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vr^r*'' -1 4 v5 - -,,, r* - *v \ i PB 212 791 s' i / Reproduced by .NATIONAL TECHNICAL INFORMATION SERVICE M'S Deportment of Commerce -Springfield/A 22151 giLJil| HAZLETON LABORATORIES, INC. 9200 LEESBURG TURNPIKE * VIENNA, VIRGINIA 22130 DUP040011377 -T/W?- ibb fllBUOGRAPHIC OAT A D D 4. \ u U* ,ui 1- U.-p.-n XV. , CRC-APRAC-CAPM-6-68-3 I- `> 1 Chrorrlc Exposure of Cynomolgus Monkeys to Lead Chiorobromide Singly and in Binary Combination with Certain Airborne Pollutants 3, i\ri Aror;.suyt /V 5. Rn'iut lUtc April 1972 6. . 7, A til hot is T William M. Eiusey, D.V.M., Ph.D. 9* 1 Vilrtmn'K N<ni*r mul As UIiv n *. Hazleton Laboratories, Inc. 9200 Leesburg Turnpike Vienna, Virginia 22180 8. iVcttHmm# KV, inn 10 cX'p)v\-^-^.8U,<1'1'1'" X"" .11, t.iHUtiu'l tlisiut Xv* 12. Npmvvor iiu* 4*1 j: it in .-mu mu tv .-tuu* iuul AtlJir:.*. 1 j. (v^`r rl Ucjuu A AYinvl Coordinating Research Council, Inc. .30 Rockefeller Plaza Now York, Mew York 10020 15. SupplcmriH:ti v ftotr.v Releasable to the general public November 1972 1.6, AI*m i iii t s Final This report presents the results of measurements mode on monkeys exposed to load chlorobromid singly and in binary combination with nitrogen dioxide, sulfur dioxide and carbon monoxide and briefly summarizes the methodology used. 17. X. y VI .*,! PsH l.mviil Al u |s s i:.. .17*1, TV * 1|JM I.l1 Animal Ecology Pulmonary Nitrogen Dioxide Carbon Monoxide Lead Chiorobromide Carbox}"hemog Iobi n Erythrocytes Ca l c ium Su l fate Arterial Blood Gas Carboxyhomoglobi n * 17b. Ulrtinl.icis Open Tm.I; .I Trims Cynomolgus Monkey L :OSA 1 1 |/ W* 1,1 f\ *t OM|' 06A; 06Q Q6E; 06F; Q6P. 18- .H fu!at*ilv Sc .itrmrnc Releasable to tiro Public *i?m n i in i? *!)i -x ';i i Li 19. >*'* UIUV t Us> lives Hi^s h O -s.-- t^lLA^IlilLiy til. II v . Li-.', i 1 h i fXl 1 1S.MI111' THIS l-URM MAY 1M` 1u ruonivn' 71, ,0 1'. 33# :u:; DUPG40011378 fcjy!.^jyyj5yiwmLimi im iiu-a \y s' CHRONIC EXPOSURE OF CYNOM0LGUS NONKEYS ' TO LEAD CHLOROBROMIDE SINGLY AND IN BINARY COMBINATION WITH CERTAIN AIRBORNE POLLUTANTS Submitted to Coordinating Research Council Project CAPM-6-68 Approved by WILLIAM B, COATE, ,Ph.D,, Project Manager Submitied by WIV.M. 707 Pathol ogi st HAZLETON LABORATORIES, iNC. $zoo teesewte numme * vts/mA. vtutam* ateo April, 1572 /&. DUP040011379 pMB^wyyjWMwr..wmj p ^ :^/r fe/JKAZtjETQN LABORATORIES. INC, CONTENTS Section I. INTRODUCTION Pace II. 1. 1.1 1.2 1.3 1,4 2. 2.1 2.2 2.3 3. 3.1 3.2 3.3 3.4 4. 4.1 4.1.1 4.1.2 4,2 4.2.1 4.2.2 4.3 4.3,1 4,4 4.4.1 4.4.2 MATERIALS ANIMALS, GROUPS, AND EXPOSURE DURATION Animals ; Animal Screening Animal Groups Pre-exposure Control and Exposure Duration EXPOSURE CONDITIONS Exposure Chamber Animals in Exposure Chamber Air Supply to the Exposure Chamber METHODS OF GENERATION Nitrogen Dioxide Sulfur Dioxide Carbon Monoxide Lead Chlorobromide ANALYTICAL DETERMINATION OF CHAMBER CONCENTRATIONS Nitrogen Dioxide Wet Chemical Analysis Instrumental Analysis Sulfur Dioxide Wet Chemical Analysis Instrumental Analysis Carbon Monoxide Instrumental Analysis Lead Chlorobromide Gravimetric Analysis Wet Chemical Analysis -id/ t] }? * l rs 1. `i ! it* i s1 ii ! j i i i i i ! i| j. i l j s \ j | \ i * i< 1 i \ i ] ! 1 DUP040011380 / HAZLETON LABORATORIES. INC. Section 4.5 5. 5.1 5.2 5.2.1 5.2.2 5.2.3 5.2.4 5.3 5.4 5.4.1 5.4.2. 5.4.3. 5.4.4. 5.4.5. 5,5 5.5.1 5.5.2 5.5.3 6. 6.1 6.2 6.2.1 f.2.2 6.2.3 6.2.4 6.2.5 7. . CONTENTS - Continued Particle Size Analysis BIOLOGICAL MEASUREMENTS Body Weight and Clinical Signs Pulmonary Function Tests Mechanical Properties of the Lu'.g Distribution pf Inspired Air and Ventilation Diffusing Capacity of the Lung Arterial Blood Gas. Analysis Routine Hematology and Serum Biochemistry Special Tests Osmotic Fragility of Erythrocytes Carboxyhemogiobin B1ood Lead Delta-Aminolevulinic Acid Urinary Coproporphyrins Pathology Gross Examination Organ Weights Microscopic Examination STATISTICAL METHODS Introduction Evaluation of Treatment Effects Regression Analyses CUSUM Technique t-tests Analysis of fen'ance Significance Levels APPENDICES - ii - f sI ( j i i I \ii 1 i DUP040011381 ~"Z*TXf3trmr a*riv*At*Ss* A{|0/ HAZLETON LABORATORIES. INC. XJ' CONTENTS - Continued Section HI. STATISTICAL GROUPING A Results: 0,51 nig/m3 PbCIBr and Control Appendix A IV. STATISTICAL GROUPING B Results: 0.51 ppm NO2, 0.51 mg/m PbCIBr, 0.48 ppm NO*, plus 0.54 .rag/m3 PbCIBr and Control c Appendix B V, STATISTICAL GROUPING C , Results: 9.70 ppm S02, 0,51 mg/m3 PbCIBr, 9.93 ppm S02 plus 0.50 mg/m3 PbCIBr, and Control Appendix C VI, STATISTICAL GROUPING D - Results: 65.46 ppm CO, 0,51 mg/m-5. PbCIBr, 66.43 ppm CO plus 0.47 mg/m3 PbCIBr, and Control Appendix D VII, SPECIAL BLOOD TESTS Results: All groups VIII. SUMMARY AND DISCUSSION OF PbCIBr EFFECTS IX. REFERENCES ;- ill - DUP040011382 Ha z l e t o n l a b o r a t o r ie s SPONSOR; Coordinating Research Council (CAPM-6-68) DATE: April, 1972 MATERIAL.: Lead Chlorobromide SUBJECT: Study of Synergistic Effects of Certain Airborne Systems in the Primate; Chronic Exposure of Cynomolgus Monkeys to Lead Chlprobroroide Singly and In Binary Combination with Certain Airborne Pollutants I. INTRODUCTION This study was initiated to determined the synergistic effects of five common air pollutants in cynomolgus monkeys (Macaca fasclcularjs? exposed continuously, .24 hours per day, seven days a week, for'a*period of 104 weeks.. The pollutants examined, singly and in binary combination, were three gases, nitrogen dioxide, sulfur dioxide, and carbon monoxide and two particulates, calcium sulfate and lead chlorobromide. The nominal exposure levels selected and the current Threshold Limit Values (TLV) 0) presently set for each pollutant are presented in Table 1. The nominal particle size selected for the two particulates, calcium sulfate and lead chlorobromide, was less than two microns (<2u). This report presents the results of measurements made on monkeys exposed to lead chlorobrotnide singly and in binary combination with nitrogen dioxide, sulfur dioxide, and carbon monoxide and briefly summarizes the methodology used. A series of technical reports have been issued describing the methodology in detail; these are listed in Table 2. 9200 LEESBURG TURNPIKE VIENNA. VIRGINIA 22780 TELEPHONE {703) 893-5400 OUP040Q11383 isa iwKnwgj i ,i.(pi>T~'Trr.i[i.niTfri.iri._;i'i' i'i~.TTIII . ' H'.. |,"fl* HAZLETON LABORATORIES. INC. table 1 - Nominal exposure levels and current Threshold Limit Values. Agent Nitrogen dioxide Sulfur dioxide Carbon monoxide Calcium sulfate Lead chiorobromide Nominal Concentration 0.5 and 7.5 ppm 0.5 and 10.0 ppm 20.0 and 67.5 ppm 10.0 mg/m3 0.6 mg/m3 tLvn} 5 ppm 5 ppm 50 ppm 1 "Inert" or Nuisance Particulate* 0.15 mg/m3** * A threshold limit of 10.0 mg/m3 is recommended for substances in this category and for which no specific threshold limit has been assigned. ** TLV for lead, (1971 intended change) -2- .. -1\? DUP0400113B4 Report Number 1 2 3 4 5 6 7 8 9 TO 11 12 13 14 Table 2 - Technical Reports Title Measurement of Total Respiratory Flow Resistance in Rodents Measurement of Pulmonary Flow Resistance, Dynamic Compliance, Tidal Volume, and Respiratory Rate if. Normal and in Tracheotomized Rodents Measurement of Static Compliance in Tracheotomized Rodents Calibration Procedures for Airflow, Tidal Volume, and Pressure used in Measuring the Mechanical Properties of Rodent Lungs Technical Specifications of Equipment used in the Study of Rodent Mechanics Mechanics of Respiration in Cynomolgus Monkeys Calibration Procedures-Mechanics of Respiration in Cynomolgus Monkeys Specifications of Electronic Equipment-Mechanics of Respiration in Cynomolgus Monkeys Basic Documentation for the On-Line, Real-Time, Time Storing Computer System Hazleton Laboratories' Multiplexer Measurement of Total Respiratory Flow Resistance in Primates Electrocardiograms on Monkeys Measurement of Distribution of Inspired Air in in Cynomolgus Monkeys Pulmonary Diffusing Capacity in the Cynomolgus Monkey x Status Submitted 12/65 Submitted 1/67 Submitted 1/67 Submitted 1/67 Submitted 1/67 Submitted 6/68 Submitted 6/68 Submitted 6/68 In Preparation Submitted :9/68 Submitted 9/68 Submitted 9/68 Submitted 2/69 Submizted 1/69 DUP040011385 auaij- 1 j j ^gww^jK-jtp^o^girata fej^^cg^sgejitigr l^^^.y,y_^L>, ."?'SI>U^-` qaarqa yii^ja^Bi^gijiM^jf.yegy.j)^jBggaagga*jwnj^j^^Uy >.1 I. ANIMALS, GROUPS, AND EXPOSURE DURATION 'Ll, Animals Young cynomolgus monkeys (Macaca fassrcularis) obtained from Hartelost-Thorsen of Monmouth, New Jersey and weighing 1,6 - 3.0 kg were used In this study, 1.2. Animal Screening Animals received in our laboratory were tested for tuberculosis, radiographed for pulmonary lesions, and observed for general health. They passed a screening procedure consisting of an evaluation of pulmonary function, E.C6, hematology, and clinical chemistry. Animals having values within acceptable limits were assigned to this study. 1.3, Animal Groups Seventy-two monkeys were randomized into eight groups:; each group consisted of nine animals composed of five males and four females or vice versa. One group was maintained as the control group exposed to clean air while the seven other groups were exposed to the four pollutants, singly or in combination with another pollutant. Nominal concentrations and exposure duration are presented in Table 3 for each of the eight groups. -5- DUP040011387 HAZLETON LABORATORIES. INC. Group 1 9 2 5 7 1.0 18 20 table 3 - Groups, nominal concentrations and exposure duration* Nominal Concentration Control PbCIBr - 0.6 rag/m3 NOg - 0.5 ppm SOg - 10.0 ppm CO - 67.5 ppm NO? - 0.5 ppm o PbCIBr - 0.6 mg/nr SO? - 10,0 ppm o PbCIBr - 0.6 mg/m'1 CO - 67.5 ppm , PbCIBr - 0.6 mg/nT Exposure Duration weeks V04 104 87 104 104 104 i 104 104 -6- DUP040011388 -------m.'MM HAZLETON LABORATORIES. INC. 1.4, Pre-exposure Control and Exposure Duration After placing the animals in the exposure chambers, a period of two weeks was allowed for adaptation during which time no measurements were made. A pre-exposure control period of eight weeks followed the two-week adaptation period when physiological variables were measured for' each group of animals to establish control values and the weekly variation. Following the eight-week pre-exposure period,, the 104-week exposure period was started, the exposure duration for the control group and six exposure groups was 104 weeks. The group exposed to 0.5 ppm N02, exposed for a period of 87 weeks, was a repeat group for a group that was accidentally overexposed during Week 22. 2,, EXPOSURE CONDITIONS 2.1. Exposure Chamber One of the exposure chambers used during the 104-week experiment with t/nomolgus monkeys is shown in Figure 1. The chambers were fabricated from 304 L stainless steel with glass windows and were 6' x 6' x 5` with pyramidal tops and bottoms. -7- DUP040011389 Figure i - Exposure chamber housing nine cynoriolqusmonkeys and 48 rats, for exposure to air pollutants. - 8- DUP040011390 i^.'SP^SKSRSSSB'BSi vSBs'Sssras&'ef-s^S*** HAZLETON LABORATORIES, INC. 2,2, Animals in Exposure Chamber Each chamber was designed to bouse nine monkey cages each holding one animal. The cages were arranged in three rows of three cages all on the same tier as can be seen from the diagram presented in Figure 2, Each cage was made from stainless steel bars and was 16 1/2" wide, 24" high, and 21" long; a photograph is presented in Figure 3. The chamber also accommodates four tiers of stainless steel rat cages supported on a stainless steel rack with dropping pans under each tier; these are discussed in another report. 2.3. Air Supply to the Exposure Chamber The air supplied to each exposure chamber passed through a MSA Ultra Aire filter. The temperature was maintained at 72 F 2, and the relative humidity was maintained at 50% + 5%, The airflow through each chamber was slightly in excess of 1000 Titers/minute, 3. METHODS OF GENERATION 3.1. Nitrogen Dioxide (NOg) Gas mixtures of 5% nitrogen dioxide in nitrogen were obtained from J. T. Baker Company. Known volumes of these gas mixtures were metered into the chamber air inlet and diluted with makeup air before entering the exposure chamber turret, 3.2. Sulfur Dioxide {SO^) Sulfur dioxide was generated in the same manner as NOg except that compressed gas mixtures of 1% and 5% S02 in nitrogen were used. Chamber -9- DUP040011391 .. ..... . _---- "-- ------------------------ - i Figure 2 - Exposure chamber and distribution of cages for monkeys and rats. - 10 DUP040011392 Figure .3 - Stainless steel cage for -housing individual monkeys in exposure chambers. - 11 - DUP040011393 t-*-**** HAZLETON LABORATORIES, WO. concentrations at 0,5 ppm SOg level were produced from 12 SOg mixtures, while chamber concentrations at the 10.0 ppm SOg level were produced from 556 SOg mixtures. 3.3. Carbon Monoxide (CO) Carbon monoxide concentrations were generated by metering known volumes of pure (1002) CP Grade CO from compressed gas cylinders obtained from J. T. Baker Company and Air Products, , 3.4, Lead Chlorobromide (PbClBr} Lead chlorobromide was generated and introduced into the exposure chamber as airborne particulates by means of a Wright dust feed mechanism (Figure 4). the PbClBr was specially synthesized for this study by the Ethyl Corporation. 4, ANALYTICAL DETERMINATION OF CHAMBER CONCENTRATIONS 4.1, Nitrogen Dioxide 4.1.1, Wet Chemical Analysis Samples of each chamber's atmosphere were collected with a standard Ace Glass-fritted bubbler (No, 7350} and analyzed according to the method reported by Saltzman (2), at least four times daily. - 12 - Figure 4 Wright Dust feed Hechain'sis. - 13 - DUP04001139S iji^;^wai;jj>^wi^.4^iJW< HAZLETON LABORA TORIES, tNC. 4.1.2. Instrumental Analysis Instrumental analysis of chamber concentration of nitrogen dioxide was accomplished by using an Atlas Electric Devices Company N02 analyzer which was modified for our applications. The NO^ analyzers were timeshared between a number of exposure chambers; thus, automatic samplers sequentially sampled a different chamber for six to 12 minutes out of each hour. The automatic samplers could be switched from automatic to a manual mode, and any single Chamber could be monitored continuously. 4.2. Sulfur Dioxide 4.2.1. Wet Chemical Analysis ............ -- Samples of each chamber's atmosphere were taken once daily with an impinger and analyzed according to the method of West and Gaeke (3). 4.2.2. Instrumental Analysis A Melpar Model SR-1100-1 sulfur dioxide analyzer (Figure 5) was used from continuous monitoring of chamber concentrations of sulfur dioxide and calibrated against the wet chemical method (3). The principal of operation was by photometric detection at the 394 mu-centered band emitted by sulfur compounds in a hydrogen-rich air flame. The 50^ analyzers were also used in conjunction with an automatic sequential sampler as described previously for NO^ monitoring. - 14 - DUP040011396 "1 ; ! Figure 5 - tie!par sulfur dioxide analyzer. - 15 - DUP040011397 yegpg^pwiyy *ffiuM?S^a?iaiit pj j^.1t*iBw trrsj k ^ i,.;.1 4.3.1, Instrumental Analysis Analysis of animal exposure chamber atmospheres for carbon monoxide was accomplished by a dual-range, non-dispersive, infrared analyzer (Mine Safety Appliance Company, Lira Model 200}. This instrument was used for chamber concentrations of 20 and 67.5 ppm CO, The analyzer was also operated in conjunction with an automatic sampler so that each chamber was monitored once each hour. 4.4. Lead Chlorobromide 4.4.1, Gravimetric Analysis Samples of each chamber's atmosphere were collected once daily on membrane filters. The mass of lead chlorobromide was determined by weighing the filter before and after each exposure using a Cahn electrobalance. The concentration was then calculated based on net weight gain and the volume of air passed through the filter, 4.4.2, Wet Chemical Analysis Wet chemical analysis for lead, using dithizone as reported by Fischer (4), was employed to confirm the results from the gravimetric analysis described above. 4.5. Particle Size Analysis Particle size, measurements of the PbCIBr aerosols were performed using a Royco'-'' Modal 202 particle counter (Figure 6), The instrument was used to count and size airborne particles in 15 ranges from 0.15 to 6.0 1i : - 16 - 4 DUP040011398 % -} Figure 6 Royro Model 202 particle size analyzer. DUP040011399 1 i HAZLETON LABORATORIES. INC. microns. Count median diameter data was converted to mass median diameter by the conversion equations originally proposed by Hatch and Choate (5)> To accomplish this conversion, the raw data from all samples taken from a given chamber were combined according to size intervals. From this rooled data a composite size vs. distribution graph was constructed on log-probability paper and the Hatch and Choate equations were applied, 5, BIOLOGICAL MEASUREMENTS 5.1. Body Weight and Clinical Signs Body weights were tabulated six times during the pre-exposure control period and once a month during exposure until termination. The animals .were observed daily for signs of toxicity and abnormal behavior, 5.2. Pulmonary Function Tests Pulmonary function tests including measurements of the mechanical properties Of the lung and respiratory system, distribution of ventilation, diffusing capacity of the lung, and arterial blood gas tension, were made on each animal periodically throughout the pre-exposure control period and the 104 weeks of exposure. 5.2.1. Mechanical Properties of the Lung Several variables were measured to evaluate the mechanical properties of the lung. The measurements were made with the animal sitting in a chair or a body piethysmograp'n equipped with a face mask fitted to the monkey's nose and mouth.. Mo anesthetic was used; however, a period of 10 to 15 minutes in the chair was needed to assure the measurements would be made when tie monkey was relatively quite. Prior to the pre-exposure control period, all animals were acclimated - 18 - j i DUP04001140G (iffMg'? _!1iH'i.M*i'llVl^IT>T^lll,n.rH1 '[lOOTOTWlH'll' i' 1 "fif'H'Tl "r `;f'T 1 nnTT'**"""*"l`'T*r............."'i--*" T.......................................................rtmimmr HAZLETON LABORATORIES. INC. tc the test procedure. Figure 7 shows a picture of an animal sitting in the restraining chair. Figure 8 shows a picture of an animal sitting in a body plethysmograph, Figure 9 shows a close-up of the face mask placed on an animal, and Figure 10 shows the inside of the face mask used with the attached rubber dam. The inside of the mask was filled with epoxy resin to accomodate muzzle sizes of monkeys weighing from 1.2 to 5,0 kg., and thus providing a minimum amount of dead space. Four.different sizes were used. Two techniques were employed to evaluate the mechanical properties of the lung. The first method utilized a combination of techniques developed by Head (6) and Murphy, et al. (7) and modified by Alarie et al. (8). This method involved subjecting the thorax of an animal to an oscillating pressure, sine wave in form, and at a frequency such that the mechanical reactance of the tissues was close to zero. Oscillating pressure around the thorax and airflow at the mouth were measured and the total respiratory system flow resistance during inspiration and expiration were separately calculated as the ratio of pressure to flow. Figure 11 shows an oscillograph tracing of applied pressure in the body plethysmograph and the resulting airflow measured at the face mask during normal breathing with the animal sitting quietly in a body plethysmograph. The second method utilized a combination of techniques developed by Amdur and Mead (9) and Mead and Whittenberger (19) and modified by Alarie et al. (11), In this method a number of variables - T9 - / is -if DUP040011401 Figure 7 - Monkey seated in primate restraining chair. - 20 - DUP040011402 1 I I n'gure 8 DUP040011403 Figure 9 .... .... .. ...... .