. , 1965, Oxidative metabolism of phenanthrene and anthracene by soil pseudomonads. The ring-fission mechanism.Biochem. Jour. 95: 819. 690 691 691 28. Falk, H.L., et al., 1958, The disappearance of carcinogens from soot in human lungs. Cancer 11: 482. 694 694 29. Fitzgerald, G.P., et al., 1952, chemicals with selective toxicity to blue-green algae. Sew. and Ind. Wastes 24: 888. 697 698 29 INTERIM DRAFT December 10, PV/KMM MO. I 1977 MOD 00000-4899 3 4 5 6 40. Flesher, J.W. 1970, Fossibl" role of reactive metabolites of polycyclic hydrocarbons in oncogenesis. Ptcc. Tob. Health oonf., 3rd, 99-112, 700 702 702 4.1. Foster, J.A. 1969, Malformations and lethal growths in planaria treated with carcinogens. Nat. Cancer Inst,, Monogr. 31:683. 704 | 705 | 705 42. Gelboin, H.V. et ctL. 1969, Enzymic hydroxyletion of benzopyrene and its relation to cytotoxicity. Proc. Nat. Acad. Sci. U. S. 64: .1188. 708 709 709 43- Gemant, A. 1967, Enzyme activites in the presence of carcinogenic hydrocarbons. Grace Hasp. Bull. 45: 61. 712 713 44. Gersch, M. 1954, Effect ofcarcinogenic hydrocarbonson the skin of earthworms. Naturwissenschaften 41: 337. 716 717 45. Graef, W., and W. Nowak, 1966, Growth stimulation in lower and higher plants by carcinogen:.c polycyclic aromatic compounds. Arch. Hyg, Bakteriol. 150: 513. 720 72 0 721 46. Groll, H.P.A. 1933, Vapor-phase cracking. Industr. Eng. Chem., 25: 784. 724 724 30 INTERIM DRAFT December 10, pv/emm CIO. I 1977 4900 oo 00 Gurtoo, H.L. and N. "iV ; ] / /u "epatie microsomal mixed function oxygenase. 'ncyme mol:ipiicity for the metabolism of carcinogens to DNA-binding metabolites. Biochem. Biophys. Res. Commun. S_l: 655. 726 727 729 729 48. Haranghy, L. 1956, Effect of 3,4-benzopyrene on fresh-water mussels. 731 731 49- Hass, B.S., and H.G. Applegate, 1975, Effects of unsubstituted polycyclic aromatic hydrocarbons on the growth of Eschericha coli. Chem. Biol. Interact. 10: 265. 733 734 735 50. Huberman, E., et al., 1971, Metabolism of polycyclic aromatic hydrocarbons in cell cultures. Cancer Res. 31: 2161. 738 739 51. International Agency for Research on Cancer, "Monograph on the Evaluation of Carcinogenic Risk of the chemical to Man: Certain Polycyclic Aromatic Hydrocarbons and Heterocyclic Compounds" JWorld Health Organization, Geneva, Switzerland, 1973), Vol. 3. 74 1 742 743 744 744 52. Joyce, G.H., and D.C. White 1971, Effect of benzo(a) pyrene and piperonyl butoxide on formation of respiratory system, phospholipids, and carotenoids of Staphylococcus aureus. Jour. Bacteriol. 106: 403. 3 UTCRIM D - V'T ember ' ' PV/KJ. Ho. I 1977 0q 746 747 748 749 3 4 I5 6 5 1 rnrotkova, G- P. , and. n.p. rokin, J60, D t- i mul ation of the nrocess of soma tic emhryon genes is in some Porifera and rnelenterat;j. I. ~ f. 1 cf. of ca ro inoaenic agents on some torifera- Acta- Biol. (Budapest; 19: 465. 751 752 753 754 54. Krieg, K. 1970, Experimental carcinogenesis iri mollusks. IV. Comparative studies of carcinogenesis in land and water ^nails. Arch. Gesohvmlstf orsch. 35: 109. 757 757 750 55. hints, II- 196 9, Inhibition of benzopyrene hydroxylation by various polycyclic aromatic hydrocarbons. Z. Krebsforsch. 72: 57. 760 762 762 q6, became, M., and M. D^lsol, 1947f influence of benzopyrene on the regenerationcf `'-verg'd members cfthe tadpole of the accoucheur, toad. Compt. rend. 2.24: 4 99. 765 766 767 57. f ee, R.F., et al. , 1972, Uptake, metabolism, and discharge of rolycyclic aromatic hydrocarbons by marine fish. Mar. Biol. 17: 201. 770 771 771 58. Leitch, A. 1922. Paraffin cancer and its experimental production. 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