> iuy `t tiLC u\ iK ;v i ti l OpO?'3 pd.ri.S dttSX to private .chair with monkey's snout properly inserted. A rounded plate behind the head of the animal prevents him from withdrawing from the mask. - 22 - DUP040011404 "US Figure 10 - Left - Base plate. Center - Disassembled primate face mask with epoxy filling and the rubber dam. Right - Assembled face mask with stretched rubber dam. - 23 - DUP040011405 - 24 - Figure IT - Oscillograph trading showing the applied pressure in the plethysmograph and the resulting a irflo w Pleasured a t the '"mask on a cyhomolgus monkey s ittin g in the plethysmograph and breathing q u ie tly . DUP040011406 HAZLETON LABORATORIES. INC, to evaluate the mechanical properties of the log were calculated from direct measurement of airflow and of transpulmonary pressure via intra pleural catheterization. Tidal volume was derived from integration of airflow during successive breathing cycles. Figure 12 shows an oscillographic tracing of tidal volume, airflow, and transpulmonary pressure. Further details on these techniques of measurement may be found in technical reports listed in Table 2. The analogue signals recorded on the oscillograph were transmitted directly to an IBM 1800 computer system. The computerized techniques of data extraction were similar in principle to those described by Stacy and Peters (12), Peters and Stacy (13), and Dennis, et al. (14). Following the termination of each test, the results were printed in a typewriter located in the testing laboratory performing the test. The list of basic variables being measured and the frequency of measurement is presented in Table 4. 8,2.2. Distribution of Inspired Air and Ventilation Ar open circuit technique described by Fowler (IS, 16, 17) and modified by Alaire, et al. (18) was adapted for the measurement of nitrogen washout from the lung during pure oxygen breathing. Figure 1.3 .presents a picture of an animal with a face mask and attachments needed to perforin this test. Figure 14 shows the resul ts obtained on the recording oscillograph. Further details on this technique can be found in the technical reports listed in Table 2. The list of basic variables being measured and the frequency of the measurement is presented in Table 5. - 25 - DUP040011407 w*u<.e:.'**w*: mask, and transpulmonary pressure in a cynomolgus monkey sitting in a restraining chair and breathing quietly. Vertical lines drawn indicate 'imultanepus phases in the three measurements. - 26 DUP040011408 HAZIETON LABORATORIES. INS. Table 4 - Mechanical properties of the lung and respiratory system measured in cyno* molgus monkeys during exposure for a period of 104 weeks. Variable Total respiratory system flow resistance during inspiration Total respiratory system flew resistance during expiration Tidal Volume Respiratory rate Dynamic .compliance of the lung Pulmonary flow resistance Work of breathing during inspiration per ml tidal volume Work of breathing during expiration per ml tidal volume Abbreviation Rrs(i) Rrs(e) VT RR Cdyn(l) R1 W(i )/rnl VT W(e)/ml VT Frequency of Measurement A A 8 B B B B B A - Measured on six occasions during the pre-exposure control period, every week during the first nine weeks of the exposure period, and every four weeks thereafter. 8 - Measured oh four occasions during the pre-exposure control period, every two weeks during the first ID weeks of the exposure period, and every four weeks thereafter. - 27 - DUP040011409 Figure 13 CyoomoTgus moakey in chair with face mask and f?r sarnplin9 nitrogen concentratii tpd0y i!!na(ttaCSent f0r chan9e from air breath to oxygen breathing. ! - 9 _ DUP040011410 - 29 Figure 14 - Oscillograph tracing o f tid a l volume and %nitrogen during pure oxygen breathing showing nitrogen washout from the lung in cynomolgus monkeys. DUP040011411 ****" 9*m'*&* HAZLETON LABORA TORIES. INC. Table 5 - Ventilation and distribution of inspired air (nitrogen washout) measured in cynomolgus monkeys during exposure for a period of 104 weeks. Variable Tidal volume Respiratory rate .Nunber of breaths to 1% nitrogen Cumulative tidal volume to 12 nitrogen Abbreviation VT RR N(l% N2) CV{1:2 N?) Frequency of Measurement C *e c c / 1 3 C - Measured on six occasions during the pre-exposure control period, every two weeks during the first four weeks of the exposure period, and every four weeks thereafter. - 30 DUP040011412 HAZLETON LABORA TORIES. INC. 5.2.3, Diffusing Capacity of the Lung The carbon monoxide uptake and the diffusing capacity of the lung were measured by a rebreathing technique based on the same principles as those described by Bates (19), Lewis, et al. (20), Kruhoffer, et al, (21), amd Long and Hatch (22) after mod''fication for its use with monkeys. To perform this test, the animal breathes from a closed loop system containing 0,06% carbon monoxide. The decrease with timb in carbon monoxide concentration, monitored continuously with an infrared analyzer, is used tp calculate the animal's carbon monoxide uptake, which provides am index of an animal*s diffusional properties, A picture of an animal connected to a rebreathing bag and closed circuit is presented in Figure 15. Further details on this technique can be found in the technical reports listed in Table 2. The basic variable.measured and the frequency of measurement is listed in Table 6, 5.2.4, Arterial Blood Sas Analysis Measurements on Arterial blood were performed using a Radiometer blood gas analyzer. A list of the variables measured and frequency of measurement is presented in Table 7, This measurement was performed 10-20 minutes after the intramuscular injection of phenylcyclidine (Sernylan^) for tranquilization of the animal. Blood was withdrawn from the femoral artery with the animal supine. - 31 - DUP040011413 Figure 15 - Cynnmolgus monkey with face mask, pneumotachograph, anti rebreathing bag <n place, .and with the connection to a closed circuit for the measurement cf carbon monoxide u'otake in ineasurinn" DLu~u.,. - - 32 -e 2 ii t | DUP040011414 Mjj_' JWieMMiffiaM HAZLETON UiBOHATORlES. INC. r Table 6 - Gas diffusion measurements in cynomolgus monkeys during exposure for a period of 104 weeks. Variable______ Diffusing capacity of the lung for carbon monoxide Abbreviation' Pl~0 J Frequency of Measurement C C - Measured on six occasions during the pre-exposure control period, every two weeks during the first four weeks of the exposure period, and every four weeks thereafter. Table 7 - Arterial blood gas measurements in cynomplgus monkeys during exposure for a period of 104 weeks. Variable Arterial blood oxygen tension Arterial blood carbon dioxide tension Arterial blood acidity Plasma bicarbonate Abbreviation s PaC02 pH plasma BC0~~ Frequency of Measurement D D D D D Measured once during the pre-exposure control period, at Weeks 1, 6, 13, during the exposure period, and every 13 weeks thereafter,. - 33 - DUP04001141S HAZLETON LABCWA TOPICS. INC. 5.3. Routine Hematology and Serum Biochemistry Several hematological and serum biochemical determinations were .made on all animals in the control group and the seven exposure groups. The blrod was obtained from the femoral artery. The variables and the frequency of measurement are presented in Table 8. 5,5. Special Tests 5.4.1. Osmotic Fragility of Erythrocytes Erythrocyte osmotic fragility studies were done during the last 24 weeks of exposure On the monkeys exposed to PbCIBr, NO^, and CO, alone and in combination, and the controls. These studies were done using a Kalmedic Fragilograph and the procedure described by Danon (23),. This procedure simultaneously records -fragility and salt concentration curves permitting an analysis of percent hemolysis of erythrocytes as a function of salt concentration. An evaluation of the 50% and ,80% hemolysis levels were used to compare the effects of the various test compounds. 5.4.2, Carboxyhemog1obin Carboxyhenioglobin (HbCO) levels were measured in the blood of monkeys from the control group and those exposed to 20.0 and 67.5 ppm CO, singly and in combination with the other pollutants. Measurements were made on one occasion prior to exposure, weekly during the first four exposure weeks and every 12 weeks thereafter using the procedure of Contains and Lawther (.24), - 34 - DUP040011416 INC. Table 8 - Hematological and serum biochemical determinations in cynomoigus monkeys performed during exposure for a period of 104 weeks. Variable Hennatoeri t Hemoglobin Total erythrocyte counts Total leukocyte counts Blood glucose Blood urea nitrogen Total serum bilirubin Total serum protein Serum albumin Serum sodium Serum potassium Serum chlorides Serum calcium Serum carbon dioxide Serum glutamic-oxaloacetic transaminase Serum glutamic-pyruvic transaminase Serum lactic -acid dehydrogenase Serum alkaline phosphatase Abbreviation Met. Hgb. RBC WBC eiu. BUN Ha K Cl Ca C02 SGOT SGPT LDH Aik. P0. Frequency of Measurement E E E E E E E E E E E / - Measured once during the pre-exposure control period and at 4, 16, 40, ,68 'and 104 weeks postexposure. - 35 - DUP040011417 HAZLETON LABORATORIES, WC. 5.4.3. Blood Lead Analysis for blood lead levels were performed by atomic absorption spectrophotometry (25). Measurements were made in the monkeys from the control group and from the groups exposed to 0.6 mg/m3 PbCl.Br., singly and in combination with NO.,, S02, and CO two times prior to exposure, weekly during the first 10 weeks of exposure, ar.J every 12 weeks thereafter until termination of the exposure period. , 5.4.4. Delta-Aminolevulinic Acid Analyses of del ta-aminol evul ini' acid (6-ALA) in the urine were made by the chromatographic procedure described by Marver, et. al. (26). Measurements were made on the animals from the control group and the groups 3 exposed to 0.6 mg/m PbCIBr singly and in combination with N02, S02, and CO, once prior to exposure and at Weeks 1, 4, 16, 4.0, ,68 and 104 during the exposure period. 5.4.5. Urinary Coproporphyrins Urinary copropsrphyrln determinations were made on the animals from the control group and those exposed to PbCIBr singly and in .combination with N02 S02, and CO. The frequency of measurement was the same as for 5-ALA described above, Analyses of urinary coproporphyrin levels were rerformed using standard fluorometric techniques (27, 28). - 36 - DUP040011418 HAZLETON LABORATORIES. INC. 5.5, Pathology 5.5.1. Grass Examination Following 104 weeks of exposure, all surviving animals were sacrificed and necropsied. Animals which died during the 104 weeks were necropsied immediately. At necropsy, the lungs were removed, inflated, and perfused intratracheally with a volume of %10 neutral buffered formalin equal to the tidal volume for that particular animal. In addition, the following organs were removed and. fixed in %10 neutral buffered formalin: brain, pituitary., thyroid, heart, thoracic aorta, liver., gall bladder, spleen, kidneys, adrenals, stomach, pancreas, duodenum, colon, peri bronchial lymph nodes, urinary bladder, gonads, rib end, sternum, skeletal muscle, peripheral nerve, abdominal aorta, mesenteric lymph node, knee joint, and femur. Each animal was examined thoroughly for gross lesions and any abnormalities were recorded. 5.5.2. Organ Weights From each animal the following organ weights were recorded: brain, thyroid, lungs, heart, liver, kidneys, and adrenals. These were used to calculate organ/boJy weight ratios. 5.5.3. Microscopic Examination The following tissues were dehydrated in. graded alcohol, infiltrated and embedded in Paraplast, sectioned at five microns, and stained with hematoxylin and eosi.n: trachea, lung {each of the seven Ji \ \ \ - 37 DUP040011419 HAZLETON LABORATORIES. INC, lobes), heart, liver, kidney, and peribronchial lymph node. These sections were examined by a pathologist who described in detail any .microscopic changes and summarized these findings for each group, STATISTICAL METHODS 6,1. Introduction This experiment was designed to study the biological effects on cynomolgus monkeys resulting from 24 months of exposure to various air pollutants. These pollutants were administered singly and in binary combinations with each other. A control group was also employed which was exposed under the same conditions to filtered air. Each group'initially contained nine (9) monkeys consisting of five males and four females or vice versa, The biological measurements made on these animals consisted of both pulmonary physiology variables and blood variables (i.e., serum chemistry and hematology). These measurements were made several times prior to the start of exposure, typically six {bi-weekly} measurements for the physiology and one measurement for blood variables, to establish an initial base-line for each animal group... After the expos ire started , the biological measurements were made at approxinutely the same frequency as pre-exposure for the first six months after which the measurements were made less frequently. The rational for the differential frequency HAZLETON LABORATORIES, INC. of measurements was the desire to detect any early gross compound effect . as soon as possible. It was expected that any changes which occurred after this initial exposure phase would be gradual changes; therefore, the measurement frequency could appropriately be decreased. Eight experimental groups (Table 3) relevant to the evaluation of PbClBr effects were arranged into four statistical groupings (Table 9) for analytical purposes. Within the constraints of the^experimental design, these four statistical groups provide all relevant comparisons relating to PbClBr. The first statistical grouping is comprised of the control group and one group exposed to PbClBr alone. The remaining three statistical groupings are each comprised of the following: a binary combi nation group containing PbClBr and one other pollutant such as NOg, SO,,, or CO; the control group; and the two single pollutant groups, exposed to the same respective concentrations as the binary group,. 6,2. Evaluation of Treatment Effects 6.2.1. Regression Analyses The male and female values were combined for body weight and all pulmonary function variables. These parameters were first analyzed by an analysis of variance of regression. The mean pre-exposure value of each animal was used as his initial base-line response just prior to start of exposure; each animal`s individual values were used at each - 39 - HAZLFrO'l , ABOHATCftlS. MC. Sroup -A B C D Table 9 - Statistical groupings for the determination of synergistic effects between lead chlorobromide and certain other pollutants. Pollutant Control Pb Control NO, PbPNCbL2 + Control SO, Pb^ SpOb,2 + Control CO Pb CO + Pb Nominal Concentration 0.6 mg/nP 0.5 ppm , 0.6 mg/nr 0.5 ppm - 0.6 mg/nr ppm10.0 3 0.6 mg/nr ppm10.0 3 mg/m0.6 '3 .67.5 ppm 3 0.6 mg/nr 67.5 ppm 3 0.6 mg/nr r i y. - 40 i l DUP040011422 HAZLETON LABORATORIES, INC, Interval thereafter. This .analysis tested for oort-parallel ism between the time-related response patterns of the various groups. This analysis, .using repeated measures of individual animals, resulted in over-estimation of the degrees of freedom, due to the correlation between successive responses. While this may have resulted in an over estimation of the true frequency of differences, for a first analysis, this approach was desirable to ensure that all possible significant effects would be evaluated in more detail by other statistical methods. [' A third degree polynomial recession curve was fitted to the interval means (29,30, .31) to compare individual groups for possible mean differences. This procedure Liao :i,e means at each interval (in contrast to the above analyses) chefebv accounting for the correlation between an individual's response,, Inspection of these plots within a statistical grouping allowed a judgment to be made as to the need for additional statistical analysis tor group differences; especially when the data indicated abrupt changes in the mean level of one or more groups. 6.2.2. CU5UM Technique In some instances, a cumulative sum (COSUM) technique (32, 33, 34) was used to establish the time of occurrence of a sudden change in the mean level for a group. This CUSUM technique was extended to detect a change in differences between mean levels of the control group and any of the exposed groups by forming a time-paired difference between r.. a._**2*t$*****"~!jyyr. tht* Individual cumulative sums. When such changes were detected, the means of the time segments after the change were compared by a t-test of the pre-exposure-adjusted means. 6.2.3. t-tests In certain cases where pre-exposure differences were observed in a given parameter and whether or not group differences .were found during exposure (e.g., differences in the CUSUM exposure-period means) between two or more groups, separate t-tests were made on these exposure segments. The pre-exposure mean for each animal was used to adjust its exposure period measurements by subtracting each animal's pre-exposure mean from each of its exposure values. The mean of these residuals for each animal was used to derive a hew group mean for each group. The difference between these group means was then subjected to the t-test, with n+m-2 degrees of freedom (except when heterogeneous variances required adjustment of the degrees of freedom). 6.2.4. Analysis of Variance The hematology and clinical chemistry data were analyzed by a factorial analysis of variance (35) for those statistical groups which constituted a factorial arrangement. Tests for compound effects and interactions between compounds were performed. Due to the transient nature of the changes generally found in these variables, this analysis was done at each interval rather than with time as an added factor in an expanded factorial design. . - 42 - X' i i DUP040011424 *>*-* 5 4 8?? J%i^ases'?,E* sswe*w;*** N j|] NtiM*ES OF .HEATHS FO IS NITROGEN [ N i l * r ,--,-------- a ' 1 4 ---*-* - * m-~ | CHOUf 1-CONTROL 1 ..u. ____ "* 11_*_* * ,__,__ --" a _1---A--- --- - a ... . - ' a . TO j fCROUF IT - ,i psm SOj j 60 1!........................................ ........................ ' {* - ..a ,40 30 ' .'.g..n' f"ilji.B .... . -....... a ..... . . . . J ~ 1 T ............. 'u a8 ______a_ - - .** . ........... .............. ,. B 8. *a ! j GROUP HI - O.Jl i/nA rvCI!.| a * 8 '* * * ! . J .................... .. .................... i 20 . i . ......... ...... ....... . ........ . > . . . . . . - j N J OIOIIF MF>f.t3a SO*.*0,M i**.'"3*ttt> ' I oa .......... j an --a-~-W" ' 40 8 *`"`-7'- jo*___5.ai_i.__1__ -___i . . _____ i__J__ , ,-i__ .i__.. _ . ...,....'. . ...i..-_in ,;, r -- - - ..-.fc.. . -- HO a 20 .40 50 60 70 a W WO HO TIME -Mitt Figure 62 - Third degree polynomial regression curves for N(1% Ng) prior to and during exposure to sulfur dioxide and lead chlorobromide singly and in binary combination. Each point represents the jnean for the animals tested at the indicated time for the various groups. * 198 - DUP040011425 HAZltTOfit.tA0OGAT0/Hg$. INC. 3.3.3.2. Respiratory Rate Measured During Pure Oxygen Breathing (RR`) Analysis of variance of regression for RR' (Table 15, Appendix C) indicated no significant slope differences among the groups. The third degree polynomial regression curves are presented in Figure 63, Inspection oi Figure 63 indicated that RR* values for Groups I and II were essentially the same during the pie-exposure period and the entire exposure period. However, RR' values for Groups III and IV were higher than Group J following the forty-fifth week of exposure, and remained higher until the end of the experiment, Separate t-tests of the pre-exposure adjusted overall exposure means indicated that both Groups III and IV were significantly higher than Group I (t - 2.61, d.f. 16 and t = .2,28, d.f. - 16, respectively), 3,,3,,3.3. Cumulative Tidal Volume from 80S to 1% Nitrogen [CVT(1% N2)] Analysis of variance of regression for CVT(1% $2) (Table 16, Appendix C) indicated no significant slo^- differences among the groups. The third degree polynomial regression curves are presented In Figure 64. Inspection of Figure 64 indicated that Group ;IV had somewhat lower CVT values during the pre-exposure period and generally remained lower than the CVy values for the other three groups during the exposure period. Values for Group III were slightly higher overall than Group I throughout the exposure period. A t-test of the pre-exposure adjusted overall exposure means comparing Groups I and III indicated that Group II; was significantly higher (t - 2.24, d.f. ~ 13.7) throughout fhe exposure period. /// Figure 63 f Third degree polynomial regression curves fpr RR` prior to and during exposure to sulfur dioxide and lead chlorobrotnide singly and in binary combination.. Each point represents the mean for the animals tested at the indicated time for the various groups. - 200 - DUP040011427 i I C U M U IA IIV E T iD A l V O U IM 'I T O 1% N ITR O G E N [C V ,(1 % N j l - l i l . n SIPO] .TOW.WEEKS Figure 64 - Third degree polynomial regression curves for CVy{1 N?) prior to and during exposure to sulfur dioxide and lead chlorobromide singly and in binary combination.. Each point represents the mean for the animals tested at the indicated time for the various groups. - 201 - DUP040011428 re#*** HAZLETON LABORATORIES. INC, 3.3,3.4, Tidal Volume Measured During Pure Oxygen Breathing (Vy') Analysis of variance of regression for Vy' (Table 17, Appendix C) revealed non-parallelism among the groups. The third degree polynomial regression curves are presented in Figure 65. inspection of Figure 65 indicated that Groups I, ill, and IV increased slightly with time while Group IX maintained a constant level throughout the experiment. A t-tost of the pre-exposure adjusted overall exposure means indicated that Group I! was significantly lower than Group I (t - 2,44, d.f, * 16) throughout the exposure period. 3.4. Hematology The group means and analysis of variances of the various hematological variables measured are presented in Tables 18, 19, 20, and 21, Appendix C. No consistent trends were noted in any of these variables which remained within normal limits throughout. Random statistically significant differences were seen, but were not consistently related to the exposure conditions, 3.5. Clinical Biochemistry The group means, standard errors, and the results of the analysis of variance of the various clinical biochemical variables measured are presented in Tables 22 through 35, Appendix C. Scattered statistically significant differences were noted; however, no trends were seen in any of the variables. Throughout the study, the group mean values fluctuated within the normal ranges of these variables. - 202 - DUP040011429 TIDAL VO LUM E [(D u rin g P vr* 0 * y g * 0 B reothlng) - V y ' m l BTPSj,- TIMS - WEEKS figure 65 ~ Third degree polynomial regression curves for Vj1 prior to and during exposure to sulfur dioxide .and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. 1 i - 203 * DUP040011430 HAZL0TON LABORA TORIES, INC. 3.6. Arterial Blood Gas and pH The group means and standard errors for the blood gas variables are presented in Table 36, Appendix 0. Examination of these data did not reveal any consistent trend with time. No apparent exposure-related changes were seen in any of these variables, .3.7. Terminal Body Weight, Organ Weight, and Organ Weight as ;a Percentage of Body Weight The data of the terminal body weight, organ weight, and organ/body weight ratios are presented in Tables 37 and 38, Appendix C for males and females, respectively. Several significant differences were found between the f-Aperimental groups and the control group. The adrenal weight for the males in Group II was significantly higher than Group I, and the adrenal weight and adrenal weight/body weight ratios for Group IV males were higher than Group I. The liver weight/body weight ratio for Group IV females was significantly higher than for Group I females. Several other significant differences were found from comparisons made between the various experimental groups; however, no consistent trends could be discerned, 3.8. Histopathblogy Summary A detailed listing of the microscopic alterations seen in the lungs, tracheas, livers, kidneys, peribronchial lymph nodes, and hearts from the animals in the control and exposure groups are found in Table-39, Appendix C. Microscopic examination of the tissues frpm the animals exposed to 0.6 mg/m3 PbCIBr and to the combination of 0.6 mg/m3 PbCIBr and 10.0 ppm SOg revealed exposure-related alterations in the kidneys. These microscopic alterations were characterized by varying degrees of degeneration in the - 204 - : j i 1 I DUP040011431 i '! proximal convoluted tubules. The epithelial cells of the proximal convoluted tubules were vacuolated and possessed vesica]ated nuclei. Numerous intra nuclear* acid fast inclusion bodies were seen in the epithelial cells of the proximal convoluted tubules. No other exposure-related microscopic alterations were seen in the lungs, liver, trachea, peribronchial lymph node or hearts. Scattered incidental lesions .were seen in these organs from both the control and test animals. No difference in the incidence and severity of these lesions was Seen when the controls were compared with the exposed groups. Animal number 182L in the group exposed to 10.0 ppm SO^ died during the 40th week of exposure. Microscopic examination of the tissues from this animal revealed lesions consistent of monkey pox in the lungs, liver, and trachea. 3.S. Summary The inhalation exposure of male and female cynomolgus monkeys to 3 9,70 ppm SDp, 0.51 mg/m PbCIBr, and the combination of 9.93 ppm S02.plus 0.50 mg/m3 PbCIBr resulted in a deterioration in the distribution of Ventilation in the animals in the two groups containing PbCIBr, The number of breaths to 1% nitrogen and respiratory rate measured during pure oxygen breathing for both groups were significantly elevated above the controls, with respect to their relative pre-exposure .values throughout the exposure period. Cumulative tidal volume to 1S nitroaen was significantly elevated in the group exposed to PbCIBr alone, but this change was not seen in the - 205 - DUP040011432 group exposed to the combination of SCI, and PbCIBr. With the exception of higher breath to 1% nitrogen values than the control group, none of these differences were observed in the group exposed to 9.70 ppm SOg. Phis one difference was probably due to the high pre-exposure values of the control group. Microscopic alterations related to the exposure to PbCIBr were found in the kidneys of the animals of these two groups. These histopathologiqal changes were characterized by varying degrees of degeneration of the proximal convoluted tubules. The epithelial ce'. :s of these tubules were vacuolated and possessed vesciulated nuclei. Numerous intranuclear, acid fast inclusion bodies were seen in these epithelial cells. Body weight measurements made on both the control and exposed animals throughout the exposure period indicated that the animals in all groups increased in body weights. Analysis of these data did not reveal any significant differences in the rate of growth between the control and exposed animals. No meaningful differences were detected in terminal body weights, organ weights, or organ/body weight ratios between the control and exposed groups/ Hematological, clinical biochemical, and arterial blood gas measurements were made on both the control and exposed animals pre-exposure and periodically throughout the exposure period. No trends were detected in any of these variables in the exposed animals. No meaningful differences were detected between the control and exposed animals. - 206 - DUP040011433 HAZLETON LABORATORIES Appendix C - Data compilations and summary of statistical analysis for Statistical Grouping C comprised of the following:: ..Group I - Control, Group n - 9.70 ppm $02, Group III * 0.51 mg/m3 PbCIBr, and Group IV 9.93 ppm SO2 + 0.50 mg/rn3 PbCIBr. - 207 - \ 11i DU P040011434 Table 1 * Monthly means and the grand mean for the analytical concentrations of sulfur dioxide for group II, Pate n X S.D, ppm 3/31/68 * 4/30/68 31 8.2971 1.8973 5/ 1/63 - 5/31/68 31 8,6948 2,1871 6/ 1/68 * 6/30/68 30 9,2770 1,4754 7/ 1/68 - 7/31/68 31 9.5377 1.1408 8/ 1/68 - 8/31/68 31 7.8032 2.2194 9/ 1/68 - 9/30/68 30 9.4020 .1,6718 10/ 1/68 - 10/31/68 31 9.7019 1.9957 11/ 1/68 - 11/30/68 30 10*3617 0.9926 12/ 1/68 - 12/31/68 31 9,6362 1,1671 1/ 1/69 - 1/31/69 31 8,0226 2.1781 2/ 1/69 - 2/28/69 28 9.8011 0.7511 3/ 1/69 - 3/31/69 31 9.5323 1.3048 4/ 1/69 - 4/30/69 30 10.8390 0.4810 5/ 1/69 - 5/31/69 31 10,1565 0.6112 6/ 1/69 - 6/30/69 30 9.9767 0.7278 7/ 1/69 * 7/31/69 31 10.2965 0,7100 8/ 1/69 * 8/31/69 31 10.4761 0.6406 9/ 1/69 - 9/30/69 30 9.7290 0,5017 10/ 1/69 v 10/31/69 31 10.054$ 0,4867 11/ 1/69 - 11/30/69 30 10.1233 0.4409 12/ 1/69 - 12/31/69 31 10.3842 0,5963 1/ 1/70 - 1/31/70 31 10,3281 0.6158 2/ 1/70 - 2/28/70 28 10,1696 0,5316 3/ 1/7D - 4/ 2/70 31 10.1761 0.6594 If = 24 X - 9.70 : , . = i io - 208 - J \/ DUP040011435 Table 2 - Monthly means and the grand mean for the analytical concentrations of lead chlorobromide in Group III. Date 5/11/68 - 5/31/68 . 6/ 1/68 - 6/30/68 7/ 1/68 - 7/31/68 8/ 1/68 ** 8/31/68 9/ 1/68 * 9/30/68 10/ 1/68 - 10/31/68 11/ 1/68 - 11/30/68 12/ 1/68 - 12/31/68 1/ 1/69 - 1/31/69 2/ 1/69 2/28/69 3/ 1/69 - 3/31/69 4/ 1/69 4/30/69 5/ 1/69 * 5/31/69 ' 6/ 1/69 - 6/30/69 7/ 1/69 - 7/31/69 8/ 1/69 - 8/31/69 9/ 1/69 - 9/30/69 10/ 1/69 - T0/31/69 11/ 1/69 - 11/30/69 12/ 1/69 - 12/3.1/69 1/ 1/70 - 1/31/70 2/ 1/70 - 2/2.8/70 3/ 1/70 - 3/31/70 4/ 1/70 - 4/30/70 5/ 1/70 * 5/ 5/70 n 20 30 31 31 30 31 30 31 31 28 31 .30 '31 .30 31 31 .30 31 30 31 31 28 31 30 5 x mg/mf* 0.8570 0.4743 0.4565 0,602.2 0,577.3 0.5074 0,4286 0.4638 0.4752 0.6154 0.56/7 0,5147 0.7770 0,5503 0.5597 0.5010 0.4737 0.5352 0.4930 0.3871 0.4052 0.5100 0.5561 0.3070 0.1080 S.D, 1.0552 0.6379 0.3048 0.1088 0.1526 0.1497 ; 0,1.944 0.1819 0.1339 0,7173 0.1515 0,2131 0.1710 0,1740 C.2216 .0.1545 0,2049 0.2722 0.0363 0.1065 0.2503 0.3669 0.25260,5232 0.0295 H - 25 X =0.51 S.D. = 0,27 - 209 v i i. .1 DUF040011436 f Table 3 - Monthly means and the grand mean for the analytical concentrations of sulfur dioxide and lead .chTo.ro- b.romide for Group 0. . *-/ so2 PbCIBr Date 6/ 1/68 - 6/30/68 7/ 1/6S - 7/31/68 $/ 1/68 - 8/31/68 9/ 1/68 - 9/30/68 10/ 1/68 - 10.31/68 11/ 1/68 - 11/30/68 12/ 1/58 - 12/31/68 1/ 1/59 - 1/31/69 2/ 1/69 - 2/28/69 3/ 1/69 - 3/31/69 4/ 1/69 - 4/30/69 5/ 1/69 - 5/31/69 6/ 1/69 - 6/30/69 7/ 1/69 - 7/31/69 S' 1/69 - S/31/69 9/ 1/69 - 9/30/69 10/ 1/69 - 10/31/69 11/ 1/69 - 11/30/69 12/ 1/69 - 12/31/69 1/ 1/70 - 1/31/70 2/ 1/70 - 2/28/70 3/ 1/70 - 3/31/70 4/ 1/70 - 4/30/70 5/ 1/70 - 5/12/70 n 30 31 31 30 31 30 31 31 28 31 30 31 30 31 31 30 31 30 31 81 28 31 30 12 x ppm 9.0860 9,4800 8.1126 8.1710 9,8820 9,8613 10.1381 8.1694 9,9996 9.8535 10.6361 10.2061 10.0123 10.2297 10,5742 9.9700 10.U68 10.2610 10,4919 10.5181 10.4392 10,4284 10.8520 10.8500 S.D. 1.2098 1,5272 2,3330 1.8994 9.2737 0,9160 1 ,2822 2.2516 0.9223 1.4923 2,0651 0.6014 0.7646 0.7385 0,6935 0.5091 9.4745 0,3675 0.3204 0.4787 0.340 0.4740 0,2919 0.4373 X mg/m3 0.7460 0.6381 0.5897 0.4690 0.4271 0.3920 0.4500 0.4755 0.5825 0.6377 0.5557 0,6194 0,6340 0.4252 0.4516 0.4090 0.3925 0.4333 0.5413 0.5906 0.5257 0.5903 0.2017 0.2417 S.D, 0.6084 0.3021 0.!57S 9 ,32bO 0.1582 0.1834 0.1752 0.1776 0.3086 0.2419 0.2620 0,1859 0.2501 0.1405 0.2649 0.1720 0,2515 0.1563 0,2833 0,3857 0.9777 0.2595 0.0730 0.T083 N = 24 i * 3.33 S.D, = 1.03 - 210 - N - 24 ' X =0.55 S.D. = 0.27 / DUP040011437 followings Group r * ____' . . a ' t v # n rv-i -- c -n -C on-t/vropl * r GroupI ____. Table 4 - Sunwary 'of s ta tis tic a l analyses of bodyI I weight data fo r 'S ta tisIticI I a l Grouping G, comprised o f the - 9*70 ppm SOg* Group - 0.51 mg/m3 ObCiBr, and oin v{ a $ itCnu/5 PC Ctc-UDc PC 2LU cOtnoS -st' oo OLi_ a; CMO <C tLoO CoaOs CM o*. co co to T3 CCOO <c 3 s :QC UUi <rSo0-. Oi<>U IC_3 CL. io- Oto JaS - 211 - AO r* to os os Os 0 .. o roi CoO *3* *3* CO .p-- r-- 1-- *-- <>/>1 o > o * O o iT oo r-- -- CM pd" Io 1o r-- *--* -CiM *I row ro^ CiM *3i* o r-- r-- XX to CoOs 1-- CO +1 Xx CO P-- p OS r*-.co +1 XX CO CM m o j r^- CO +1 X :X m co "3* .CM *--os fi LL_ UJ o CO z o Httoo-J CtoM O o CO o p to o ipLnO p Uaci tCuD H CO +1 m +i j-- +S CM PC vp CO p P CM CM CM CM *Si Cl . O PtCJ } DUP040011438 f %. j? M 533^31WWWS?^* Table 5 id CM Po <o to "O g. Ca Oa X> o s r** i. ' . t 7) a *A t C: Oi Ca *- . 23 =S3- OS- U^ *0003 CJ O r- -Q C O Cl . id :S- VMI 4cJCO vCJf~LO)-: O.' I Sgrn. O o3fe '6~ r- ao M-- o3 + Su , *! VI 0>E e. a ^0 r5o*?1' na. rj *P r- Ol L O 0\ ai V<W3J -4I<-CU>;!>>-4 rns o?t* C3L 4o->-aOJIC2D tst U~ -r- -a O:; at- C<o <vU> Oei * V) O &. >V CO 3 o o Cro omX.I r--1 *.r'.*S-CCIO id Cl r-- i'hO i Q> + i- E TV-I .CO .f-- 4r4tf f"tz"*\ tO 4-> O O t/i *rr Vo~ 4TtA4- .I *""* '5'4C*-i;,,+i/4;rl43ili t---4* C-. B ' 3 e:-'fc. n 3 C 1to <#- CO in 41 Vi > a cn to z o M to to LU CC CD i cc O *?c r* r-'* LU XX CM CM CTl <3* CM -CO O z *--4<c co r-- cc i i < oo > r" r-- u x x o to to to to o ^to Kj* >( CO >_U z: < T9 *4Pr-- Qrtf -<3>> S- o to aco< UOuct--i co o . in in to CM sP d* CO o> to CO CO to oo X o >1 to o I** uo oo oo o O o o - 212 u. Ui oo CO.CO II cin cio oo oi co oa co co io i X X XX XX XX Oo O O to ,csia 00 r>. into to ir- !- CO CQ .co LU to i CD LU +1 -H +! +t DC M ii 1 1 c o oo o o o .r-* r-- >Oz- X X rr* Xx f-fc.r*?* XX I-- XX wo a o r-- in vo oa r> co in .1^- SJ* CO 'M' tn XX3 tn.p> ac.o t I H +i UI Q Ui o m "3* *3* be ii ii it tt oo (-* r4- J-* *-- .|-i- V-- T-* XX X x x X XX CM r-!* r-- CO CM CO +1 r-- rjCM CO co t +i .in p in co i +i n to co CM CO 1 +1 CO cn KO CO CM vM CM o oOO ooo o . -H -M +1 +1 co CO m vr o rS O oO o to .a. ->--t o a: .M H4 .M > | 1 1 i ;5 DUP040011439 JS-- *% ./ te . OCM rap. Ve: ) ,cca *;> oa-. o fss * uo> 1XO2P''.*>'!H~I lt sOSza. 3ir-- Sno- * 'O o ca W *LJ O r-- XI in o c l . <cs s~ .JirJtI 4r-r>COs - O " -s &IcAu' Ut EOi 3: -* oin o ! 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CIM* VCOM; CO +1 <coj* <o7> C1O CM 41 COMfOS L.O CM 41 C0M0 LCOO ro1 ; 41 CCoOMO .COoLfM> CCOoMO .COO4Mr o ooo .15 +1 t I M Oo^J- o o lO O O^O3r O' o o o - 213 * M - DUP040011440 9/amQ 41 -4C-a 3X 0 Q4- CD TO *0 <0S)* ig r* JU * ti 0 ?*''` uo jQ c>*a. co . cn s? vs *- &* CL : .3' ' ' Oi- rI;f"t CD ..* O r-** f& I O ,44 >.- </) * r-- 4HJS 3a. G4-O* -o'QC J. ' O'' o & :n 4- i ' * E TJ- i'.CL 4# j CL rssfros. o crl > t twi rO -h ''Oil-- r"! 4*1 EX *o*- 3s~ mi CDcaS 4Jl: *r" CTir^O *!?*[ EL re .44. 3 CEO * 0S 1 C_> >*. *iTtji* i sO* a *r? .-- O 4'M-} :tXin_J ' 3o 0 tJL. -J-CD N *>'0. C.O 'oCS.O X'r-- .CL V<2 So EL Ew.Ol <5E0 *4o---0** I 7s* o S'T*,Q ns in o y"l a. OtosJ oSC. *--# V5 CO Ui EC CD UJ. PC. CM -fr1 -iv PC o o c Ui X CO fco s LU O CO o z >--< i-- to oc +o +o Lu O to to a* CO cb .- o to '- 0? -J c .z: <c `Oivi CO sc. o < vs> xc i sso-. 1|V% tCoO a* CM CO p o oo CM CM CO CO CO CO ; X CO t>. o r-- to CM oo & CO CO CO CM to in to to to U> to in ijj i i 1 I i l t t oo 8 |j-- (MM oo r~ oo r- oo rU r X X XX X X X X CtoO Ui oCDi uoci to.-^ jrL* CO * i-- CM +1 1^.0 o as CM CM 4t O 3co to CO CM -H 0:T^ #*-- un 00 CM +i cr> co CO CO J- CO co co >i \t it fi to : o oo oo oo oo fi-- r"* r** .** r** y-j 4* X X X X X X X X ..o 0 to t: VOcM o CO a tn 00 r- ; as sUJ us a: CM to sr co to I--I O It 4*1 41 i 44 +i CD LU a CD cc r~ r*" fmm r-- CM r* 1 t 1 1 . 1 1. t i oo oo oo oo r~- *- rr* r~ p4.r* !- .pr* to X X X X X X X X CO LU PC CD Ui csjco U> .00 0 CM r-- 8S st CM to co r" :tr O m to CO :f-- EC +1 44 44 4*t CM CM u> o o> o tSv r>. i-- CM r** ** +1 . -H fri CM a> O o f*> r* to CO CM r CM CO <o CM - 214 - *+ w > 1--4 V<4 >--* DUP040011441 mi JZ :+> O Q. -a o <i; u l CO K?* . %* XJ CLC r 3 O o > s~ ca O r*p O C'JJQ c; o. c.co 2), , c>'~s i. cn cs g If!*" .PT" ra l o C.J p O +J > +J t--1 US H4 -M v-i CO CL 5- rs OQ <*-- u 'JD eo 4J A ; *0 O .to ,0 J-V. 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UJ UJ a: CD LU .0 .0a: --4 1 i-- X os P ^r CM > to co ps to CM CM to pr-- to to to p m l o to LO 00 00 'op 1 .1 OO r-1- r-r- rr-:rr- r~" r-- r--- i--!* Xx Xx XX XX P CO to eo co Os to C0 CO p.p to .as CO Pin CO jSs. to f-- CO 1-- f!-- eg CM r~ +1 *1 +t UJ CO CO coco ro co CO CO . 00 0 p 0-0 P 0 0*0 _r-i- r--- *-- f~" r-- r-- .r-- r-- +t X X X x X X X x to H- p z: UJ 1 0 P-4 u. Ll UJ O P z: 0 P-4 to CO CO UJ 1 CD UJ 0c 00 "3 .OS OS CM { >. r-- as o> 0 10 CO ) +1 ca co O CM Kt* I 41 CM O i--IS. csi fi i-p 'r-- \\ 11 OO OO r" ,r-- rr- 'rrr it PT F-- 11 pO QO fr-- r*r *4- r-p X X XX XX Xx to CO CO CM P^O O CO p-- CM O CO 'VO CO r-- CO -p- CM p-- CM P" rp- -H +1 +1 +1 P eg CO CO CO CO CO .* p- fT- r-; 4*^ ft +1 +1 0' to *4 Cn cn CO OS O CO CM "4* co *> - 215 LO c_ 23 :>-4 O DC CD >-- M >--4 M P*H i / DUP040011442 a u Q. Ol RS cs Q.S~ 3 cn <s3-Xo3 CL <u131*s0 w"* lS*y *o>f Ecn P,r? to ns in P . VI o Lo : * 'h- M 4-4 <tf >- -P Tt3tt 3CL O Co* <S3- 3 r-- * 0J-.Q04 -cr to P ip eQ. 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CL .CO in 0 cp 0 O VO CM si* I--Of .rL CO in ! <* CO CO * > ' LU LU CL UJ -4 o ^ r-- sf 1 1--* i--- F-- OS 1 +1 H H -H o: LU a oca Ui o .0 ; cvi CO CM CM CM CM CM tj ,1 1 1t 11 0.0 O O r-- p-- fmm r--> OO r-- OO 'iw r in to CO oc <3 pi XX co to cp in .* * ,r~ Si* +1 XX CO 01 co VO co t +1 Xx ; tn CM VO ** to in *H Xx sf CO M3 ** 1-- M* t +1 SO CO si* CO ur> ^i* 0 0 OO <K H fi -H r~ !> Of Of O 0 si* to CO ip LO 216 | to CL =3 'M ^4 *---* > O 4-4 4-4 4-4 QC 4--4 O *\ v\ DUP040011443 Table TO - Sufiary o f the. f M statis o llo w in g : t i cGarloupanIajl-yseGsonotfrolp,uMGroouMrpy.I.Iflo-w resistan 9.70 ppm ce data fo SiC. ,2 Group rI SI I ta tis tic a l Grouping C, - 0.51 mg/m3 PPOTffr, comprised and Group IV - 9.93 ppm SO2 + 0.50 ing/m3 pbClBr. in o in vl & >- CL in o itnn cc ** or it 1 00 < 'r*?* XX 0 eo LO st* u_ CO o in ro z: vcw--cci 7O 7O o u> cn tn tn .10 r> ; m in cr CO >-- S t-^ VI s 0 n: r* l <C- ir>* .01 +1 iti r~ r* u. ir-- o flj '> O :LU S_ P *J o Q. t. o: t O ID e S- O (j X- to LU CO CO AO in CM 10 . ! O Ip p O coCM CO .IT* CcsOi iO AO r>> tn PO00 O 9 O O O OOPP CO CO J coco or CO CO CO i I II. 1 1 .1 1 P 0 P p p.p 0 0 r- r-** r* r-- ,r r*4** r-- Xx XX XX XX Q 0 0 p O 0 o: 0 0 CO co CM fn. OP ip r*v . rj-*n tn ^ co in tns* +1 H +1 +1 LU to +1 co U1 I-* O *--4 H- 10 .1 i tOl MD1 r> ro t1 IO AO J1 O0 OO Pp PO TT- r- -- r*? f5" ^ r~ r-* XX Xx XX X x CM O CM CO P in cn r*>. co j-i-.cn f-* rr-- Ol O coco P.l*s ** P CTi K l11 +1 +1 +1 H tn IO nt* 1 11 00 0 0 OP r-- r- r- r r-- I .1 OO r^ r- 4i po xx CO 00 in * r*v co XX *3" CO m r~ co co XX *3-CM PP 0 CO XX ; r> t>*P .* . CM CM 41 -H +i H :i AD CM 0 r- CO CO CO 0 OP 0 O OP 0 O * OOpO ft -M +1 +i ^ P tn 0 CM r~ CM CM 0O OP PP P 0 217 / .* DUP040011444 S- aS * CM do,i0/1 s n oau. r O> iOs. i-rrd* Ql t? I H 0.1:0 u 3r OO 3U ..Q ; ; a. c CO Qr* r 0's. 43 s- o> + S Vc 0 <0 CLO 1-0 1VI Q : O p * IrH -h o> c a. .CM' >r Sii 0 Oi GO o cs e d. O* 1H. 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O in co 0 CO co ro a. h-- 0 0 "O* Ps CM UJ z LU tors. to 0% r*-.CO CO <3t UJ cc CD H +1 +1 +1 UJ a 0 UJ o CMIICM CIM tCM CIM ICM *I* CIM b UJ 0 0 .0 0 0 .0 o X X XX XX to O n *3* to *?j- to ui Qi O cn is* o to to cn ; ; c- .^ rs. ro CD ui +l ce - 218 0 CM to 0 CO ^3" CO 0 O 00 +1 + +1 H *? to CO CO cn CO CM CO CO 5f to, IV o occ o 3.86 x 10 \S - .> DUP040011445 \I y ^ *O m ; 43 nS (/) S. E CL 2T f-- O .O'W > : > 13% r* X<T ' I r* M il<-4 u rrr 3l <33 S 3 -- O CJ $. L M'03 CD C3-. l**CO 0 o^ .$* o P 4J H j c LOO -r- f,,J tO P. x ro o> 05 Gt CL OS J-- 3 O 5-v O <J'. 3 ; :IL ' 1 0(3 g JL 01 3. SL r- Oif) C CO) *4*^ *r* os ?r p i '4** t|- --j O ' OJ c.-x .c: 3. S- 4- G :CssV4- c&a o; *4- *0 073 C U 03 to V) QJ *r- . *> V) *- 5L >> CL03 r-- .S:*-^ r3 O CJ E o -Q rcs c l . r-. K^C0 rj s u o-*s. r- El,,05 4-> *p* I H vi n. U oui <TS JLi- -M CD O o/t 4~ rn--3 t O Cj .*-* r* m >vPM !L *r e 5 3 + * S?/? LO CD JO -AS H* in 0 vt 1 1 CL 2: 0 to to LU 4X CD LU cc CC C LU 11. -^zz \ *--1 --1 . 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CD LU O :i. -a' cc >-* 3: .1^ .0 00 P CM .05 CM to CM O -O P 'O <0 LO to to so tp t>> LO *Op 0*0 100 o'o p* p*! f-- .r-- r-f X x XX XX XX a 0 0 00 00 00 O .s*- ; CM PAT CO CM r--CM 1-- CM P CM 1 +1 1 +1 +i -H 1 1LU 5** "St* *?4* *5#* W 1. r ! r I t O 0 O O OO P P to .P- *-!- l-r- P* r*-*.r-p rp pi* +t X x X X X x X X feto 05 <0 CM O fN,.^ sf <7> k t r>p CO.lO tO :VO JS ~4 LO CO CM CO coco C]O CO +i -H +1 +1 .1LU CM CM CM CM CM .CM CO CM o o Ii 1 1 f I 0 0 O O OO 0 0 r-- ^ r-! r-- r* r** pp* f""* XX X X Xx X X to to 0 in 0 LfJ h>. CO to LU to to Lf> in p*-.m a: CM! * p--* 1-- Wr- (Off 1 1CD 1 4 UJ +1oc +1 H H ;! !| - 219 - 1 . tp uo p"* .0 P pp pp 0 00 +! *1 ^*1 -H in 0 CO CO CO tp I> ,r^ P-* r-p cu o :> --# DC .CD DUP040011446 ;:-fr5L m. *** E: rtf's-. O CD rtf O t*>o .i co fs- CD :U> CO ip CO fs. fI Io Ir a d a ta G roup "O *l" : CM Xo O co K1; iq i-s H a- CL c oo jQ f*s Si-,, : rtf <J> O t 5* Om tfc w Ctf Oc rs rs o n*', 5~. * CD <D . " 4> r- O ,t> 5. c sa >i o 4> O CD r* D fj l Q. rtf aw <Wtf', CL 'ss*. 3 ipl o> a s SS'-U . CD CD c/j in ! <4- - O 05 "XHS -irf-f + 2 CM H- o CD Or- to ;ii,r-- to, o 3 a> *-- :a- tA <:x >b a> r-- JO CO rtflll&J cn C rtf H- On O *"--!!! ! rtf *a CJ r- Co jl S>- < 4* <n U i'X !- ?rt ;:i 4J .3 O rtf O S- Ut/J U0 *T3 s~ O CO rtf o> >t sr * 15S- -r- S~ rtf 1:0. CD .S: impl-* j Ci to t.o n, 2 O *-r CO to ! LU i'l cc CD UJ X C <c U | .u jl. fi O LU CD ? 2 !'':i *1?*C4 i'''; cr: il'l C r^ ,Uo to 1 1--4 00 i': _>_-s. 1: C i;!- 1 ; co f--1 . y -O rtf 1-- UJ o vl d. Ot u_ CM M CM Ii Oo XX to CO s: co co -! *=r CM r* *o *0 to to CO in in co u> *4"P to CO CO CO 2S O I-- J<--c4 H VJ nc '>< * QJ cn s. o ss- CO O co CO CO co coX CM in 05 CO fs. r>m o^*1 CD o*3 CD oUJ 0 p d LU O o Js* In fs N N l> r^* fs* i O o QP O O o o r-- r-- r-- #r-- r-- r-- /-- p-- 2 o XX XX XX Xx -- I to to o o 0.0 o o o o LCl SO <71 CO l o r>. rv ; LU cc r- Cp ,oo in CD LU * 4i 4J 41 41 DC :vp in in in st- in l o LU o o O O ,o o O O o to r-- r-- r-- ,r-- r~ r* r-4- r-f- 2: >-. +i XX Xx X X XX -j o n_ UJ to LU PC C1M fs. CD cjri r-- CD ^i-a> to co CM r* *-- r-- ts. co r>. is- LU ccr o 41 +j 41 4! CLUD Q O OC o o coco <o oo coco coco i . i i i r * i O p o o cp o p P o to XX XX XX XX to UJ oc r-- o <n co O O r-- OO co 00 03 eon c; n co CMCD Ui cc rtf- cotf* r- 00 I 4i 41 41 41 CM CM CO O o5** to o CO o O Q o CD +i +1 +) 41 CM CM rs O to rs IQ - 220 in Q=3 Occ. CD t / DUP040011447 .J..- p OJ #crNPO IX 5H 3's O o> t-- LQ o *oo p t VI r- h i 4* H-t 3>-t 4> to o. .at &- Q o s4-p <3 . * *4iPt*s otCO\] ot CL -SP foS* *1-- . > c: c* ** i 0 M i. 4-> a.13--3 VI 3 40 -c a .a P S-(L U3 <y co 5- 5 i3r-N O :OI 4- &. 12 OP LO. QQcUo^ .O O 53 t -i* .C w 4P- 3Ou OU<TNI vi S H 04 tS CL Vi Ck cnIBs p3i<p:-j i)>i .S 0f^l*j rOH I F- o M L> Mid La.#C--O eo CaO -aU L-aL j 3l S m p v] a. CO o O H4 to to. UJ cc: co 04 CM +c, +o Q to XT iv;SI. CM CO Otn* Ui o CM to f. + ac p o <c U. O to CO CO to CO r-- to >* <C 2: **3* CO CO ,o c a: a ,<C p ft? i-- > o to XU UJ X CJ as o a. u o: =3 P4- s- Oo CO CO CO sr to o CM o CVJ CO co co <7> to to to U3 CT* rX cn Ui to d* U) co M o K--i u. u. Ui o to1 to1 tn in tt to to ii toio ii or"-*io-- #a--ro~ oo p-- r-- Oo r-- rr-- P: 21 X x X X X X X X o HHI to oo oo oo oo fX CM p to St* t> r>- to to ui e ts CM tO +1 co *^ro l +1 M +i Ui a: co <o 1i CO co ti c1o c1o C,1O CO1. O .z 00 OO k- h ** ro* or~* oi--vro** op h -- r- >- +i X x X X X X X X o (X uj Ui o tO to H z CO CO ; ai to to <h m 0.CO oven r-O ton *m UI H P> to to ; in i +t H +1 +i us p u. UJ o .ce o o CM r I fO-- rp- Op _p-- OP p-- r-" OP r~ r^ to X x X x X X X x to UJ OC, P to to .in CO tn ; CO CM oi cn lO Cl :CO CM 13 co n CM CM CM CM 1-- CM -H +i 41 41 CM >s** 3 CO P to CO n co CO CM -i-l -41 -II tn cr ' r-^ CO CO r^. r>. CO CM f--. <4* r-'v co - 221 - to tx. rD o boe DUP04G011448 1 a U*-- 1 *MrM- >Mm--i* P . j ex zs co a ]L CD O'.' * CM! RSO PV) (O "O' & ' , ex *r->jfx co r- N ''1 HP cn j i a? < j sQ- ;M4 ' m * C ' *. <UrO> iSO C13 iM x>> ox. .oa O CD IX O rfO rS-S irO- *Ev c. .x. a 3P = T3 C woO QJ o to 4-# 1 O rtJ 1-M -|- >9, ja. m L 20 +o-> oX co fO CD & J iX - IX CL ! M o:v> U C CO X-**-* 3s ci Mr o OMrmm !l M Q> tVrtM1*' > i >k a cx .rf-MJS: "3 ra 4-* a c t,, CO $- C!> r--<0-O0 TcJ: u U -Cl in Cl , ; On O lOJV6*,. >!mV*mT B> C3 C5 E 3 rEoui 3X WOO 1 to '--<1 cc <c lip' LX O 1V--O< V) ! -U <2Tc to o V| 1 1 a IO r t 1 lx cJ <M j M 4- + .Or ' *Om \n X x .E O vj D p co sp co r-- SO CM +. + o!-! Po" XX to to O IS* fv cO . oo to LO M- CO CO *o cp z Ko-4 fc- =. cc iHfr--t r-r >r . Q> M tx r-- O J Ul X oQC 23 eCIx Oo to 5= ,rco, > .a -r> gj o osX_ x LU 1 CP a 1 to <x> .ois. CM u? o co X 9- o p O p i= CM CO O co CM CO CO Jt--o X . ist* 5h CO o u> CM P r>% a L2U to M CM co CM M* CM3l IX LX LU O CJ in to into so to SOLO 1s i i. 1 < t1 o.o O P p p oo rM ,m M *" * f-- :m* m* 2 MOl' t0o0 XX X X XX X X o' CM CO to CO O CM O CO u> SO CO CM Cn . Vf `-O UOLl SO M* *M- CM T**.CM *n ; CLUD +l M +1 +1 (X -U M?cl E 2o -->*1 .a a. co co CO CO co <o LU to 0*0 op p o f-- ,M- I-- F-- r" :M +1 X x X X X X to CJ H r>* ;* CM M SO co CM LO r-- LO .Op.rM CO oo r-- m- XX CO LO co o Ul Ul cc Z UM4l o P CM r>. co i tM >*j* t CO -M* H +1 +1 -H CD Ul LX a LX LU a o: Ml .a1--: OCJ> M-1 M*.r-- ,m rr Csl r-- 11 11 ii .* 1 . z o*M CO Oo .M-,r-- XX oo FM M- XX oO XX oo 'r*r M Xx tUol ca P SO coco o p^-f-- tv IV p tv <t* to UCDl Mr-- CMM r-- r^ P r*" 1 C +1 *H *H M 5 O COm rv. p** M P" r-- r^- <c +1 +1 to CM CO * ,o M< Ml ClC ; : Me s s i i l i 1l DUP040011449 a c c: ?Cfc. 3 03 - CD co H u o *v- Ks - T* 1.0 4* <S O P to 1 5m. .-4 a i*-t H-j -i <0 IX 44 3 <TS *o L. CD C QJ <M Ol '.```I oo S- O') 44 *r- 5? c . a. ** F-- O IPS' o M Cl* a> i e 3 *-* . * r-- >* JU O CQ .> .tU- .3 0 r-- O .3 3 S~ 0. '`O C> *r* <'0 44 * i= o o cn > uHs r -U +* c o fD 1 *-- O 3O * 3 -h U M: JCM 4- CUO D 3 CO -O *,], w l- H CD f.:c to !X i-- CO <9 CDGTi; Cc " <0 r- Cl 1-^ O 1 H- D>- r"* O H 4-9 tp. Vt G, ^3 4-*J2 o ,s - 44 C5 >**<- - H- .e O "TO (O - >> </l .* 1.*^. * U ; Q,rn S i= O 3 .a CO Cl X | < X) * H in o . ii v| z: o H-* cn co LU ' , CD LU X S' DC =C LU ,. 5--Zr -4 Uo UJ U s: <c - HI(X Ll . CgO Ll .* O to to CO ^4 tn >+ v <C ,2T 03 I Q It Oo Xx to so r~OO U3 <M 1O o X p c>t.* V CM en <**o co ccoo z o *--* H* < c 'A o cc <c -<-> rtJ U. O <>19 O a.UJ 3 o ' .5- Q i Z> c: U UJo o to z S- i a CSJ CM ,r>. LO CQ CP Oo oo c CM CO Oco CfOM rco- 223 co X tn 03 CM UJ tn o o r-7* r~ oo u. LULU to r>.to CO AO vo to 1 o o o o o oo o o O *3" o to CO r- O CM l4i Q CD LU -O +i r-- CM r~ 1t +1 +1 +1 QC U> rJ" to UJ : i i t f 1 1 |. O Q o O .o o 0:0 K-- F-1- I-- F~~ ir-- CO X X X >C X x X X CO LO CV| C\J o% o c\i in CO w f^-LO ON *?rco U4Z ^-.CM to .CM cM r-- fOr* .1 +1 +1 H ^1 LU o o. cm CO CM CO co co it 11 1I ti o oo .* *? r*-* oo rr* r-- oo rs- r-* oo M Xx X X X X XX CtoOLU Q o tn O VO in *3* tn.u) is-o> U> O us o coco .* * ccCD UJ LO 03 +1 ^r.r^ CM N* +1 +i +1 O o o < 4-1 to SO .03 -rj* O O CO o o O o +1 +i +1 <D CM ' tn ir> Cf> CM rr" ,rF r-- CO Cu V-H > O. G CD / DUP040011450 o CcZr=n*3L OOj ..'.to o-J>Hcnn ;JjiIiMr^t'1 nm--s KfO LO 1 5,. ^ C>. "-* * nfCMt!i c3;Oiu- OJ * .Tj4rCSQcapCCtJJ?Jn.- NOoVmsCXItMv &. o J-4 F0CiTm>*R-03H.1C0--SO- -*-C3J**tOwD QJO- CO r3QE-) nJ; r.:j.' HScn O> *cor' ion rX1a----Js t-l'. 1 O* + 4-> *-.i CM Q c3v^o)` VVaiI ooS- s. C; !L ! --: .fclJ, r* .ffO eOO)* id <r* fih. rf~C rO--3> I r4yr--MrO^ >i>4 *V-* flJ OV +n4j J424 *- LOm3, >. O O^ TV3 0Sc3S3 `r- S sS Vtipc"a* , V-s>I Eoo oa-C>. ;4 IN 1--0) JiOtx 1 m o vi ><3. i Os: o U. o i ttLCooUC 'CLCUDC. CM <CLUC % +Q 21_-CJ4 Lx. o LU t2o: X *-- in !" X fCNO ro cn O cx: ><C, co ^r +o + o u_ o CO ttoo CtoM CO <>uztoc CM CO < M-- X5 CO *3" CO CO 5O>--S4 1<--c cc sto -oc < oj -M *3 u_ o UoCOtCODCJ; fSO~ c<ub co: > Q<L> LUo5SU- iOo 00 CO IN. CO to ; # o C3 Q O c CM co O CM r-* CO CO CO 224 * yo CO *3" to CM CO -o CO XX. u. LU o CJ tn* ui> oI-- o in<ro--inio tiror--t.n1o mtpo*mio.p* .2O*o--So4. CO X x XX X X XX CtaO ^cn Or-- rC--O \cpo cCoM tcno c; $n cUcJ co ^3*CO fO CO CM CD ac(j U -H H H K o21' >- UJ to rOi fO. fomm joi-- CiO CiO of?-- To-- CO CO 1o->- 1ro--. co CO 1.or-- 1po-p +i X X X x X X X X yi W CM co cn to ccon csof cfNn. ion o UJ <cUDcJ d >L*Un tL--u_>i ui> u> in co ^ <P -+* +i +1 +1 u. QMcc jo--n-' oOLU 2T o r!-- r--1 *O-- --.1QU--tO. r-ti."Offim 1po-- r--f 1 r0?-.r0-p CtLoUO cQa LU cc XX COM In CM CM +1 XX CM fN LO O i-- CM +1 Xx tN IN, NO r-- CM +1 XX CCOO CCOM CiM ! -- H CtnO fOimm F--n &y* CM CM CM r-- +1 +1 +1 +* CoO f*jzyt Wl .o ICN*:J .c.ao> jtn co t-- va>o sO 1 i DUP040011451 Table 18 -Wean values (S.E.) and summary of fa c to ria l analysis o f variance fo r hematocrit (Hot. - percent) fo r male and female monkeys in s ta tis tic a l Grouping C. ,o 00 in 3<QiD:l CIO t<s3/~ul o CL Xat> Qi S~ a. r>.* co p toco .* CM* . 0>.* CM' to o too to o COr-r Mn > CO>-^ CO>--' ro>^ to Q*. v\ CL CO *f*tO ^ r-- CO CM nvr>-r-- ctoov' nwtnr-- <r*o.>* .r-- o o to <o at r-- * J<tf0>**r---e' P)wO C*3O* Os-' ^CO?r Q O* Oip COCO CO to r-* LOO LO O n r-- Ov-" cj-w' cO'w nw co ON CO cp CM Cm PtoJSO-' mCO*o--- CM O COTv-.' 4o<1-1A1 4+ca5-j>> 01 4- nJ C0HM1 L. GJ Uxal. 4oc wo r- J SCL 'o1 * o rr* oo 00 to 2: 22 ** to (/) I/) co -S<0CuJ CO f tn atftt |2 g " Of L. a. V5 == r** o S-. 4-.' c o o vr 1 3CQ. JH* 5_ CD * CQ O JO CM CL o 00 CO S a d. at a. H cO*. r--^ to cn o t1 -* W *- * 5*. CO rh O -Q CM CL o LOCO B ;S CL v-* CL H CO O Oto Oi o 1 r=* Hi - 225 - 1 t f i, if l \ DUP040011452 tK ** `'A*, Ur. t Table 19 - Mean values (S.E.) and summary o f fa c to ria l analysis o f variance fo r hemoglobin (Sigb. * grams percent) fo r male and female monkeys in S ta tis tic a l Grouping C. O cncv so co pj ** tn o d d 0 0.00 d d vl a. v> CMO3 %r> co o ; &; *j - -o o r- O d o' *-- o aay 44- QSO VI o d V --)I kMxO>Sv>T so 2: VJ d CM CM r-- -O rior--"* CoM o* co4. *-- CO ,* . r- O r<S*u- V irpf.so'* -200E1) v> d Vo1--4I ' (o to to ; co ; ?-- to dd 0.0 end do 01 CL X 4- o ICO l to co lO CM <SI CM CO co do op do do nf sCL 1. a. V? V> d d V) h01 V3I gg-o*- I CSli.l O o oCM 1 o< k--4 ' CiQ- zuo ov>CM CPSLL jOaQ. CXOEcr . ov+CjMOOXCciLIr aCSL.<rH^n. orc>n.* rU--> O. cQoo%v* oCoO i 1. M M*L---*. >-- * S- 2*3 L0uO31 v>: - 226 av: osCoM u 2 01 4.-C DUP040011453 cn c rQ. .3 O x 13 its <d HP VJ O^r- V) 0$.4.->** M- 3 +-* fU</> co c <0 p" X.<A >3 ><n* SX S5 o VI . Of >d i fO?f cv (d "O f-- c *d ? - X Of O*4- o H.4-* rtJ ns *x X O Mro &'! ns :'P &o* 30 V f- o * c dU Q3 lu to.* F4* o +1 u VI. Oil 4) HP =3 ?> rtJ > X SZ .c: +> 2 ?*> Of X .si a) t o CM Of *?-- O d X- (n^ co^s* O 0\ COt -- m O O so p. in. o COrr- io, p (ON in.. O v| p. s O <** f-4 F--!* cn r+ CO jM* %cpr<; *o ; ) in in CM a 02 mo u> o wo mo Ul Jp V> o >~t m * m z: VI Jxi <li a- [CO as x 3v> O CL X Ctf It 4* P <M nn mo CO CM cn p-- o avo cn on mo ome; +n mo *# co O *j" r- Wr* in O mo .0.0 CO CM ON CM r-!" mo +- id Of L id -M C x Oexf X LU r ? cn -c** o mo >*s. CO CO oo mo .r-y. m CO tr-- p" mo OrO CM wo c o w l" id CL e 5u pO VO CD m Xl 02 2: m a c/> m 22 <? of X 3 v o o. O M X Of VS Of X a. CD ,X m m 3C *-- o X >> G O O wf a 3 --* O .x CD x CQ CM O CO H ex CL o > <n .^ M ex CO s cn r-- m ,o i M - X ca + rO* XI CMIX men E..f ^s*. a. o ag cn to o?o v - 227 G O 4J CM o -Q O ex. m XS Of a c | ' - DUP040Q11454 Table 21 - Mean values (S.E.) and summary o f fa c to ria l analysis o f variance fo r to ta l leukocyte count (MBC - per ctnm) fo r mate and female monkeys in S ta tis tic a l Group? ni O cn O 0to0 tA <o . <7*>-- OO CM fs CO 00 w- oo r-O uva- CO.>r--r* to o vj CL O O Q OO OO CM 03 CO CO r-- tO to CO CM MO VO to rSCO OS cow r-->-- cn>-> cn>-- OO OO OO OO r>.-- ior-* o *o oo ** IN CM CM f> d\ tOC\ Kt.r** Ov* o--v' (0 c601 XOl XCL <O*- QsCJSMr-O--*^0s--0r> vOP--SOr;-,*>- TCoQOO*)oVCVOO O tft S- d. E 3 O r-- *c-s4 CO* co V) z: z: C4O3 00 O S-4 O*-*S-i z: 00 oO o CO 2: 0 1 01 3L. vp <oX0Iu). Q- r-- -O 4-> c o o i/t I a 3 O LO CM O to S Q. Q- O. fs * *. p 1 h>l *--l esoo -a ' 0L CO e >s o E to .* ,.o 1 1--4 M s. ca + o43 CMPSlCO s-S tx C7i CL S co.o ovin at o t 2* -C a 43 CM L> O d a. CO 50-> c - 228 - i j*i \ *^ DUP040011455 Table 22 - Mean values glucose: (Glu. (S.E.) - mg p and erce nst)umf omarrymoafle fact and o ria l analysis female monkeys of in variance S ta tis ti for cal blood Grouping O CO M3 V) -GX1 ;c/qr>^. to co lo - .; ; co^f>in to to ocpnw- am y\ CL CO co to o .* * M3 tO (5v ^to * . CO CO Ct" CO CM iPs-< 4J U01 **HrUJ 4-> C o ^ co O* tO LT> tp" 0o ; O CM CO" 1; cn in l> toco co tp p p r^p oto**c-o- in co tn-"4; co 9t*r ch COCO C> CO CO ip I~i ip- rt cn COr- CO CM CM CM VOsy rs.--' ouIt>s 4to- C<S1 *r+ 5<u- o. UXi HO co tr *r* ifl-j Q. E oo 00 V) CO z* *s st CQ CD O * <D CD-* M *4 to V) CO to -o0X>1 3 VO CD CD CO*-4 i-C* V> N5 ft i3. CD CO 00 t-- 2 4- c o <D v 1 1 *-- o s~ CD CM O CO E SL XX o <X\ 1 t. CQ OjQ CL CO S S r^tO o .1 M *--1 M + O43 CMO. O toco "cs Cl c* <xE CO o Ql to 0*0 1 > M Co +>a i2f>i* oCM u o 0)01 U CO s- s- 3- O VO, - 229 - DUP040011456 Table 23 - Mean values (S.E.) and summary o f fa c to ria l analysis o f variance fo r blood urea nitrogen (BUN - rag percent} fo r male and female monkeys in S ta tis tic a l: Grouping /t / *3* CM O O CO i-- Ol O O .CO O O Ol r^- OVrH- v| CM ' CM s--' n ** . O in IO to = 2= </ 4-* ^r-- O PN r- CO CO AO CTl CO <D CO M3 m * CM O <3flr* ; in r* <4- CM s--* CSIN-' CM---" LU CO <3 CO 0 *0 --* *44 CO J3S 40 O co NO r-w* **"!S '5T K CO O rr-Tw' co cn . coo CO 0 COr^ CM>^ CM** Cl *- *1--* r-O 00 tn in in Kf ,r- in 0 to co r-- >--* CM---' 43 _c <D E +-> (O p > jh- r-- (U 4-> C O EE 1-- p a X LU M3 .0 V) (rr <2 O1--1 P in CO to O to C3 M to CO *- 0 ICO SS to *? \0 sf-O O . > . fO .CL Q. X CD CO f-- CO r- 3" O P- f-- r*->--" r<"" >--* r->-- EE <3 t .CD t. ob t C O- O CM O CO ft CL O ,rx 0* .1 1 .1--1 *4 sCO 0 .a O- ro E CT5 E r-- CO O j M M M s. 0 r-- * ;5 JO ; 67 . 0. COl'OE E >*. O- C5 a: E co 0 o*1 .in* cn 0 1 *-- Co r* M Srt~ - 230 - CO oCM CO ./ ur- X' > DUP040011457 Table 24 -Mean values t (S.E.) and summary o f fa c to ria l analysis o f variance fo r to ta l serum b iliru b in (mg percent) fo r male and female monkeys in S ta tis tic a l Grouping o CcoO in ::ces0iu>i E COI Gu3inJ o ;8 X <2i io. o to p Oo O r-^ <np o .o co r-- coo o r-> co co.o oo in o v) CL ovco CM O oo *** <M CM-* oo CM O* oo LOa O' OO 'S--* CO CM *-- <1- CO CM O iO CM O SfO CM O St* O OO OO 0.0 0:0 CO CM cvl p oo I--CM CM O oo OO CM CV O oo O CVI l^r- oo rs cn ts- cvt oo r-- o co CM p CM O f-- O kOO . P0 0 .0 O o u <D MUl sz i<<Mud s. +(J0 ct> ;L .0) UCX1L n- o c o v> sr SJ- Q. uEO Pen Ol <3 40 <2 43 C3 H-a CJtf <Sl 40 CO CD 00 co sl* o CJ o 40r-4 *- 1-4 to GJ t- :i3n g.5 . 1--4 *-- 3<tu co 40 JO. O -SM- 3 oo M n3. o C5D- 0L3 O XI O4C0M Q_ ros E5 Cl :cen O' r- u? 3> o tI i- ;9 +CSJSO. Sfi _><E*. a. cn ;: a r<o3 po cn o i o<r CM > JZ o u Q. V> <0 O 5Q.) 34O- LO 231 - DUP040011458 Table 25 - Mean values serum protein (S.E.) (grains panerdcseuntm)m faroyr of fa male ctor and i a l analysis o f female monkeys variance fo r to ta l in S ta tis tic a l Grouping C. 13* o ctoo V> QWJ 00 i Qu ax<v0uj 1 G3 L a* CO 03 in f"s. r".r-- ri o <nto C\l-- Q 0Or* >r^ Jo <3* CO r r* o I-- AO to O r*^ o o CO O i>- o to o> :in no *r.o p-- to tocsi oo C*4 -- to. p* r>*.csi oc vi co o r^o r** o coo v| - .> L<+u0<4U*U*-* GP 4e(fP-OU> i* to o r> r-* O o<vi CO * rv o ^r<h * svjsr O r-- co o o <*i r>- csi (*3 r-- if} i-* r?s O p CO ir> p-^ fs o CSJ so c.O o 1*^0 .CJ <* Sa*Xaxu. o c o VI *ri jrt S-*I O cf Q .0 to CO H CO ;z: 5 CtoO ;t/5 M 1/3 CO 2: V) j aox> lO ,z:* 1C--O4 to CO C3 2CM r-i CO CO <D t- P (A o a. to .* v> to rX 25 35 p u cu CSO- csa~ -oosp- <o<oVfl ;sCCLL CJoOL. COB "oS> oKo> yto--rs C+COvCJ0oC.Os3Ls. OCL.O=J C0O3 in at o 1VI 1 1 i a3 O CVO. c* P *o <uc3ou. -Q a. pOJ co u -.UPPnJ CO 232 - DUP040011459 u . .. ff Table 26 - Mean values (S.E.) and summary o f fa c to ria l analysis o f variance fo r serum albumin (grans percent) fo r male and female monkeys in S ta tis tic a l Grouping C. s rmv too oco m iai>> too ; ; ** UO> <MQ ; => CMO CM.O Vi CL \smo tA S! top- com mm toto rr-- cop mo r>o ; ? o ; @ o Np <N o -- to o CO O co m mp CM O ovsr o CM O to co mo CM <UU H- ;4-> . 4(5CU4 0JJ im co m mo CM.O i ts (MO O to o CM O CM CO co o COO -t0z1 ia-j a. uxt 1? co 3s- cx-V> 0 to ^ in m f--co m~ CM fr- sf o mo 01 <SX CM CM O CM O CM O I (U li wte?* to* *m jKopo m CD --* CO to z: opo CD cD Sto-* CO co hr o 0 -4 ico 0J 3s. :/> 0 CO X ' X01 01 CD m ir-- .Pu ,4- .sr o 1 a CsD.i CM . CO S a. L r>< a i Sca rr* o -Q CL. CO E a e r-- u*i 1 M -* M 1--* M sCQ o -ip CMOO toco S CL C5> Q- co o cjvm CO O t >* sz p -r44 rt3 T* s T. " o 0) o i3 XX OCM a. to - 233 - DUP040011460 Table 27 - Mean values sodium {Na - m(ES.q/E-T)Itear)ndf osrummmaalrey o f factorial analysis and female monkeys in Of variance S ta tis tic a l for total Grouping C. O ;tcoo ip .tfl r-L 0J P v03* 1* [r : coo p CO . . to o ^-w r?* LO to . co o jr-* pv*? ,* i-v o .-* CO CO M>0 ! to o *J*N?-* 1" o oo 03 O f*1* ,ON CO O s--* r- CM KQ &<=> !> CT> ^ ! 0*0 r* oo l o co in * r-- r^- O sf ^ s/ tn v| a. ."s> V 4^ a Q} *- 4txl 44 cr s 4- j 01 S- H- c? co o , o fr* O VO CMP to o m o -c- >-- .^rw it5 4J C CO o *" ).*) r^--.o <ors-< " ^ - p cr to/% ift-} eu<s fit * * v>_ CD in ss .tn ,2t DO CD tn in H-4 v> sg .=5 O in sc in.* 2: in 2: r? flj :k3. Ot/i CD CD CD XCL t--o w VI t/*> <tu l&T p^" 0 s. L> e O u I1 >--< l! tIow Jo3 CM CL O tn cn a. P> CL H O r-> 10< 0 CP 8 .*-- .M --4 cUa O4- O CM Q* 0:. cnco s S ti. a> CL ,S ro 0 Pi u> 01 0 1 2* ,Nt tof<<S3OuLj!l v - 234 - cp oCM XC5L OtO fXJ sG-J wpaessssas > 1 DUP04G0114ei / 1 Table 28 - Mean values ($ . .) and summary o f fa c to ria l analysis o f variance fo r to ta l serumt potassium'(K^mEq/liter) fo r male and female monkeys in S ta tis tic a l Grouping G. in to d to co >-- co oi o vjo Lf) r-- no CO Csl CO o <no coo no coo CL M c& so 0CMOr- no- ors. to in 00 r-* O CM 4OO* o ^ ; A <o.o 'M*o V) 0a3s CO i Qi .3 Ml O CL X <0 1 03 u a. sf to csi CO o co o -st* <i<t o so co 03 r-- co O oun SO O CO 0 o <0 CM * * CO o tO CO CM CM CM CVJH- O co o =P ci in ?5t* NN CO O CM ef O CM sr o V ca 0 r*- CM too 0* CM coo o P o na 4c0-1> r* 50>- CL X 4o c o U) srt?. Q. O O 40,CL3< 40 z: CsoO 2toE* to 2: <0 (/> <* 40 CO M to 0>3 01 34. t/1 > 9CL < o ^01 2 I oi 'Jfc. O. o 1--4 40 tro p e O0 i .tSo- sCQ r*;* O -Q CL Oto CO CL CL O * . to P> O 1i >-* t-4 *--4 *--4 .-?4 SQQ r-** 4- t_> XI ; B; L o toco CL O* CL co o O*i. 'LO Cl o .1 3* J-* c o f* p fO jl: co s r 4o -aa. otoM Prorj a5. <u o s 3 o to - 235 * i DUP040011462 Table 29 - Mean values (S.E.) and summary o f fa c to ria l analysis o f variance fo r to ta l serum chlorides (Cl - mEq/Titer) fo r mate and female monkeys in S ta tis tic a l Grouping C. o CO so 4i*n 03 :,soi>c i com -?o.^r ro<r q*L*N CcJ rr g o ; o n o too v| ; D co vo to to CO *3* CO o o r> o r-- o o o .O-P--- *3* o 0*3* o* vo o vo CoO>r^- <ro O'--" o>o*> Oo>VO> owapi 44 C 44 0rt1S fr-- r^s vp ow> ; E s** in xt* go *-o on O VoO o^ aaH> r* s- .01 CL X oc 03 U v 0 O. X0i01-31 Or--.* n* to. oM* n.cvi*.-* CMx-r oa o CM o a. uo o. O mC--D PtCo^D-* CD VO <n Min in n <0u) ;Pto -* CPD4 in CD P-4 cn ** CD Pin-4 CD -P-4 V) to 2: o<o di c3- X<tQvOLinu.. CD </> tMCoD <s .1--4 in a. io44 O O a3w { M O S-. CD CM O </> .H aCl. . O a% 1 *--* *-* "SCQ 0 -Q D_ CO e 0 S to 0 t *H--4f 1-4 SCO +0 CM4C3L Ococo es OtZ. t:S ro 0 o.. *n o> 0 1 ? --> pe tp- O 0o> 43 OCM u n* CL V) 4C04>- C t- 3 too - 236 - J? DUP040011463 o m eS . 3sttot-l Q. os- CO *0>1U0 4-rr- s- 4O-4-rJp.sJ+2ywc-> 53 oc to S 03 Vp CM VO VO Cf* J fs. o UIO co o VO o CM* Mn ^ v| tx tCoO ^f.N CvoM'o*-'* OtCo' M NoS-* vo to VCOS*>o-- 00 fo*9. u Of IP V> CD M CA 55 in is fed to <D CO Ko > M CO h* M* a* r*. in d. >r* COO CM*-- tCoM*o--* .CM*-> f*VO CMw Its 5i.3 F GHro co ; -m* ^ ; to. to* *i*0 cp o too CM O CM>-- CM*-- CM*--- .CM*--- c 53 r U .& M? CD to w 53 53 H- 5* CD to CD *--* in z v> u53 u<y -M E`- '3 -M-itft *** cr lu c fd t CM iUO Po V3*T* +IT3 I-** v> X .go f--T3 id >c o CJQ XSU 5J 13 s: o i o CO .a nj to H to 53 r- * c;S tT544_ r * O s 0.S Sr <4- o O **- O *c o 53 .t/i S- *r- 3 V. */% Q ,o3.a o co =f r* vo CM jr-ia- 3 ou a. X 53 sfr- r*..o toe CO rCSlN--* CM*--- CM*-- CM*-- o p I 153* a. CO p u ts Vt O </> <D to .ex ' * --< xz 53 CO JS I 53 U cu r-- O &- c o o 1 to, Qj 3M O C. CD CM o to a. sx o r* - P i -- &. CO o Or Q. CO 03 r-m. to * o 1 M `*Ht JCO . * +o -Q CMfX O toco _ : **. CL C? o. S CO o erv to CR O 1 3* ** C P T* <3 c C. o CM u - -JO o ITS P a. v> u a 53 +> Oc i. o tOo 237 i1 ~ DUF040011464 Table 31 - Mean values + (S.E.) and summary o f fa c to ria l analysis o f variance fo r to ta l serum calcium (Ca - mg percent) fo r male and female monkeys in S ta tis tic a l Grouping C. o CtoO tU 03 t&UI GO1 01 3sv0> 03 0$1 U a. COCM fsOl CM tO i** to COri o% o <0 r-T- t*> ;r*H oi o o> o o o o> o .40 O V| CL uto> too OVr-- O' rr -*f 40 .I** rr 04 O .04 Q O' o 04 ,0 to CO r-.O .. , po CO j to... a 04 0 to CM CO CM 04 C. CO t>* CM OVQ Vi 001 ,LU <cu B 04 u 40^n r* cno MO Hr Hr a* o CSi? .Ol'rrro h - CO r-- cn O CO o s p c 0J rsr* 3. 0 Cu >< Ui ors N CM CM 04 O H-- CM CO m r" .* ov O Srn^ r**. co i-- q> o CO O H- * .* 04 0 C o v |r U Its Q. E O u Q 40 to to .si ..sr CO to <o to ftp . r(OH to JkC zr 0 CO CJ HI to <y 3: t 0) sr to O Hrt to to 2; CO 1 01 %. o ta 0 CL X oF** toa 01 o 1I HI H- --* M CO -t- o cvi-oO, otoco C.eL>E0*4. CL S= co o 04 io cry o 1 3 n* ou osc. to - 238 - CM -Q O Cu CO ra 3- at- +-> i) DUP040011465 I \ Table 32 - Mean values * (S.E.) and summary o f fa c to ria l analysis o f variance fo r to ta l serum glutamic oxaloacetic transaminase (SGOT - K units) fo r male and female monkeys in S ta tis tic a l , Grouping C. O -* CO y> VO Ui r"1* 03 03 3S 1 $te r* h- CO 1 41 s* 3 V> O O. X --* ---s l o -- CO CO .* rs- r~" O CM. CO PS c .cos-- --!*fc COLO COd* CO O CM r-w to O V| a. S-- ui *p 0 r 4- 4LU 4-3 C CM CO O <3 CM*---- p--^ p^t* in co ro -- co K pC 0 *-- LOCS1 CO LO H* to co co CO CM CO co*--- L> CM r^CM CO*!--' CO p% * . CO cO ^s-- ... CD co CO CVJn -' co CO *0 CO*.--' CM r- P CM Ovy tM Q tn csi CMS-- s 10 Of > H* 40 <4 G cu E U. OJ CL UXi 4O G O to *h fc. fO CL D 0 0 ^ CX3 r i."< co CO O *-< :zr </> 03CO S3 1C - *-. SC 2S CO tn 0J3X to CO as 2: :$sI o to =? J-3 C0Xtom .. co to ; 41 1. u CO r* O XI CM CL u pa + %-> JP CMiQ. O CO co Otoco Es t-T" E Q. G> .Ss 0. 01 8 CL E 3. S Q CO 0 *G O O IS cn LO O 0% LO o> 0 t i .* MM : HI M HI ft? <t3 co o <oD JQ Q- oCJ o to iO-f {. ros co - 239 - asA1 \ \ 15 i DUP040011466 /- Table 33 - Mean values ($ . ,) and summary o f fa c to ria l analysis o f variance fo r to ta l serum glutamic pyruvic transaminase (SGPT - RF Units) fo r male and female monkeys in S ta tis tic a l Grouping G. o J*C \ tn ; IJ xn* CM*-' CM* CM P sttn.* r-- CM . <o s> O CO co to fxr-- o CM CM>--' CO<^ CM*--* Ov 4aa3i H+UJ 4-> G gj E +j 0J ;! H- r~ <0 M c0E>r fi* 1. caa* X JUI CO. tn ; K ,, S, CM CM r-> cn NV co in CO CM <** into CO i-- iy)'V' c: o </) *r-- fc. ns Q. <s w p an* t/> i/i 5S mS z; CO v? a* CO CO p *-* sc cn cn p l/Y Oi ai SB t . v> tn - co tn VI 01 &. ss v> o CO a. X 01 5 .z: 1 0 L a. o s- 4* e o o owa3 1 --1 tsa- CM O l/> o_ CL O iX cn ;i M ^4 iCO o -Q Gu co_ s-,, cn E rr* m p i 1--4 t-4 u CO +o -O' CMQ_ o. /r<n c l cn CL c= co o o>tn > op 1 5s *r* oc fr -{ns3> L**3 c; o 4o~ <ouZ1S1: -O^ OCM o Qi. CO 4aCJ>*- O V5 - 240 ! DUP040011467 i u &% w 2 ,U T-. U Si (/) ++J0>J- .4rn-~>3 . *> 1;^ H j- 4J H ** flj r hJ ^ca **- fll O r~ iO *mr- m ?w* <+*f-l*i* -ca "nSs '* n>$ ^flj ,sr". '6S5 P Qsa *: n$ Hw -M O **r .SC ft = fS CO g Ocz :3 3 * i "?3 fr0ttxO: LU (U *w s0.3-* IetS H-.i -cVn 1o ians xs. 52 i5 (U > XI .= 73 Q> V s: <0 ^CiO* J<3ss Is- *sr o N* <*> r> co o ^ t co in O ian%-*<-3*% cj in U)w CMCsi 00.r- Vt p. oo M; sz CO cCOo in Ad CQUJ .25 i coco ; L /-- co av ; M *** r>- m cn co o ; N ^ Ifl .f" ---------' CO rr* CO NO to co ; R ro ; S r> co CM r- cvi.r>. O co tn->> 00 co *-- p-~ r--f* ,r> N> co co :is. .m ; M ^t sa toco a* co n n rs**--* h>.w r-**--' cow o as *C* i 4- 10 01 > fr ns p c OS <aUD. x <n <3 t--* . 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CO C0M.^0 0% -St St *-* o Oin cMo M1 N* \.0 CM ; x> \IN CM . o* ; OP co ~ IT) CM =r * in 2C d (/) a cr r-l .> o V- - 244 - v? 3 0 D C <11 01 0 ai 4* ,< .JZ 01 Sa> 3: Vi Q. 3 O U a* a> V) a) JC O VI (V o c: *0 re ,> :&> jk> j O i flS r-- CQ > ,|j r-- ,t- 4 3 3, J" O P - I v<*- J O' r <*V y o . to .> zco +> ;S VI > . S^ >*0 4- CT> r- c* Q E ta_o ,CSa`0'Pi* *a " to 9 .UJ .C C31*r~ 0 o S- -O CX 1 -*-> E -II* "O O U C" U *ri t- -- 4- ^ f- 0 Q. Vi*rs :3 to * o> o S C3> c t(j j O .CL * M 3 ^ i. fll Jc: o CMCQ r* Cr> 5-- o *"" P>-r* P CO O J*= t ,,*o Eo- vi (oa c: u tiro 4- w t - e O C44 0\ s.. v rs o> >v .. *r~ S i- -H to <o <t# o E,^ -m i m E > to 3113 m o WN-' L -* O+ TJ +J'S CL C^C; 3 CM io ovin o o OJ 03 0**- > S- tO oCO'"3">O\^cQS:r. *Or* HoQ.. w o; - co +1 JO W Hf0lJ3- 4CO->OCTJj *l (A R3 E O 03 .C .03 I 3*f* I rm-- iE. k mm> > 03 6 rOtj +3 S ms 3OQ. 3OQ. s0JivQ ^tsS- o$. CO CO -O flj lO GX iest OO CO sl i-- o OP OO co ^r in o a Po to CM CM O o OO S>' cvco in ^ oo ' Sm* OO CM CM O OO OO **^s CMCft ^sO PP O 4 CO ^p vv J . sfr-p- > to a; \U o o 3c.; *C r-- OJ cp sH '' * list' CO M cn tf co o oo pm in o op rs o C\l p> co CO M- COrKt& do p CM to OO (/) C3 </> . ! * *-* Z Z Z .to Z .2? * .* * to to to p to Z 2t ^ b? .Z to to 3 to to - * '*--* < sc *o z .2: ' ! * j* .. <0 tp CO tO tO Z Z ,'z z 2: r* 4-> <3 i. a> &0 PS r* r* . CM O > *r* ; co ^r J *i 4J i o r* 4-> to +J S_ <CJ 03 ; | ac: 3:1 co o oo fs. 00 o in rs csi r- CD PS .00 CO ^P M CO CO o op ; ^ in rr^ i-- rs* CM p Ps rj- O CM O CO Z O PS ms-* ]; is CO*** in vl io CL ps in no oo COM3 CO O op CM PS P CM co r-* .i-- CM {/I 03 O C fi 03 H- tow p M to p .* z to z to tr -- to to to j to p p * ' - >M M Z Z Z .W) .00 to to to to to ,Z z z z 2? to to to to to Z Z 2 '2 z o o co CM IP IP CM VO Li * *+~> r> o to IS..I-!- Ps o C to to to to to to L- o o O O CT s^* 0.0 O u M z: z z z z z Z 4- 3 ,, 4-> to *>P * r- CM m r-- * CO f~ rs ; _ ** O CM M cn rs :c * to CQ O *r* * a to to to p .to CMs-^ C\3>-- r* S-* to z z z to .z o W*" -^P r-- O OP . oo CO Rj* r-!- o o * P N,*\- t*-W O oo -. * oo . ^-tsr r-^O OO OO . to to ,lO to to to z z z 'Z z z com -o* o > fff o o v~-' O CQ Ip - .- 0.0 o* P Ol r--" .Ps O CQ CO r-f O i-**- s--<*. fO >v i- m r-- p CQ ^ * cn co O CM in'--" IQ'*--' O 1-^ CO r-- ' po .. to CM s- CO CM p S->' cn co CO IQ m -w in CO r-- .* # OP Sr> 09-rf-r r-- >** rs o in*--> * to to to to >--* p M .to .SC z Z to p z -a > . to to to to to to Z z z z z .z a a .a to to to to to p .z: z z z z z 4-> - JZi 3! ut6: 3aH' .03 >i1 H- T3] t! --> tn to Ps o O CM CO W .____ m CM CM co U3 COS' O CM in *ars oo CMS :l o rs rs co O CM ro>--* a . , a a a to to to to to P z -Z Z Zz VJ p. CT O in > to to >> \A v> > .> v > i- p 245 The variances o f these groups were heterogeneous* / / X DUP040Q11472 - table 39 - Histopathology incidence table for -Statistical Grouping g, comprised of the following: Group I *- Control, Group II i 9,70 ppm" SOg* Group III - 0,51 mg/in3 PbClBr, and Group IV - 9.93 ppm SO? + 0.50 mg/m3 PbClBr. r' " 4 ' LUNG Focal Pleural Thickening Peribronchial Brown Pigment Artifactual Emphysema Alveolar Duct Fibrosis Thickening Bronchiolar Wall Bronchiolar Epithelial Hyperplasia Bronchiolar Epithelial Hypertrophy Pneumonocyte Hyperplasia Peribronchial Lymphoid Hyperplasia Emphysema Focal Necrosis Focal Hemorrhage Parasite Perivascular Edema Pulmonary Edema Bronchiolitis Bronchitis Monkey Pox Vascul i ti s Granuloma Pneumonitis Abscess Lung Mite Infestation Adenomatosis Bronchiectasis Purulent Pneumonia Epithelial Necrosis Thickened Alveolar Wall Pleuritis Crystal1in Material (yellow} Mucous Focal Fibrosis Pleural Fibrosis Alveolar Wall Fibrosis Vacuolated Media Endothelial Hyperplasia Stenotic Chronic Pneumonia Eroded Bronchi Emphysematous Bulla GROUPS I ,11 ill 2/9 2/9 2/9 1/9 5/9 3/9 4/9 5/9 9/9 3/9 0/9 2/9 D/9 0/9 0/9 0/9 f 1/9 0/9 1/9 0/9 2/9 1/9 V9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 1/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 1/9 0/9 1/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 Q/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 n/o 1/9 0/9 2/9 ri/Q 0/9 0/9 0/9 n/o 0/9 0/9 0/9 0/9 0/9 0/9 0/5 0/9 0/9 0/9 0/9 0/9 0/9 0/9 Q/9 Vn//QJ 219 0/: 0/9 0/9 0/9 0/9 0/9 IV 1/9 2/9 0/9 2/9 0/9 0/9 0/9 2/9 2/9 1/9 0/9 0/9 0/9 ,0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0 /Q Q/9 n/o 2/9 0/9 0/9 0/9 0/9 0/9 0/9 246 - DUP040011473 Table 39 - Continued LUNG - Continued Atelectasis Congested Extravasated Blood Collapsed Alveolar Wall LIVER Pericholangitis Bile Duct Proliferation Focal Necrosis Sinusoidal Pigment Focal Hepatitis Focal Lymphoid Infiltration .Nematodiasis Thick Capsule Granuloma Abscess Hepatocyte Vacuolation Greenish Granular Material in the flepatpcytes GROUPS II lit 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 1/9 3/9 0/9 1/9 2/9 7/9 0/9 0/9 1/9 2/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 3/9 3/9 0/9 2/9 0/9 1/9 0/9 0/9 0/9 0/9 1/9 1/9 PERIBRONCHIAL LYMPH NODE Phagocytized Pigment 6/9 5/9 - Lymphoid Activity 8/9 6/9 Lymphoid Atrophy 0/9 0/9 Adenitis 0/9 0/9 Granuloma 1/9 2/9 Reticuloendothelial Cell Hyperplasia 1/9 0/9 Lymphadenitis 0/9 0/9 7/9 0/9 0/9 0/9 0/9 0/9 0/9 TRACHEA Tracheitis Increase in Goblet Cells Exudate in Lumen Necrosis of the Epithelium Inclusion Bodies Epithelial Hyperplasia Cilia Atrophy Squamous Metaplasia Focal Hemorrhage 1/9 0/9 0/9 0/9 A/9 0/9 0/9 1/9 0/9 0/9 1/9 0/9 0/9 0/9 0/3 1/9 . 1/9 S/9 D/9 0/9 . 0/9 0/9 0/9 0/9 0/9 0/9 0/9 - 247 - IV d/9 0/9 0/9 0/9 4/9 3/9 0/9 0/9 0/9 o/e 0/9 0/9 0/9 0/9 1/9 0/9 7/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 D/9 0/9 0/9 0/9 0/9 < 1 I : i = i' | i \ ij '' -------- : .. : ; ; * i j | : f' f ?. ) I f DUP040011474 Table 39 - Continued KIDNEY Interstitial Nephritis Epithelial Vacuolation Tubular Dilatation Loss of the Brush Border Nuclear V.esieolation Tubular Hypertrophy Pyelitis Focal Mineralization Glomerular Degeneration Inclusion Bodies Vasculitis Congestion Focal Fibrosis Perirenal Abscess Protein Inhibition Intima Thickening Endothelial Hyperplasia GROUPS I II III 0/9 2/9 2/9 1/9 3/9 3/9 3/9 2/9 0/9 0/9 2/9 3/9 0/9 0/9 j 0/9 0/9 0/9 0/9 C/9 1/9 0/9 0/9 0/9 1/9 0/9 2/9 0/9 0/9 0.9 7/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 HEART Focal Myocarditis Endocarditis Epicarditis Myocardial Degeneration Vasculitis Subendocardial Hemorrhage Thickened Endocardium Foral Hyperplasia in the Endothelium Intima Thickening Granular Pigment 3/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 2/9 0/9 1/9 0/9 0/9 1/9 0/9 0/9 D/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 IV 0/9 8/9 1/9 3/9 7/9 1/9 0/9 0/9 0/9 8/9 d/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 J - 248 * DUP040011475 HAZLETON LABORATORIES, INC. VI, STATISTICAL GROUPING 0 - RESULTS OF THE CHRONIC EXPOSURE OF CYNOMOLGUS MONKEYS TO 65.46 PPM CARBON MONOXIDE (CO), 0.51 MG/M3 LEAD CHLOROBROMIDE (PbCIBr) AND 66.43 PPM CO COMBINED WITH 0,47 MG/M3 PbCIBr, Four groups of animals comprise the fourth' statistical grouping-D. One group was maintained as the control group exposed to filtered room air, while the other three groups were exposed to carbon monoxide and lead chloro- bromide singly and in binary combination. Group designations used throughout this section are presented in Table 13. Table 13 - Group p designations Group Designation (No.) Nominal Agent . Concentration I (1) Control 0 II (7) in (9) CO PbCIBr 67-50 ppm 0.60 mg/m3 IV (20) CO 67.-50 ppra PbCIBr 0.60 mg/m3 Mean Analytical Concentration 0 65.46 ppm 0.51 mg/m3 66.43 ppm 0.47 mg/m3 1, Exposure Concentrations The chamber concentrations as determined analytically are presented in Tables I, 2, and 3, Appendix D; for Groups II, III, and IV, respectively. The mean and standard deviation for the group exposed tD CO alone was 7, 65.46 ppm 3,33; for the group exposed to PbCIBr alone 0.51 mg/iti * 0,27; and for the group exposed to the combination of CO and PbCIBr, the means and standard deviations were 66.43 ppm 2.28 and 0.47 mg/m * 0.21, respectively - 249 - 1 DUP040011476 HAZLETON LABORATORIES. JNC, BtT<TnwiBiBwmsni*ni !- / i. i 2. Particle Size Determination The. mean and geometric deviation of all count particle size determi nations for PbClBr converted to mass median diameter (MMD) were Q,550u a 1.57 and 1,050m i 1.79 for Groups III and IV, respectively. A composite size /s. distribution log-probability plot from the pooled count data is presented in Figures 66 and 67 for Groups III and IV, respectively, 3. Biological Measurements 3.1,, Body.Weight Analysis of variance of regression for body weight (Table 4, Appendix D) indicated no significant differences in slopes among the groups. The regression curves (Figure 68} indicated a trend toward increasing body weight values in all groups and growth rate was similar in all groups except Group II which started slightly heavier and ended slightly lighter dye to the deaths of two male members of the group. 3,2, Survival No deaths occurred in Groups I, III or IV durij.; the 104 weeks of exposure. Two deaths occurred in Group II during Weeks 42 and.78 of the exposure period. Daily observation of the animals revealed no clinical signs of toxicity or abnormal behavior attributable to the exposure atmospheres. - 250 - DUP040011477 / w t f .* ii }! t' :' iI : i *ti; Count Diameter microns (jo-)- Figure 66 - Particle size distributions (count diameter) of PbClBr ] - 251 - DUP040011478 Couht Diameter - microns (ju ) Figure 67 - Particle size distributions (count diameter) of PbCIBr for the group exposed to the combination of PbCIBr and C.C. - 252 DUP040011479 SODY WEIGHT tk j.) "6 y^ t Figure 68 - First degree polynomial regression curves for body weight prior to and during exposure to carbon monoxide and lead chiorobromi.de singly ana in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups.. 1253 DUP040011480 HAZLETON LABORATORIES, INC. 'VJ' 3.3, Pulmonary Function Tests 3.3.1. Mechanical Properties of the Lung and Respiratory System 3.3.1.1. Total Respiratory System Flow Resistance During Inspiration [Rrs(i)] Analysis of variance of regression for Rrs(i) (Table 5, Appendix D) revealed non-parallelism among the groups. The third degree polynomial regression curves (Figure 69} indicated that Rrs(i) values for Group I decreased slightly at the beginning of the exposure whereas values for Groups III and IV similarly increased slightly. Separate t-tests of the pre-exposure adjusted means for the first nine weeks indicated that Group I was significantly lower than Group III and Group IV during this early interval (t = 4.33, -d.f. = 16 and t - 4.66, d.f. - 16, respectively). 3.3.1.2. Total Respiratory System Flow Resistance During Expiration [R.rs(e)] Analysis of variance pf regression for Rrs(e) (Table 6, Appendix D) indicate;; non-nvrallelism among the groups. Third degree polynomial regression curves (rigure "J) indicated that Group II started into the experiment with lower Rrs(e) values ttari the other groups, and did not exhibit as much of a decrease as the other groups. A t-test of pre-exposure adjusted overall exposure means comparing Groups I and II indicated that Group II was relatively significantly higher throughout the exposure period (t - 5.03, d.f. - 14.3), A similar test comparing Groups I and IV Indicated that Group IV was relatively higher also (t f 3.72, d.f. - To), -Group III was not significantly different from Group I by this test (t - 1.92, d.f. = 16). - 254 - DUP040011481 JS. -f 1 / / TOTAL < (rtfc *;c *y SYSTEM FLOW '*$iSTANC - INSPlUTJON ^ i ^ - c m . H j O / A i ^ l Figure 69 - Third degree polynomial regression curves for Rrs(i) . prior to and during exposure to carbon monoxide and lead cfilorofcromide singly and in' binary combination. Each point represents tbs mean for the animals tested at the indicated time for the various groups. - 255 - DUP040011482 /j \ I w/ .5* V ISfAt lUPtHATOKYSVSItMftOWitsisrwice- tXflUTION // s? Figure 70 - Third degree polynomial regression curves for Rrs(e) prior to and during exposure to carbon monoxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the Various groups, - 256 - l b- DUP040011483 1 HAZLETON LABORATORIES. INC. 3.3.1.3. Tidal Volume (V^) Analysis of variance of regression for (Table 7, Appendix D) revealed no significant differences in slopes among the groups. increased with time in all groups, as shown in Figure 71. 3.3.1.4. Respiratory Rate (RR) Analysis of variance of regression for RR (Table 8, Appendix D) indicated slight non-parallelism among the groups. The third degree polynomial regression..curves (Figure 72) indicated that Groups II, HI, and IV exhibited essentially no change during the exposure period, while Group I demonstrated slightly decreasing values due to an abrupt increase after "exposure" started. 3.3.1.5. Dynamic Compliance of the Lung [Cdyn(l)3 Analysis of variance of regression for Cdyn(l) (Table 9, Appendix D) revealed no significant differences in slopes among the groups.. The third degree polynomial regression curves (Figure 73) indicated that all groups increased in Cdyn(i) during the experiment, with Group I showing a sharp increase after "exposure" began. Although the pre-exposure adjusted means of the first year were significantly different between Groups I and III (t = 2.69, d.f, - 16), the fact that Group I showed a large Increase at the start of exposure renders any interpretation difficult. -- " /, --- . 3.3.1.6. Pulmonary .Flow Resistance (Rl) Analysis of variance of regression for R1 (Table 10, Appendix D) indicated non-parallelism among the groups. The third degree polynomial regression curves (Figure 74) indicated that Group I did not decrease as much as the other groups during the exposure period. During the first nine weeks - 257 - ' DUP040011484-- i V-s^ TIDAL VOLUME ( V j ^ m \.) Figure 71 - Third degree polynomial regression curves for Vj prior to and during exposure to carbon monoxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 258 - DUP040011485 ! i5 '\.,y I RESPIRATORY RATE < RR. tiM lh t / min } TIME - WEEKS Figure 72 - Third degree polynomial regression curves for RR prior to and during exposure to carbon monoxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. { | ] | | - 259 - DUP040011486 OYNAWC COMPLIANCE OF THE LUNG [c5fn (I) * mi/era. H20 ] Figure 73 Third degree polynomial regression curves for Cdyn(I) prior to and during exposure to carbon monoxide and lead chlorobrotni.de singly and in binary combination.. Each point represents the mean for the animals tested at the indicated time for the various groups. ` - 260 - DUP040011487 PU.M O NAHY F lO tt RESISTANCE (Rl ; m . fHi/ 'mV tUl- Figure 74 - Third degree polynomial regression curves for Rl prior to and during exposure tc carbon monoxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 761 - ' j i | I DUP040011488 rMZlirrptf LABORATORIES, iNC. sr of exposure. Group IV was significantly higher than Group I (t = 4.66, d.f. = 16) as; was Group III (t - ?..66, d.f. = 16), Separate t-tests of the pre-exposure adjusted means of the overall exposure period and of the first 52 weeks exposure between Groups I and 11 were not significant (t < 1.64, d.f. " 16 and t = 2.05, d.f. = 16, respectively). 3.3.1.7. Work of Breathing During Inspiration per ml Tidal Volume [W(i)/ml Vy] Analysis of variance of regression for W(i)/mi Vy (Table 11, Appendix D) revealed no significant differences in slopes among the groups. The third degree polynomial regression curves (Figure 75}.. indicated that Groups III and IV were lower Than Group I throughout the exposure period, 3.3.1.8, Work of Breathing During Expiration per ml Tidal Volume [W(e)/ml Vy] Analysis of variance of regression for W(e)/ml Vy (Table 1.2, Appendix D) indicated no significant differences in slopes among the groups. The third degree polynomial regression curves (figure 76) indicated very little change in W(e)/ml Vy values throughput the exposure. 3.3.2. Diffusing Capacity of the Lung for Carbon Monoxide (DLq q ) Analysis of variance of linear regression for DL^ (Table 13, Appendix D) indicated that there were no significant differences In slopes between the groups. The third degree polynomial regression curves (Figure 77) indicated that all groups increased in BLC0 values with time. v 262 * DUP040011489 A I l / / / WORKOFBREWHINODUllNOilNIHRATIONKR lmTlbW. VOI.UMI [w[i)/*l V,-*.(./ml V,] Figure 75 - Third degree polynomial regression curves.for W(i)/rol Vj prior to and during, exposure to carbon monoxide and lead chlorobramide singly and in binary combination. Each point represents the mean for the animals tested at the . indicated time for the various groups. - 253 DUP040011490 sVKQt:OP SMATHiNG DURING EXPIATION P*l.. TIDAL VOLUME Qv(t)/m1 V j j r / j uv^ IV ^ * ! I i .?! I- 1 i j \ Figure 76 - Third degree polynomial regression cuives for W(e)/ml Vt , prior to and during exposure to carbon monoxide and lead chlorobromide singly and binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 264 - 1/ i i DUP040011491 earn DIFFUSING CAPACITY OF D lU N 6 fO * C.AHSON MONOXIDE { W i.,,- Ml/WnAmi. H ji STFO)I ` :i il ' Figure 77 ' - Third degree polynomial regression curves for DLgn prior to and during exposure to carbon monoxide and leas chlo.ro- bromide singly and in binary combination. Each point represents the mean for the animals tested at .the indicated time for the various groups., - I .* j; |r 1. :l 3. - 265 =i J DUP040011492 HAZLETON LA 80ftA TORIES* iNC. i. 3.3.3.. Distribution of Inspired Air. Nitrogen Washout. I 3.3.3.1. Number of Breaths from 80% co. 1% Nitrogen [N(l% Ng)] Analysis of variance of regression for N(l% Ng) (Table 14, Appendix D) inciicated.non-parallelism among the groups.. The third decree,polynomial regression curves (Figure 78) indicated that values for Group I were somewhat higher during the pre-exposure control period than values for Group II, III, and IV. During . the entire exposure period, N(T% Ng) values for Groups III and IV were at a ' higher level than Group I values. A t-test of the pre-exposure adjusted overall exposure means of these two groups Indicated that Group III was significantly higher than Group I during the exposure period (t = 4.55, d.f, = 16). A similar t-test comparing Groups I and .7 showed a similar relationship (t -- 5.24, .d.f. - 16). A t-.test of the pre-exposure adjusted overall exposure means of Groups I and Ii showed them to be significantly different (t = 2.21, d.f. = 16). | i i \ 3.3.3.2. Respiratory Rate Measured During Pure Oxygen Breathing (RR') Analysis of variance of regression for RR1 (Table 15, Appendix D) indicated ,r.o.significant differences in slopes among the groups. Tfr third degree polynomial curves (Figure 19) indicated that Groups II, III, and TV were slightly higher than Group I after the 45th week. Separate t-tests of the pre-exposure adjusted overall exposure means comparing Group I to each of v the experimental groups. Indicated that the first two groups were relatively higher than Group I throughout exposure (t = 2.18, d.f. - )6; t - 2.61, d.f. = ]6, , and t ^ u . t.Oj TtiS p&cxi vt?! y; * - 25.6 - i DUP040011493 \ 7 [f< N % llN j N jp o a ilN * 1 01SMiysas 1 0 OT.VON TIME - WEEKS Figure 78 - Third degree polynomial regression curves for N(l% Ns) prior to and during exposure to carbon .monoxide and lead chir.-obromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 267 - DUP040011494 y JIT - Kt$Pia.V!OKV fcAU jjD utin?-tw i* 0*Y9** 7}W -WfEKS Figure 79 - Third degree polynomial regression curves for RR` prior toward during exposure to carbon monoxide and lead chlorobromida singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 268 - DUP040011495 3.3.3.3. Cumulative Tidal Volume from 80% to 135 Nitrogen [cVy(l% li,)] Analysis of variance of regression for CVj(l% N2) {Table TR, Appendix D) indicated non-parallelism among the groups. The third degree polynomial regression curves (Figure 80) indicated that Group III was slightly higher overall than Group I throughout exposure. A t-test of the pre-exposure adjusted overall exposure means comparing these twe groups indicated that Group III was significantly higher (t = 2.24, d.f, - 13.7} throughout the exposure period.. 3.3.3.4. Tidal Volume Measured During Oxygen Breathing (VT*) Analysis of variance of regression for Vj' (Table 17, Appendix D) revealed non-parallelism among the groups. The third degree polynomial regression curves (Figure 81) indicated that Group I had lower Yj' values than the other groups during the pre-exposure period .and. exhibited more of an increase during the exposure period. The lack of increase in Group II:, when compared tc Group I (t - 2.51, d.f. -.16), was probably due to the deaths of two males during the exposure period. 3.4. Hematology The group means and analysis of variances of the various hematological variables measured are presented in Tables 18, 19, 20, and 21, Appendix 0, No consistent trends were noted in any of these variables which remained witnin normal limits throughout. Random statistically significant differences were seen,, but were not consistently related to the exposure conditions. - 269 - DUP040011496 ,S ms jm-(V%s)Vo} NipcaiiNsi onvintOAtytmjiyuvinwro TJM *WJEtt Figure SO - Third degree polynomial regression curves for CVj(1% %) prior to and during exposure to carbon monoxide and lead chlprobrcmice singly and in binary combination. Each .point represents the mean for the animals tested at the Indicated time for the various groups. - 270 - DUP040011497 i- y \{ \ JICM. vCluWE'(<Oufl*s ) W 0 - ft* n fccoihlnj) VT` -m l IJM ^- v* / rtME 'WEEKS Figure 81 - Third degree polynomial regression curves for Vj' prior to and during exposure to carbon monoxide and lead ; chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups.. - 271 - DUP040011498 c HAZLETON LABORATORIES. INC. 3.5. Clinical Biochemistry The group means, standard errors, and the results of the analysis of variance of the various clinical biochemical variables measured are presented in Tables 22 athrough 35, Appendix D. Scattered statistically significant differences were noted; however, no trends were seen in any of the variables. Throughout the study, the group mean values fluctuated within the normal ranges of these variables. 3.6. Arterial Blood GaS ana pH The group means and standard errors for the blood gas variables are presented in Table .36, Appendix D. Examination of these data did not reveal any consistent trend with time.. No apparent exposure-related changes were seen in any of these variables. 3,7. Terminal Body Weight, Organ Weight, and Organ Weight as a Percentage of Body Weight The data of the terminal body weight, organ weight, and organ/body weight ratios are presented in Tables 37 and 38, Appendix D, for males and females;, respectively. Single classification analysis of variance revealed that the brain weight for the males in Group IV was significantly higher than for Group I males. The mean terminal body weight for the females in Group IT was higher than the terminal body weight for Group Til females. The kidney weight to'body weignt ratio was higher in Group III females than in Group II females and the heart weight for Group II females was significantly higher than Group 1 females. - 272 - DUP040011499 HAZLETON LABORATORIES, INC, S'- 3,8. Histopathology Summary A detailed listing of the microscopic alterations seen in the lungs, tracheas, livers., kidneys, peribronchial lymph nodes, and hearts from theanimals in the control and exposure groups are found in Table .29, Appendix D. Exposure-related microscopic alterations were seen in the ikidneys of the 3 animals exposed to 0.6 mg/m of PbCIBr. These microscopic alterations werv characterized by varying degrees of degeneration of the proximal convoluted tubules. The epithelial cells of the proximal convoluted tubules were slightly vacuolated in some animals and a slight to moderate degree of nuclear vesicularion was present in some animals. Acid fast intranuclear inclusion bodies were seen in seven of the nine animals exposed to 0.6 mg/m of PbCIBr alone and in five of the nine animals exposed to the combination of 67,5 ppm CO and 0.6 rr.g/rn^ of PbCIBr. Incidental lesions not related to the exposure conditions were seen in the lungs, peribronchial lymph nodes, tracheas, hearts, and livers from the aninriTs in both the control and exposed groups. Animal No, 157L in the group exposed to 67.5 ppm C0 died during the 42nd week of exposure. Microscopic examination of the tissues from this animal revealed lesions consistent with a diagnosis of monkey pox. Necrosis and hemorrhage were seen in the lungs end liver from this animal. Numerous inclusion .bodies;.were present in the epithelial cells of the trachea. / /> i - i?3 - it DUP040011500 - ............. --............... ............. ---------- -------------- ---------------- - HAZLETON LABORATORIES. INC. xy 3,9, Summary ' The inhalation exposure of male and female cynomolgus monkeys to 65.46 ppm CO, 0.51 mg/m3 PbClBr, and the combination of 66.43 ppm CO plus 0.47 mg/m3 PbClBr resulted in a deterioration in the distribution of ventilation t i y.| iI i I J ?j =* in the animals in the two groups containing PbClBr. The number of breaths to 1 % .nitrogen measured during pure oxygen breathing was significantly elevated in the animals in beth groups exposed to PbClBr. Cumulative tidal volume to 1% : nitrogen and respiratory rate measured during pure oxygen breathing were significantly elevated in the group exposed to 0.51 mg/m PbClBr.. These latter. differences were not seen in the group exposed to the combination of 66.43 ppm CO plus 0.47 mg/m^-PbClBr. .................... Statistical analyses comparing the control group to the group exposed to 6.5.46 ppm CO indicated a significant mean difference in the number of breaths to 1% nitrogen, respiratory rate, and tidal volume measured during pure oxygen breathing. However, these differences were attributed to alteration of the sex ratio and hence the animal size distribution due to the deaths (not compound-related) of two male members of the group exposed to 65.46 ppm CO. Microscopic alterations related to the exposure to PbClBr were found in tbs kidneys of the animals of these two lead groups. These hisiopathological changes were characterized by varying degrees of degeneration of the proximal convoluted tubules, ina ep'itheiia 1 cells of these tubules were vacuolated and possessed vesiculated nuclei, Numerous intranuclear acid fast inclusion bodies were seen in these epitheli a] cells. - 274 - DUP040011501 1HAZ .ETQN LABORATORIES, INC. Hematological, clinical biochemical, and arterial blood gas measurements made pre-exposure and periodically throughout the exposure period on the animals in the control and exposed groups did not reveal any meaningful differences. No trends were noted in any of these variables, and, in general, the exposed animals were comparable to the controls. Statistical analysis of the body weights measured periodically throughout the exposure period revealed that all animals in both the control and exposed groups increased in weight with time, although the group exposed to 65.46 ppm CO showed a slower mean growth rate which can be attributed to the deaths of two-of its male members. No meaningful differences from the controls in terminal body weights, organ weights, and organ/body weight ratios were found for the exposed animals. HAZLETON LABORATORIES Appendix D - Data compilations and summary of statistical analysis for Statistical Grouping 0, comprised of the following: Group I - Control, Group II - 65.46 ppm CO, Group III 0.51 mg/fflO PbCIBr, and Group .15/ - 66,43 ppm CO + 0,47 mg/m3 PbCIBr. - 276 - DUP040011503 r^nar-j.'B'rjewtt - %.jr table 1 - Monthly means and the grand mean for the' analytical concentrations of carbon monoxide in Group II,. S*i Date 4/ 7/58 - 4/31/68 5/. 1/68 - 5/31/68 6/ 1/68 - 6/30/6$ 7/ 1/58 - 7/31/68 8/ 1/68 - 8/31/68 9/ 1/68 * 9/30/68 10/ 1/68 - 10/31/68 IV 1/68 - 11/30/68 12/ 1/68 - 12/31/68 1/ 1/69 - 1/31/69 2/ 1/69 - 2/28/69 3/ 1/69 - 3/31/69 4/ 1/69 - 4/30/69 5/ 1/69 - 5/31/69 6/ 1/69 - 6/30/69 7/ 1/69 - 7/31/69 8/ 1/69 - 8/31/69 9/ 1/69 - 9/30/69 10/ 1/69 - 10/31/69 11/ 1/69 - 11/30/69 12/ 1/69 - 12/31/69 V 1/70 - 1/31/70 2/ 1/70 - 2/28/70 3/ 1/70 - .3/31 -'70 4/ 1/70 - 4/ 9/70 n, .24 31 30 31 31 30 31 30 .31 31 28 31 30 31 30 31 31 30 31 30 *31 m f- .Yvr 1!128 5 31 9 X ppm 52,7229 S.D. . 18.6179 64,9416 3.5378 66.0280 3.2531 65,6890 ; 3.3289 65.2639 2.3260 63.8380 5,09.75 63.9106 65.2470 3.2811 2.8780 66.2948 4.1976 65,3729 1,84.54 66,9978 2,1481 65.9987 2.4073 67.5077 2.3761 68.1716 2,2823 68.4580 1.9130 66.8609 1.2850 67,4068 1,3534 65,5323 - 1.9411 - 65.6203 1.4197 67,35'`7 1,8847 64.7923 65,1948 3,4599 2,1385 66.7646 2.7352 65.8845 1.7923 64,80.81 . 5.7551 ! i = 25 X = 65.46 S.D, - 3.33 ~ 277 - DUP040011504 Table 2 - Monthly means and the grand mean for the analytical concentrations of lead chlorobromide in-Group III.. Oats 5/11/68 - 5/31/68 6/ 1/68 - 6/30/68 7/ 1/68 - 7/31/68 8/ 1/68 8/31/68 9/ 1/68 - 9/30/68 10/ 1/68 - 10/31/66 11/ 1/68 - 11/30/68 12/ 1/68 - 12/31/68 1/ 1/69 - 1/31/69 2/ 1/69 - 2/28/69 3/ 1/69 - 3/31/69 4/ 1/69 - 4/30/69 5/ 1/69 - 5/3.1/69 6/ 1/69 - 6/30/69 7/ 1/69 7/31/69 8/ 1/69 - 8/31/69 9/ 1/69 - 9/30/69 . 10/ 1/69 - 10/31/69 * ' 11/ 1/69 - 11/30/69 12/ 1/69 - 12/31/69 1/ 1/70 - 1/31/70 2/ 1/70 - 2/28/70 3/ 1/70 - 3/31/70 4/ 3/70 - */ 50/70 5/ 1/70 - V .5/70 h . .. - 20 30 31 31 30 31 30 31 31 28 31 30 .31 30 31 31 30 ' 31 * 30 31 31 2.8 31 30 5 5 .. mg/nr 0.8570 0,4743 0,456.5 0.6022 0.5773 0.5074 0.4286 0,4638 0.4752 0.6154 0.5677 0,5147 0.77.70 0.5503 0,5597 0,5010 0.4737 0.5352 0.4930 0.3871 0,4052 0,5100 0.5561 11.30 70 . j.H-80 S.D, `- - 1.0552 0.6379 0.3048 0.1088 0.1526 0.1497 0.1944 0.TS19 0.1339 0.7T73 0.1.5] 5 0.2131 0.1710 0,1740 0.2216 ' 0.1545 0.2049 0.2722 0.0363 0.1065 D.2503 0.3669 0,2526 . G . 5 732 0.0235 N = 25 X = 0.51 S.D. = 0.27 * 278 * | j 1 ii DUP040011505 table 3 - Monthly means and the grand mean for the analytical concentrations of carbon monoxide and lead chlorobrcmide for Group TV, CO PbCIBr Date n 6/ 1/68 - 6/30/68 7/ 1/68 - 7/31/68 8/ 1/68 - 8/31/68 9/ 1/68 - 9/30/68 10/ 1/68 - 10/31/68 11/ 1/68 - 11/30/68 12/ 1/68 12/31/68 1/ 1/69 - 1/31/69 2/ 1/69 - 2/28/69 3/ 1/69 - 3/31/69 4/ 1/63 * 4/30/69 5/ 1/69 - 5/31/69 6/ 1/63 - 6/30/69 7/ 1/69 - 7/31/69 8/ 1/69 - 8/31/69 9/ 1/69 - 9/30/69 10/ 1/69 - 10/31/69 11/ 1/69 -- 11/30/69 12/ 1/69 - 12/31/69 V 1/70 - 1/31/60 2/. 1/70 - .2/28 70 3/ 1/70 - 3/31/70 4/ 1/70 - 4/30/70 5/ 1/70 5/13/70 30 31 31 30 31 30 31 31 28 31 30 31 30 31 31 30 31 30 31 31 28 31 30 13 X ppm 66.0710 66.4219 65.9850 66.6103 64.8868 64.2883 65.0668 66,0261 65,7504 67.8374 67.2590 66.5474 66.3283 66.2529 67.2252 67,5253 66.4932 66.8467 65.9313 67.0703 67.7143 66.5290 66.1123 67.6277 S.D. 2.5214 2.2956 3.0532 3.7002 3,8590 3.2099 2.3837 1.8732 1.7250 2,1281 2.0255 2,114] 1.3444 ' 1,4520 2.1208 ' 2.2677 2.0110 1.4641 2.8099 .2,1.003 1.9892 1.5245 1.8950 a .759.6 X mg/m3 S.O, 0.5133 0.2917 0.4619 0.2142 0.5868 0.1252' 0.6360 0.2128 0.4477 0.1979 0.3627 0.1645 0.5590 0.2247 0.3787 0.1047 0.3350 0.2189 0,4094 G.1794 0.6210 0.3262 0,4374 - 0.1435 0.4703 0,1416 0.5313 0,1443 0.5042 0.5493 0,5365 0.1467 0.1569 0.2504 0.5010 0,2181 0.5203 0.1853 .0.5419 0.2456 0.5368 .0.1744 0,5568 0.3247 0.3607 0,2049 0.4669 . 0,2514 N - 24 X = 66 ,43 S.D. = 2. 28 - 279 - fl 24 X = 0,47 S.D. = 0.21 ;i j i 2 .t j il *3 i A DUP040011506 a. d. "O 4 so-> d* -Ccn, mf <Df- SO ^* - o ja ' 'a3. M- O OS- * CD iU </J CO d) * f U r- C-> i-->a*.4;Oj-u ,-; Oa a cw id COJ >&s ,r<- %P 3 ' 6? .<t* w i** p trt Q. - --iMr/P15*i COt3D-LOUO+ 4** * r O Oi Bi w -Ou m o co r -* P. O VD V? 4~ iO 3* " <D oO *d JLO; O V) oJ 5Sj o! CO CD oi <C LU LU a C 5 ? CD.i CO X .<o LO 3CO M a! cs rO CO r> in co om y> CM CO o o -set o* J-4 h: to r-- c: o -<C o> <d u. fMM- o A3 V- UJ 40 O a; a. c. o ::=> o OO .c o 7. S. 5^ UJ SO ov to p> CO o pi . o co to co CM CO co X ^5 r--r r* CO *-* CO r-p co .* oQo Q If b 1 1 1 1CVt CO to CM cf CM ^ I . f tt V.o o oo o o CD O i-- f-- PT-- Xx ro io cr XX K. CO vT O :X X <r# <si LO o XX <J\ CM CO -- CQ cO CO +1 +1 H CM 00 u? o CO UJ1 o DC CD 4to to AO S - o> r o O o oo o H H +r sOCO \o- o p> r>- 04csi CM CM CO ao*,, CD.* 280 4 | * * 1{ - - :[ | I i '^ * , " * \ | | i. / DUP040011507 *S*SS3: .05 .15' f* U CL VO- OS? S,a *V >J <** *> o <o 4J VS V7 f-- VS C r-->1'^ ffj V) 5 >% *3 03 -X J5 C OO r- S -M ns as O #-t*r^- ra H- H *-- ,< VS 4rVI 3 -O .rr* p nj as ai n- r-- OS <SJ E g r* VS S- o H- 4 >4- J- G *j -Oi E Cl E irs > .' c05 *oo> s<U: ix--* oCSI 03 ja *3* CO CM O WCQNN-* h*iO co>-> is. CO co co <3* to ' ' ID fN.U> CO CO 05 05 *-- s VJ JSC 01 a? .at i 01 E r-- i-- PS > 05 N-' p-S* CO CO . cn *j ID s--* .Q-sr 05 :*3* M)w 05 CO 05 CM r^.>^ CO 40 os CO IftV 05.0 pp-CO GO I 01 -3 CO co CO 05 VS <r.<o 00 CM in--- Ip'VP CL X 01 1 .01 u Q. O u 4- VJ C Cl 5p s o s- CD CQ o D CL CO .B cn e in o i #* P V) to o CO VO u p <+- VS4J c o CD *-4 <0 ITS +-> 5 CD i-- < > 1 ** t. <31 CL X m C 00 ft! 1 CL S' .01 o o sO.f VI 0 o. X i 1 a. vs a. sCD so - DUP040011509. table 21 Mean values (S.E.) blood urea nitrogen and (BUN summary of single - mg percent) fo r classification analysis male and female monkeys of in variance fo r S ta tis tic a l Grouping A ;s -CM j CO i TO i C* i CM* & U3 !>. AO tO to CM O CM -r-- CM*"-** sOcf 1/3 X& I** P>. cd o o to co coo CM ' oo in & a% * in o CO I <D no -M* ip =3 V0> to;*-" ***.0 CL X <1D ) <U21 4r* C 4fO-> 5- C i<-u o, X t/> 2 C3 CO o i/> 0 V3 if OO i Cl 1 p - 91 - * The Variances of these groups were heterogeneous DUP040011510 tfod-stotoavy -of sfngte tl'a s s lfte a tie n analysis or variance fo r to ta l serum b iliru b in (mg. percent) fo r male bnd female monkeys in S ta tis tic a l Grouping A. &O O co OJ co o do o q tCoO CM O to CM CM O O QO o co CO O OO O*3" .CM oo atxu Q3 to CM CO CO CM O CM O OO o o toMCOO oo Noer>. ; oo 00 i P 3 cs. r-v hs CM ; O ;t-- O t0oCL oo oo X<01131 i- Q, SCQ o -aQ. On#* LO o Vi CL tCoO p 42 4U-jr 4-> o sr 4<40 4(C40 .Zja0i*>J UD oo z vC*>D4 CO0 ,Z v> z c yo> ns ICO CL O o 23 cij 0 00 CX011L 2 la. Jleaft -yateefr io ;cby m .Jg to ai U4sCo4. a - 92 - * The variances o f these groups were heterogeneous. y DUP040011511 ztswoofrodna Table 23 - Mean values fS.Ei ) and summary o f single c la s s ific a tio n analysis o f variance serum protein (grams percent) fo r male anti female monkeys in S ta tis tic a l feroupi * The variances o f these-groups were heterogeneous. - 6 CS- JS 3C' -of 3aI> x. 25 03 4OA C. 3 8 co oo -0i> oV) Crt X -0j mO I 3r1t 03 7(sfADT: Oi. Sit 4* s? 3g f3t ni * tA O CuOs 3 OcVti* xT ]A as - , cn CO o o or "oe5n =5- l/v rt* O 3to 03 o ^4 -- Oi CO o -i CO 4* O -*So' *0X-cwc3tJI> IT> 1 CO O O s-4 ^4 ~**4 o 4*> to o o*tO fN>C0O3' o * asQ7ITt:. V> s Gs j * -*' 4 O --*4* CO o CO 4 O 03 o'<4 c* T* ^ 0y*fS0S3. oo 4O* emn)(m)dna Table 24 - Mean values (S.E,) and summary o f single c la s s ific a tio n analysis o f variance fo r serum albumin (grams percent) fo r male and female monkeys in S ta tis tic a l Grouping A. * The variances o f these groups were heterogeneous . -H- <(/> cr> 3co Vi 5S` io or3> *T3 t CD 3Otrt (/> m CT> *xa A % (/) =3 *-* rf 1. fia SET CD m PC Vi 3 HP O 3os 32 On to CD *o IA tan o 5} I 0 01 O s- o"coS w>` t3Q S3w. d*oTr3 P o r\> Otn ^- o ro Ui Cl OS "O TXOn03i> c 3 1 P O rof O ls$ Oot 03 o Oci oC>l p"ro 07 P PP O >1,0 ors? t o to cn on O fSO ooo CO <4 ^4 t Cl fD PC W pro o n O Ci: P oi r*o* c.&i pOS o rso o K> OM 1o0i *P<4'S4*! o nsuoovodna / *' Table 26 - Mean values (S,E.) arid summary o f single c la s s ific a tio n analysis o f variance fo r serum potassium (K-m Eq/liter) fo r male and female monkeys in S ta tis tic a l Grouping A. * The variances o f these groups were heterogerieous. - 96 - < Vi Ooc-s Vi o mp> TxJ sc P(/> C <D I Xo0r3J>* CO *1j to3o P sc Cflr *-n*> i. 7pPsTC vr H031* *1 Pc* 2 0' tCnO z;. Lo 8 sr 'rcin> i cr> o in 3-noifyfr o 3Q p ~cOar t?3tirni' o co --cn ro o co r!o*w-vj *T?5 p T-x0WpyJ p 1 o co o co tS5 ro*c4i t--o CO cn Oi*y ro cn ro 4^ co -- co to ow mi~i QQ 4* O CO --weCnO 0 -0* ro CO co o co - r4o5* c--o -- cmn o SL9!400N)dna - S6 < -*nj toc3 VS o cn 3oo *tWOCT73> ft "U -at>j xn> 0(caA o cp o 3 c1o TJ -Cti iri O 3 O -b ni x *o fD 3 to M r> 3ft P* iF 7fDC H Vi & to MG3 o -3ft *mh oSIZ>' OS fVtI- CD X5 !A oat CP o 03' O NI cn --* CO tn f-"DIt fD S Sc fD CO o m o to <4 t) "N| <3 ""* OiNj ^W O (O N4.IS3 o to oo a> n i w?mrr 4O* O -si. otn CO to CO cr CO 00 O 00 4* Table 25 - Mean values |S . .) and summary o f single c la s s ific a tio n analysis o f variance fo r serum sodium (Na - mEq/Titer) fo r male and female monkeys in S ta tis tic a l Grouping ft. MsnootQdno r l * 36 u<t Vto-c;3s* *d *t $o TIO X "0tOo 3fTtO- 1 oa *3a TO CO o S3 0"H CO TXoO 3 CMO' o 3 t TsTOO: TrOfr XT' (A -TTSOO r* CO 9-- 0 o 3r+ m TO n CO 0 JA h> cn -oTO .i o cn CD 3o 3oo 13 B10 TC3T r> -T*sO O SJ O 00 "O 3TO TIO xXs 0 Cn Z 1TO I CO ^oTwO ^o>--ToO tnsi O CO 7TOT "o<5 CO O ^TO: o CO 0SI -TO O ^-S-TsOj orS*TcOn. o> to co Oi CD ^oJ-Soo- *-**.TO O 00 Oi .TO *<4 O TO Table 26 -Mean values (S.E,) and summary o f single c la s s ific a tio n analysis o f variance fo r serum sodium (Na - m E q/liier) fo r male afid female monkeys in S ta tis tic a l Grouping A. .aswoorodna Table 26'- Mean values (S,E.) and summary o f single c la s s ific a tio n analysis o f variance fo r serum potassium (K-m Eq/liter) fo r male and female monkeys in S ta tis tic a l Grouping A. The variances o f these groups were heterogeneous. - 96 - 01 OS3 Ou> 1f"lO> I- CO X "c0(O/>' r& 1 *o3oo CO wo3' *xamo> 3 1 nfi)r tA 4* 33' r* S* H 0 J2Zisi C00h rr? #Rr>i 07 4o* (A b CJI "*T> I o * in 3*ooi- O fwro- <a o -p" t-$o o u> o to o?ro 4S tn *T7 rnot> *6xo (cA;: TS CO 0I6 OCJ Ow r4o*^4*4 ro*c4n ota O ca --*00 rsi o to d r\>-p* oca O to ttoa 1^*00 CD I uonnS>>Cr $ pea a-ft- *tn-*ecno -r-ro to roco 4*.--# ota o--*cCvJi O 4 *JWWa**^?TT?'rifa 8i,si40otodna Table 27 - Mean values (S.E.) and summary o f single c la s s ific a tio n analysis o f varianee fo r serum chlorides (Cl - mEq/Ttter) fo r inale and female monkeys <h S ta tis tic a l Grouping A. * The variances o f these groups were heterogeneous. - LB - o < O3cw-: -io -oWAXoi OO %o> 03 o3 l/> O* w<W *Xno> I =cptjt- om v> 3pr+> t/J M0 O g -m**> oo 05 S* CO 03 I* oC71 0 01 lfti* " J-oO7f:5 v> 3 to *0 0cr 103 pro tn to io to ""<*tiU>5- rt> "xU CVI 3 1 03 O 4*> <OStOp 4* fO OS O o to 05 to **0o0 *-<o 4* Oi ansi> fD 7(<A1T3 4* o -* CO'W o' o 03F-*: OS CD p fO --*ro 4* JO 4* -<4 o # smvoQWdm CO <ro O cSTf CD CroO to o e x? . t/ ro ro rror r+ CD O CQ IS 3 fl> o ts w 86 - < w tf> 3 tco: Vi M ? CD X -o 25 0 Vi C/> iz CD 2O -i 1 CO -* V) o =3 0 -* 4* m .-CxIDJ 2 1 in 3 h -< cr> :CfDD TV tn --? 3 &J rf* -P O3 c* S' O 2=' CTi tn CO XJ lA o C7I o 4* o CDI of Or tn Q ptn ip3 .. ** O 3 <*i ~v" cr 0 1CO ro o ov Cft-'xf *f 4ro*. O Cb "O s CD I: CD X "O 0in C tn> 1 CO ^-sfsS d ot ^ ro O 4* 5 *SJ CO to ^-SfO * ro M t> o CO vj to r^N ^-s, ro -rt*i o si 0 4* tn a\ 40 4> -4 --j 3ro c*V sroi ro ?r V) ^*ro O <sv VltJI O Cft *<J 4* Pi Cb M2 ^-SfO o tn ro os ch co O f 3r^o-n-3c*i ro --ro * ro PQ.~roo* -roh ttn* 3 -h r_oi -h ro c* ,,'*- c--s'j - 3 o' 7roT-3 t<n r3o ro 3 *<: tc/+j (A Vi: & <* O -t*n -** C+Q-<l o-*>* -r4o* 3: O ID 3ro; xl tt* -* -i t3d m' 3 ozswoofrodna Table 9 - Mean values t (SvEt ) and samaaiy o f single c la s s ific a tio n analysis o f variance fo r serum calcium (Ca - mg percent) fo r male and female monkeys in S ta tis tic a l Grouping A. * The variances o f these groups were heterogeneous. * 66 75 3. V* <A *xocmWo- CO oo3 Tf"3tI WO3Ht- Tmxm3 3 CO *** ffttG> C* 1 ft s: X* Ul fZt CO OHI I 3 Ol CO CO "a4* nft *3 |A con I I -csr> *tn. . Oa=cs* MTWa* . CsQ 2o. S3-*-3 co-or CD to VO N> 4s* CO SJ XffItt a o 0i0 IO 1 CO -to t>$ ISD. CV *O ' ID' ro co 05 o' o O *H 00 05 - Oo *tn-*coo o-*u i < >-* i CTi * fafttc ?T W o>5 --*to CO O' O co ui O 4k- tn o --*o h * c o*~ toco 4* I'ZSllOWOdna Table 30 - Mean values (S .E i) and summary o f single c la s s ific a tio n analysis o f variance fo r serum glutamic oxaloacetic transaminase -(SGOT K units) fo r male and female monkeys In S ta tis tic a l Grouping A. * The variances tif these groups were heterogeneous. 001 <n $ jxmss T3 3 > -"tXOtcro/te*>t * "oOO3Of Cb 0=? ^-h MCO m cr> re --t. tG--oT> 1SJ' ch . orit Xrt/e>" {3* 5*CO* =cfrr m 3 n 55' CO occs *t3 OOt t o iji 3 -rOr*s5* c-ooo* If} c-or O' C^5O *->td ^>ro JS5 O os -o "3xO0teroeIr re c1o ro CO UT isj o> ro u> 0*^o4s ^rs> oo n j o Co ro CO CO cb- cnov * 7rrtoeeC 4* ? rstfi rvi.iO -r*ro --^ ** 4> fStf o CO 014* ov %o 4*o> i\*o ?zsi400K)dna * N .S . The variances o f these groups were heterogeneous iot - <w, 3 Syf' M **. i o 2- m. i mxni> to nG> xoC?/f c- 3 oo3 0t0 T*J 42/> o=y c> 4ZZL * tn 3CO X X *C1D , awl* 52 H >U| mmj =3 C+ in Os if. & fD ?as wJ 7T to & 4* o cl* r-*n* O3* trof D XI I* 5=' in 4o* to o> orto rso tn 4CO * XXmtJ CD XX0(cAJ CD 1 CO --`s.ro: tn **4 ^ro u> o *>4 4* *-<fc to o ro ro tn --j Ml Oi <^-to Oi\& dtn 4*-> * Co ov ro <Ti,4^ O'<4 *M4s* -~^4* . to co Os CO rC*O*T4O --OJ`-4O* 4 ch 40 * G ro u p in g A . om fo nvk ae yr isa ni nc e S f toa r t i ss et ri uc ma l , iasl e af el yms a na dn am tai olen oi f irc sf )s nci tlsa l eu in g RF s- 31 - Mg leuatna mv ai cl u ep sy r u,v (i cS . Et r a. )n saanmd i ns au ms em a(rSy 6 Po Tf T a b le /> ezmootodna Table 32 -Mean Values (S.E.) and summary of single c la s s ifie a tid n analysis o f variance fo r la c tic acid dehydrogenase (LDH - WROB unit's) fo r male and female monkeys in S ta tis tic a l Grouping A. 68 The variances c f these groups were heterogeneous. - 201 <w -Ot ToP3 --=6s1 P *Xo oo CHO-t akc/) it' i CO oo: *.U3 -sJ;t vi p O as* 4* m in >c XJ n> *1` 2$ " Jm1 _. j 3P arrf CO OS & sc iiml & txort-t -Hi* Pft ef st 4* o? o i3 cf rn St os in CO po cv>+ ?r |A St It s o 4* Oor C> m o5ot5+* ~OcGaS> in tSp' "O cr r> oo --ctrn>votroos *tt-oo^c--rnoj TPTJ' "oXrart --^<0 CO to ro to- 4vO*4os* 4^ O co ro co --* --oi CO o <ro4 OS * ^OS oOsV to fO rr-^otfrsocaoo 4O* * rNto* OCoOs -j j cn or >4 os co ***** *-*>os 4* 4% to to ro o CO *4 .f O' Table 33 - Mean values (S.E.) and summary o f single c la s s ific a tio n analysis o f variance fo r alkaline phosphatase (Aik. PO4 - KA u n its) fo r male and female monkeys in S ta tis tic a l Grouping A. * The variances o f these groups were heterogeneous. WSHOOfrOdfia - 01 <m J^-ooC3s 1"rot3 /*< 0a cKfl 0 3n> 0g c1o XJ & -3 C/l <33 O * *> ni X *0 n> w^t 3S 2: t/*: 3 tcv* m w 3B* rt 25' * iSi -of* 1 Ct rl Tb OCD Oi sr CO *o |A & o I C^5D p tjrt o3o Oc "O to r+ p3' ois; 3co co13r iCsD' Cb e4*r-r. Sh -fa- -r- tn "n I ti--o> ro "O -aS> xt>. 1civms3>: r 03 pi O : c co p -NJ to Oi **t~o<<o4i 1 cn -~>tn C*O *u i co ro or od 03 Co >^v .* CTJ CO jb. ^ 7masi>Cc- -P* ? CO to *<1--* CO i cn cb <4 -- OS .<--'4 CO 03 *S> 4s* O P* ritawrUfcittamiiiiia^r szsnoopodm - voi - *Table 34 Me&n values . (S.E.) fo r blood gas and pH variables measured in male and female monkeys In S ta tis tic a l Grouping A, comprised o f the follow ingi Group X - Control and I I'Group 3.51 rng/ml PbtlBr. 96,4 S3.7 39.8 O VC> -o eft u> res --- ^ -r co tn vo eft t*> eft. 33 CIO Jp}r < Ctf ---C0 N5 CO Cft Vft * 4> Cft 'w-' mimtM pS eft is 3H4 CO *0 *--*C3 --' Cft pi Cft N*"* ^ CO Cft *CO -- cn rp Co CD --* 00 --s CO !-- <0 VO Cft CO *--* 4^ * '~*tn h-- -^co O ^*4 VO Cft v-SVO --* o i Co cn ^co --*-^4 VO cb Ni"- '-`Co --* 03 VO VO "*^03 -M sj. obco '-SVO eo --* , a. VO * -- ---~AO ro o cn w^ ----co - vi-f 1O *--i o c *t3 "O o i\> 73 HO -*:C *o ~r* ro 4 rs? ^4^ -M Cft Ov -- '-s 4S --o 03 4* ^**45* --` O fp CO ^-stO --VO CO 00 * * 4* ebi* f g' ; *- s*j CO >sU) ovo Sif VO -- VO eft OD " W ---sett CO O'HI QO-i* ^-<to --* *-4 to.4* p 03 0**0 '-Hi CO -- CO --* fO ^H<jO - ' -JVO -HJ <o coco o 03 0 "O* **oco: T3 .sro>i 75 .3 7 .3 7 (0 .0 0 ) 7 .3 8 (0 .0 1 ) 7 .3 8 (0 .0 0 ) 7 .3 8 (0 .0 0 ) Osj bw ^JSs| o^d o to *-* oi o *Si O to ~i'VO Ssl ~i-pto* P-S4 to Cft C?-H* O CtfOt p h4 to 4- H4' 7 .3 7 (0 .0 1 7 .3 8 (0 .0 0 ) 7 .3 7 (0 .0 0 ) o -.2 c x O <o O H4 *<J b co ---tft o t -*3 c *CJ 39,1 7.36 7.34 939H.G(M>dna SOI Sr n> s? o rsO' G o < & 2 Ci r13t o> rs>-* cn fcocv*H, fO'V <JT K ---*?<f4s0> r< <r> n !\> O oo D: 3 ct> -j . -Ji 71 >. CU Table .3S - Mean values (S.D.) and summary of single c la s s ifie a tiin analysis o f variance fo r terminal body weight (g .), organ weight { ,,}, and organ/body weight ratios `(SO fo r male monkeys fo r S ta tis tic a l Grouping A* comprised of the following': Group I - Control and Group IT - 0.51 mg/m3 PbCIBr. us 3p CO *<4 co C tn *P Cft CO >f CD co S' "f 01 Q O -r* tr tn <& co tn ct- n> "5 O OO oo CQ fl- --'-.4v co tn 3 -*CO sr fD < O *3 C OO Op o 32: I/> oo oo O c> o -f* CO` iO: 4> O IQ P <> rc\b5 /-n W oi ^ n O 03 pj P- O cb p p o^4 rcsr>j Ococtno c 3: j Q" tp- ~tps j ETJ =3 tn 4*p c+ n in CD 4s* OvOS -5 xj O, O O o*.' -s r* jr -oo tpoi *o to Vt--n< 4* r .tI. O &* 3g' Ir ro cx> cr> 4* *- do too? c+ in co to -- *--** >~s o 0j ;r * rt- ro co ro cb j* *<4 co tn tn O 2C toil- , E r ^ P3 4^00 ri* tr> to CT O o' o O co tn to O O O to pi o? 1 m rat*, O / Saf OO OO crs4in --*cn > Q to otn oi s' n> 13 OO * # OO o -- to Oi pp OO o ro to zzsi40owdna * T-t ar rt> < Qt n-j . 3 o n> v> o ^h *+ cr fS i/j a> ?*rsO JC T3 0' J n> (D 2T n> H* f& 3 G tQ 3. o c tr> * r.. *--t < w M W Z * C/5 * 32. * in * * * C/5 Z cn 2: a' 1/5. z a pi . ss CO z. * CO fzt </> sft a CO 2: CO 23 . PI 23 * 0 ' 2 CO * -'SOI W O w. o c Q in \ CO ^ -ft*cn WO v4 c*~- CO ro o o s* erf cn ' CO o Cl . -K <- m .. XI3 n> -*-v 3 jb o i cr --* to CQ 3 o & 2? O rH m ~S ft> 3 n to *>-v "O 1* o cn ^>Ol cnto a *' COtD OKs * CO --* ro oi a--* Oo a < *--* to "!-* O oo ' 1 oo O--* s- --sen CO co a* cn o-- aa --j ID CO 4> *--* oo aa o;4* Cp CO' -ft*". oo -a aoo o 4* 4=> <^IS2> WO ft ' CO >3. N--f '""'a oo , C><4 cn tn ro ro -- a 4s- ov ^~soo * ..ft O S4 CD O .-'a-ftft poo a ft : si Ka <**- 1 *"S. oo a. ' O CO tnsi n --a- CD tB a asi o S**' ^ "ft o K3 ~ft -is* 4&Sftft -OtO; COSj S--' aooa oot <no' *-'a o u> ft. cosi oo a OCO ftiaaft * cn 4* OY ft a 4= CO *ft--^ O Ks a`- a a^'-i SIW aiaJ' --* CO a- feafSS OO ft a 4* CO w .r* CD *5 Cu -s V =3 f+i. O --1 zr <^s p Cl . D? Ct O r+ * r* c 3 P Gi rf- O . c+ z (0 D t Gl rtr*- O 3f r+ aft. < -? n> t_+! o rt X Cl . 3 m cu tt w O OO a. a . ~-*cr> coco Ni_a fCt JftO OO o ro res cn s-*' oo ft a* ro -k j co tn oo a oo ro o cn <--a- 2? ff 5sx "S p 3 Ol "5 05 o> c+ _*. O J - 1*1 a to cn . * 3ft ^ ^ O CD O *a->*^ OI P3 T3 -h c* O CD < h -'j 3 h 3 --* i -n CD 3 n> O 3 to i* o o --4 3 ^ !+ ft CD 17 ^ O ft-s. o g ex tn --* O ^< 3 ' G? G X * is G G w %n <q cu o r isn -h <+ q .. Oo c -J^SV -o IQ SC cn. 3 -!* c+*ft--'3 V-4 0} * u rt 3 l - G *< W -J O rt-O O * -*a oi -** <n o 3 c . in *-*' --J< 3 G3 LQ T> -i,CQ. -<s. *5,tQ Lis 3 Off c*>o rt -p. p *73 "J* "Ocr-3-O oi OtQ 0 co 5 # o* 3 - a or -I- 030 Q CLO 3 rt* "P o -* S "J o 3 W S3> G3G as. p it * n o c-- CL*< v< w C+ , ftjf 3" W CD CD -?- HsCGl -`H O 3T` -^C^< ft- in O rf' -5' : u5 -2. J ft Oi 3 -ft* 3 to o n * w. ns 82SU-OOt'OdnO * 01 - 6/0 6/0 6/0 6/0 6/0 6/0 6/0 5/G 6/0 6/0 Bung snoq.PMasAt|dug iipuoug papoug' piuoiunaurf oiuoaqg. 314011035 PtSBfdaad^H t[aqqonug 6/0 6/0 ELpsy p3^e[on3EA 6/2 6/2 6/0 6/0 sisojqtj LLeM Jt>L03Aivjf SLSoaqij jBunsLd 6/0 6/0 SLSOUqLJ (.EDOJ I 6/0 6/0 snoDnw L 6/2 6/0 (mo l 1,0/C} ifiutaqBW u t LLBqs/Cu;) : 6/0 6/0 i 6/0 6/0 siqiJneLd Li EM J.E[oaA.'LV pausipiqi >1 6/0 6/0 6/0 6/0 j 6/0 6/0 6/0 6/0 sisoJDSM |Bn.0qqid3 eLuoiunsud qua [fund s].SBqo0Lqo'ioag s.LsoqBuiouspy 6/0 6/L uotiEissiui aqiH Su it ] 6/0 6/0 i 6/0 6/0 ssaosqy siq-Luouinauj :. 5 6/0 6/0 6/0 6/1 6/0 6/0 i 6/1 6/0 t i' ? 6/0 6/1. 6/0 - 6/0 suio [nupug si.q.LLnoss/v xod AEquo^ siqLqDucug si4t'tor.tpiuug Euiapg '/CaEuotiiLnd ( 6/0 6/0 6/0 6/0 EUI0p3 JELOOSEAUSd aqiSEJEd 6/0 6/0 gBeqjJoujaH |.e o o j 5 i 6/0 6/0 6/0 6/0 SLS0U33|J [BPOJ BtiiasAqd&d 6/0 6/1 Qi .jD [duad/CH ptoqdiuXi |B iqoucuq usd i 6/0 6/L ELS5[dJ0d/CH aqAaonomnaiid j i=0.- 6/2 6/0 /CqdoaqaadAH [EtLoqqidg aBtoiqouOvig 6/L r 6/0 EisELdUsd^H LEiisqqtdg JEioiqnutug 6/1 6/0 [[EM a8[oiqouoag fiuLiis^otJqi 6/2 6/6 s i souq id qsng UEjoaAji/ 1 6/0 6/1? EUias/Cqdug jBnQDBjLqay 1 6/ 6/1 qasmBtd UMOug LBtqoucuquad j 6/2 6/2 6u lus^oiqi LEanaid ],D kkl smt II sdnoaa vt3L3qd e^/firn LS`0 II dnojg puE iduquog * % dnoug : 6uiMOt l o j . sqq 40 pasiuduioo `V Buidnoug [EoiqsiqBqs udi SLqBq souspioui /C6o[oqqEdOqsiH - SiqBj 62SI400fr0dfia - 801 - 6/0 6/0 8/0 6/0 6/0 6/0 6/0 6/0 6/0 6/0 6/0 6/0 6/0 6/0 6/0 6/9 6/0 6/0 6/0 6/0 6/0 6/0 6/0 6/0 6/t . 6/0 6/t 6/t 6/0 6/0 6/8 6/9 6/t 6/t 6/0 6/0 6/0 6/0 6/1 6/0 6/t 6/0 6/ 6/t . 6/0 6/0 6/0 j/0 6/0 6/0 6/0 6/0 6/0 6/0 6/1 6/0 6/2 6/0 6/t 6/0 6/0 6/0 670 6/0 TT ~r sdnoyo 3SD I).U0UBH [EPCy BiSBjidBqs^ snotreribs A'ljdcuW Qm [ ig D noQ [d-iadAg [B L-iaijq. idg S3 IP03 UOLSn'DUJ uin 1 |3tp id3 sip. j.o s 1. p; qr s uawrn u l sqepmq SU9D ^.siqog ui ttQQj p u j s ir*. laipGJi . raravsi st4iuppi3i|diuT BtsB[dji3d4i U33 |B1 istjjopiiao[ n 314 ay etuo[nuBU3 S13.LU9PV ptoqduiiC~| ^ pioqdffi/Ci quaiufiiy psz Lp./'DoSpLjj BOON HdWAl 1Y!H3N0>J8iy3d ss^/CoQ^sdaH sift ut; [Bua^BM uBjnuBJg usiuaeag UOl5.B[On3Bft S-4^30^Bd3Sj ssaosqy ' - BU101PUBJ3 ,3insdB3 >jDim SI.SB LpOqElUSfJ UO'pBuqtyui pioqdujX''i |B uv siiiqBdBH LBOOJ qUBUlild [BpLOSnULS stsoaoaN [B wx uoiq.BU&j.itoJd rpriQ 3|ig Siqt8UBlOl|PU3d H3A1T tlBM UBLOSAtv p3Sdfiu.oa pooyg peqBSBABjpQ pspsgfiuoo sisptpaisjy ppnuiquoo - gum LABQRA TORIES. tNC. A single classification analysis of variance was used for those statistical groupings which did not constitute a factorial design, this analysis includes a test for homogeneity of variances by the method of Bartlett (.3.6). If homogeneous variances were found, the analysis of . variances was then performed. When a significant F value was obtained, significance of group differences was determined by Scheffe's method of multiple group comparisons (37). In those instances of heterogeneous variances, a log transform (38) was performed on the data and the test for homogeneity was performed again. If the transformed data had homo geneous variances, the analyses described above were performed. If heterogeneous variances still existed, comparison of individual groups was made by a t-test for unequal variances (38). This single classi fication analysis of variance without log transform was also used for the organ weight and organ weight/body weight ratio data, terminal body weights, and osmotic fragility of erythrocytes.- 6.5. Significance Level All statistical analyses used ,05 as the significant probability level, with two-tailed t-tests and one-tailed F-test. - 43 - f i .i ;l DUP040011530 SBW HAZLETON LABQHATOPICS. INC. 7. APPENDICES Following each statistical grouping's summary of results (Section 2.9) will be found an appendix containing a statistical table for each measured parameter, including chamber concentrations. The tables which contain the analysis of variance of linear regression for non-paral lel ism also include the third degree polynomial regression coefficients corresponding to the fitted curves appearing in the text. 1 'i $ * 44 - HAZLETON LA$ORATQttlS. WC. III. STATISTICAL GROUPING A - RESULTS OF THE CHRONIC EXPOSURE OF CYNOMOLGUS MONKEYS TO 0.51 MG/M3 LEAD CHLOROBROMIDE (PbCIBr). . Two groups of animals comprise the first statistical grouping - A. One group was maintained as the control group exposed to filtered room air, a second group was exposed to lead chlorobromide alone. Group designations used throughout this section are presented in Table 10. Table 10 - Group A designations Group Designation to.-) i 0) ii O) Agent Control PbCIBr Nominal Concentration 0.60 mg/m.'3 Mean Analytical Concentration 0.51 mg/nr 1, Exposure Concentrations The chamber concentrations of lead chlorobromide as determined analytically are presented in Table 1, Appendix A, for Group II. The mean standard deviation for this group after 104 weeks of exposure was 0.,51 mg/m3 0.27. 2, Particle Size Determination The mean and geometric deviation of all co*jn particle doterm* nations for PbCIBr converted to mass median diameter (MiQ) was 0.55y t 1.57 for Group Ii* A composite size vs. distribution graph constructed on log- probability paper from the pooled count data is presented in Figure 17, - 45 - -I 1 'ii DUP040011532 . J [t t i in i i i j j | j.L jn I,,., | i jj ;r 11 a i ii i_h i .ri[ii 'rfinxfn| _ 17----t '-' . .--1_ .v. 111 - i' . j|ii i^ii~unii '.I'. r._ i r. j i .h i. i. rT i n j 1 1~!`i; if"i-"~ -- 1. ...*.*.**i.'.'i" ' ' T --------- h i . 7rTi r1.r-1--.-r7--! rninnnTirfi rri.r-T--. ij . ...............- r- . v - .. . --T; ; / ie ' is -j 1 Figure 17 - Particle size distributions (count diameter) of PbCIBr A 'i .4 '3 - 46 - DUP040011S33 Sfe HAZLETON LABORATORIES, !NC- 9 3. Biological Measurements 3.1. Body Weight Analysis of variance of regression for body weight (fable Z, Appendix A) indicated significant slopes among the groups. As expected, the data indicated a trend towards increasing body weight values in both groups and growth rate was similar in all groups. Figure 18 presents the linear regression curves for the two groups, 3.2. Survival No deaths occurred in Groups I and II during the 104-week exposure period. Daily observation of the animals revealed no clinical signs of toxicity or abnormal behavior during the exposure period. 3.3, Pulmonary Function Tests 3.2.1. Mechanical Properties of the Lung and Respiratory System 3.3.1.1. Total Respiratory System Flow Resistance During Inspiration [Rrs(i)J Analysis of variance of regression for Rrs(i) (Table .3, Appendix A) revealed no significant slope difference between the groups. The third degree polynomial regression curves are shown in Figure 1.9. The apparent increase in Group II, relative to Group I, in the first nine weeks was tested for significance by a t-tesc of the pre-e.xposure adjusted means of tnis exposure interval and proved to be significant (t = 4.33, d,f. = 1.6), l* 2 5 - 47 - DUP040011534 SODY WEIGHT U s-) Figure 18 - First degree polynomial regression curves for body weight prior to and during exposure to lead chlorobromide. Each point represents the mean for the animals tested at the indicated time for the various groups. - 48 - DUP040011535 rO fA l MSPIRAICW SYSftM HOW tt'SISTANCE INSPIRATION firlti)-eil>.H;20 /m l,i i]` Figure 19 - Third degree polynomial regression curves for Rrs(i) prior to and during exposure to lead chlorobromide. Each point represents the mean for the animals tested at the Indicated time for the various groups. - 49 - DUP040011536 ^^ggat@gswi59ag>^flPis^ sw#<ws ****KGe" j>^jdu,asntgsgq3^^ ' HAZLETON LABOfiATQMES. INC. x/ 3.3*1.2. Total Respiratory System Flow Resistance During Expiration [Rrs(e)3 Analysis of variance of regression for Rrs(e) (Table 4,. Apnendix A) indicated no significant slope difference between the two groups. Figure 20 presents the third degree polynomial regression curves. A t-test of pre-exposure adjusted overall exposure means comparing Groups 1 and II was not significantly different t = 1.92, d.f, * 16). 3.3.1.3. Tidal Volume (Vj) Analysis of variance of regression for (Table 5, Appendix A) revealed no significant slope difference between the groups. Figure 21 presents the third degree polynomial regression curves, 3.3.1.4. Respiratory Rate (RR) Analysis of variance of regression for RR (Table 6, Appendix A) indicated non-parallelism between the groups. The third degree polynomial regression curves (Figure 22} indicated that the non-parallelism was due to the abrupt increase in Group I at the start of the "exposure" period. 3.3.1.5. Dynamic Compliance of the lung [Cdyn(1)j Analysis of variance of regression for Cdyn(l) (Table 7, Appendix A) revealed no significant slope difference between the groups. The third degree polynomial regression Curves are shown in Figure 23. Although the pre-exposure adjusted means of the first year were significantly different (t = 2,69, d.f, = 16), the fact that Group I showed a large increase at the start of exposure renders any interpretation difficult. ' - 50 DUP040011537 1* , if i\! i* \/ ?0rA l *5fl*AI0SY SYSTEMF lO A tt. SWNfl-tX>lATI<JN fUnM '-M .. H jO itoil/m ] Figure 20 - Third degree polynomial regression curves for Rrs(e) prior to and during exposure to lead chlorobromide. Each point represents the mean for the animals tested at the indicated time for the various groups. - 51 - DUP040011538 I? Ti&AL VOT.UME (Vf *1.)' Figore 21 - Third degree polynomial regression curves for j prior to and during exposure to lead chlorobromide. Each point represents the mean for the animals tested at the indicated time for the various groups. - 52 - DUP040011539 ( a ) 51Vb ASOiVSIJSJS rigure 22 - Third degree polynomial regression curves for RR prior to and during exposure to lead chlorobromide, Each point represents the mean for the animals tested at the indicated time for the various groups. - 53 - DUP040011540 wruwi mn irii i n> '[0*H "o/iw- (i)^P*>1dN.m 5 4t! f Figure 23 - Third degree polynomial regression curves for Cdyn(l) prior to and during exposure to lead chlorobromide. Each point represents the mean for the animals tested at the indicated time for the various groups. i - 54 - i 4*t i DUP040011541 ' HAZlSTON lASOHATOMSS. INC- 3.3.1.6. Pulmonary Flow Resistance (Rl) Analysis of variance of regression for Rl (Table 8, Appendix A) indicated non-parallelism and significant slopes among the groups. The third degree polynomial regression curves (Figure 24) indicated that while there was a difference between the groups at the beginning of exposure (Week 2), there was also an opposite difference at the end of exposure (Week 1:04). A t-test of the pre-exposure adjusted means of the first nine weeks of exposure showed that Group II was significantly higher than Group I during this period (t = 2.66, d.f. * 16). 3.3.1.7. Work of Breathing During Inspiration per ml Tidal Volume [W(i)/m! Vy] Analysis of variance of regression for W(i)/ml Vj (Table 9, Appendix A), revealed no significant slope difference between the groups. The third degree polynomial regression curves,shown in Figure 25, indicated that W(i)/ml VT values for Group II were lower than Group I throughout the exposure period. 3.3.1.8. Work of Breathing During Expiration per ml Tidal Volume [W(e)/ml Vj] Analysis of variance of regression for W(e)/mi Vj (Table 10, Appendix A) indicated no significant slope difference between the two groups. The third degree polynomial regression curves are presented in Figure 26. - 55 DUP040011542 0.045 1 i; PULMON-&V FLOW fiS(STAHC'(Kt - wn. HjO/mt/ttft)' Figure 24 - Third degree polynomial regression curves for R1 prior to and during exposure to lead chiorobromide. Each point represents the mean for the animals tested at the indicated time for the various groups. i \ % - 56 DUP040011543 ^ t l VfORK OF ttEMMIW'DURING INSPIRATION PERml TlDAl V O W ** Vy Figure 25 - Third degree polynomial regression curves for Wfi)/ml Vj prior to and during exposure to lead chlorobromide. Each point represents the mean for the animals tested at the indicated time for the various groups. - 57 - DUP040011544 i i; :2t WORK O f RREAtriVNO OURlNO tXPlWTION Ptft'mi. TlOAl VOlUME tftc)yml V j $m*em./Wl v f j- < i \ i i Figure 26 - Third degree polynomial regression curves for W(e)/mT Vj prior to and during exposure to lead chlorobromide. Each point represents the mean for the animals tested at the indicated time for the various groups. i - 58 - r*f3. * 1 J DUP040011545 "h a z l e t o n LA80*ATOMS. INC 3.3.2. Diffusion 3.3.2.1. Diffusing Capacity of the Lung for Carbon Monoxide (DLcq) Analysis of variance of regression for DL^q (Table 11, Appendix A) revealed no significant slope differences between the two groups. Doth groups exhibited an .essentially identical increase in DL^q values throughout the experiment, as shown in Figure 27. 3.3.3. Distribution of Inspired Air, Nitrogen Washout 3.3.3.1. Number of Breaths from SO* to 1% Nitrogen [N(l% N^)] Analysis of variance of regression for N(l% t^)- (Table 1.2,. Appendix A) indicated significant differences in the overall man levels of the groups. Third degree polynomial curves (Figure .28) indicated that both groups fallowed the same trends with time for N(l% Ng) values. However, as seen in Figure 28, Croup II had somewhat lower pre-exposure values than Group I, but throughout the exposure period. Croup II demonstrated higher values than Group I. A t-test for pre-exposure adjusted means of the overall period indicated a significant difference (t - 4,55, d.f, = 16), 3.3.3.2. Respiratory Rate Measured During Pure 'Oxygen Breathing (RR*) Analysis of variance of regression for RR` (Table 13, Appendix A.) showed non-parellelism and significant slopes among the groups. The third degree polynomial regression curves (Figure 29) indicated that Group II was similar to Group I until Week 49, after which they deviated somewhat. - 59 - DUP040011546 . Z&OflN I j 1 m DlWUSlfca CAPACITY OF TKt lUNO FO' C*SK3N`W3NOXIOt ( O . - t f if.H ti*/'" * . M. S?PO> Figure 27 - Third degree polynomial regression curves for DL; y prior to and during exposure to lead chlorobroroide. Each point represents the mean for the animals tested at the indicated time for the various groups. 5 Si 1 .5i 3 '% yi "M - 60 DUP040011547 NUMEK&F SSEATMS 10 (A. NltHOGlN Figure ?$ - Third degree polynomial regression curves for N(l t^) prior to and during exposure to lead chlorobromide. Each point represents the mean for the animals tested at the Indicated time for the various groups. - 61 - DUP040011548 \> / JitATOHVK i f RATE (During Pu> Qkygw Rreattong} RR* > Figure 29 ~ Third degree polynomial regression curves for HR1 prior to and during exposure to lead chlorobromide. Each point represents the mean .for the animals tested ..at the indicated time for the various groups. - 62 - DUP040Q11549 t .U4 HAZLETON LABORATORIES, INC, A CUSUM plot of the time-paired differences in the means of the two groups ^ (Figure 30} indicated a change at Week 45, as well as a change from pre-exposure. The two time segments. Weeks 2 through 45 and Weeks 49 through 101, were evaluated by t-tests of the pre-exposure .adjusted means which indicated that a small but significant difference between the two groups occurred in the latter exposure segment (t = 2.94, d.f. ~ 16). A similar test of the overall exposure means of these two groups was also significant (t = 2.61, d.f. * 16). 3,3,3.3. Cumulative Tidal Volume from 80% to 1% Nitrogen [CVT(1% to It,)] Analysis of variance of regression for CVy(1 % Ng) (Table 14, Appendix A) indicated no significant slope difference between the groups. The third degree polynomial regression curves (Figure 31) indicated chat Group II was slightly higher overall than Group I throughout the exposure period, h t-test of the pre-exposure adjusted overall exposure means comparing these two groups indicated that Group II was significantly higher (t 2,24, d.f. = 13.7} throughout the exposure period. 3,3.3.4. Tidal Volume Measured During Pure Oxygen Breathing (V-j.'} Analysis of variance of regression for V^' (Table 15, Appendix A) measured in the nitrogen washout technique revealed non-parallelism and significant slopes between the groups. The third degree polynomial regression curves are presented in Figure 32. - 63 DUP040011550 J! Figure 30 - The time-paired differences between the cumulative sums of RR* between Groups I and II (control and 0.51 mg/m3 PbCIBr). 64 - DUP040011551 N[cT{1 '%N^t<f|`i 'TPjD Figure 31 - Third degree polynomial regression curves for CVj(l% N2) prior to and during exposure to lead chlorobromide. Each point represents the mean for the animals tested at the indicated time for the various groups. - 65 - DUP040011552 n 1\ j I ii ? Figure 32 - Third degree polynomial regression curves for Vt ' prior to and during exposure to lead chlorobromide. Each point represents the mean for the animals tested at the indicated time for the various groups.. - 66 DUP040011553 XAZiETON LABQHAT0H1ES. INC. 3,4.. Hematology The group means and analysis of variances of the various hematological variables measured are presented in Tables 16, 17, 18, and 19, Appendix A, No consistent trends were noted in any of these variables which remained within normal limits throughout. Random statistically significant differences were seen, but were not consistently related to the exposure conditions. 3.5, Clinical Biochemistry The group means, standard errors, and the results of the analysis of variance of the various clinical biochemical variables measured are presented in Tables 20 through 33, Appendix A, Scattered statistically significant differences were noted; however, no trends were seen in any of the variables. Throughout the study, the. group mean values fluctuated within the normal ranges of these variables. 3.6. Arterial Blood Gas and pH The group means and standard errors for the blood gas variables are presented in Table 34, Appendix A. Examination of these data did not reveal any consistent trend with time. No apparent exposure-related changes were seen In any of these variables. 3.7, Terminal Body Weight, Organ Weight, and Organ Weight as a Percentage of Body Weight The data of the terminal body weight, organ weight,- and organ/body weight ratios are presented in Tables 35 and 36, Appendix A, for males and females, respectively. Single classification analysis of variance revealed no significant differences between the groups. - 67 - DUP040011554 iSS "eff.jmrjw-wj'.T HAUBTOfi LASOftATOfUeS, tNp. <*.. .y * j i*. 3.8. Hlstopathology Summary A detailed listing of the microstopic alterations seen in the the lungs, tracheas, liyers, kidneys, peribronchial lymph nodes, and hearts from the animals in the control and exposure groups are found in Table 37, Appendix A. Exposure-related microscopic alterations were seen in the kidneys from the 3 animals exposed to 0.6 mg/m PbCIBr. These microscopic alterations were characterized by varying degrees ,of degeneration in the proximal .convoluted tubules. The epithelial cells of the proximal convoluted tubules were Slightly vacuolated, and there was also a slight loss of the brush border in some animals. Acid fast intranuclear inclusion bodies were present in the epithelial cells lining the proximal convoluted tubules in seven of the nine animals. Incidental lesions primarily of .an inflammatory nature were seen in the lungs, livers, peribronchial lymph nodes, tracheas, and hearts from the animals in both the control and exposed groups. The incidence and severity of these incidental lesions in the exposed group were comparable to those seen in the control. 3,,9. Summary The inhalation exposure of male and female cynomolgus monkeys to 0.51 mg/m3 PbCIBr resulted in a deterioration in the distribution of ventilation. The number of breaths to 1 % nitrogen, cumulative tidal yolume to 1% nitrogen, arid respiratory -rate measured during -purt oxygen breathing were significantly elevated in this group. The other physiological parameters measured during exposure were not significantly affected. - 68 * i | | 5 DUP040011555 HAZLETON LABORATORIES.. INC. Microscopic alterations related to the exposure to PfaCIBr were found in the kidneys of the animals in this group. These histopathological changes we. characterized by varying degrees of degeneration of the proximal convoluted tubules. The epithelial cells of the proximal convoluted tubules were slightly vacuolated, possessed irregular luminal borders, and in several areas, had lost their brush border. The nuclei of these.epithelial ceils were vesiculated and many contained acid fast intranuclear inclusion bodies. Hematological, clinical biochemical, and arterial blood gas measurements made pre-exposure and periodically throughout the exposure period on the animfls in the control and exposed groups did not reveal any meaningful differences. No trends were noted in any of these variables, and, in general, the exposed animals .were comparable to the controls. Statistical analysis of the body weights measured periodically throughout the exposure period revealed that all animals in both the control and exposed groups increased in weight with time. No significant differences were detected between the rate of growth in the exposed animals when they were compared with the controls. No significant differences from the controls in terminal body weights, organ weights, and organ/body weight ratios were found for the exposed animals. Appendix A - Data compilations and summary of statistical analysis for Statistical Grouping A, comprised of the following: Group 1 - Control and Group II - .0.51 mg/m3 PbClBr. \i I\ 1 - 70 **a Table 1 - Monthly means and the grand mean for the analytical concentrations of lead chlorobromide for experimental Group II. Date 5/11/6$ 5/31/68 6/ 1/68 -- 6/30/68 7/1/68 * 7/31/68 8/ 1/68 - 8/31/68 9/ 1/68 - 9/30/68 10/ 1/68 - 10/31/68 11/ 1/68 - 11/30/68 12/ 1/68 12/31/68 1/ 1/69 - 1/31/69. 2/ 1/69 - 2/28/69 3/ 1/69 - 3/31/69 4/ 1/69 * 4/30/69 5/ 1/69 - 5/31/69 6/ 1/69 - 6/30/69 7/ 1/69 - 7/31/69 8/ 1/69 - 8/31/69 9/ 1/69 - 9/30/69 10/ 1/69 - 10/31/69 11/ 1/69 11/30/69 12/ 1/69 - 12/31/69 1/ 1/70 - 1/31/70 2/ 1/70 - 2/28/70 3/ 1/70 ~ 3/31/70 4/ 1/70 - 4/30/70 5/ 1/70 - 5/ 5/70 n 20 30 31 31 30 31 30 31 31 . . 28 31 30 31 30 31 31 - 30 31 30 31 31 28 31 30 5 i mg/m 0.8570 0.4743 0.4565 - 0.6022 0.5773 0.5074 .0.4285 0.4638 0.4752 0.6154 0.5677 0.5147 0.7770 0.5503 0.5597 ; 0.5010 0.4737 0.5352 0.4930 0.3871 0.405.2 0.5100 0.5561 0.3070 0,1080 S.D. 1.0552 0.6379 0.3048 0.1088 0.1526 0.1497 0.1944 0.T813 0,1339 0.7173 0,1515 0,2131 0.1710 0.1740 0.2216 0.1545 0.2049 0.2722 0,0363 0.1065 0.2503 0.3669 0,2526 0.5232 - 0.0235 N - 25 X = 0.51 S.D, =0.27 - 71 - y <i , '1 DUP040011S58 fable 2 - Summary of' s ta tis tic a l analyses o f body weightI I data fo r S ta tis tic a l Grouping follow ing: Group I - Control and Group 0.51 mg/ia3 PbCIBr.' comprised o f the to o vl I a CO oS5- -O nItLCtUt--OofUcCJ*l O=Sc: LU Ol -to 03 O VO <o LOzU: M <a: o V) <to/? acto>o r>. icnvi >--tO: VO crv <a>c: <co Uo- rtS *- <>3u oPLoUc: oto <0 ia. c a OS. uS- U4 - 72 - so No> p CO CO CO CO co x>nj r-* o co r* O tCoO 4LOCU Ui oa. LU LU aCD: LcUx; acnd u. OLU 0, oZ I--I vto> LcaUo: LoUc n <r C4 5f f M .1 * op O O .**- r-y* XX XX co CO CU so cn to o i-- co r^-.CO +1 +i X>J ipn VO oo -H CsoO to a. <J3: ' '4 >1 r.S : 3 -'I DUP0400li559 data mg./m3* 1 iration - 0.51 IsIp m CSJ vo in O vf <7% CO aoo a. resistance during in * Control and Group respiratory system flow the followings Group 1 -Summary o f s ta tis tic a l analyses of to ta l fDokrr'lDSuitatis tic a l Grouping A, comprised o f csi r-- oCoO VO oo w <Si SLa<SUz>i taici tcu=cc: jd- I oo rtoo icr>n cr co LU CJ CM oOL C I o .2* o t/> I--I co CO 00 scho jmh*. CO >- <c vo -CO LO u. Ui; 8 CO CO LU OS. CD LU OS LU CO O -H f2 Oz Cu LU -- tLduUc O CD LU LU Ocu Qa; ST: *-* O --t CO CO LU OC CD CLtUC CO CO Io Io Xx oo j---- r" CO to +1 lVO V.*O oo Xx Cr>M* OCO os o I +1 io Io. XX CM ** #-- CO CM CO ai co ii Oo XX 88 C1M *3* +1 <0x0* 0.0 Xx -CM to CO to r>. -H *tto*siot XX Nr-. to o toi co -H S- fr~ a e:v> o j **-- *3; z 3. nj r-- r~ rOolA. #-* <>W Q fpto o CL. S-. o; I O tD C 1- O o s- in, 2 LU CO CooO o ** o to az>. o CO CD vo oCoSJ. o hi <o -too - 73 - 3 Table 5 *r-- tO go<* <0 ll a i I1 o> 11 % :2p IT* *4-- 2*3 Jo Q!T3 +J <y VJ 'Sr tf rg-* :<C.* si 4J m <3 rr .4-* r-- 3s 4- v> O >, 4*---9 <0 8V U37 VC- t <#* rW--P o Vl I | o -< CO Tin i 2DC <c o r-- XX o su CO r> 10 <=> ; { r--* to 1 O r-r X 7 O 4"*X Sto o CO CM AO to CO M3 o <c *-t G v e 9 QC <c 5 OJ 03 >r< > o 3 u a 03 o or 7 c ov> o ; in to 5 nM 4to-- z UJ M u *-!-* U. ih M CO <UoJ CD IUDJ CD < M S >-J 4UJJ g UJ ca Q Q** ; !, i- X *o in 8 8 > CO O - c? 77 go Q XX oo o\ Cm ; | in 41 UJ to +1 to O t-- zU*-*i CJ M u. -4LUo o 2: ow to 1 CQ IX UCOi CD to to I tO <D #** *-? Xx co oi r*1 N H ti ro* ro-- XX T's o P CM . CM CO 1 +1 cp cp oo fr*-?*-* XX OO cr CO 7^ +1 77 oo r*~ r-f XX o^coto pv to H i .i QO rXX ; }~ o r> to CM 4 4.1 CO CM Q O o < H s04 o CO 1 i o fl sCO o 74 m %o cxi ID Table 5 - Sunwary o f fallowing-: s ta tis t Group ic I a - l analyses o Control and f tid a l Group I volume data fo rI - 0.51 mg/m3 S tatis PbCIBr. t i c a l Grouping A comprised o f the mo yf a <on co CO <UcDci <(cJcLcl: ; O i** <71 N CO uo. *3* uzc Mccc **0 o 00 CO ui r-- at r>* fv CO CO <2c: CM *C3O* o r> CM <0 ca O 2: <sr & ro i CM p CO UI sUu.f Vu0aC?0J:i iC.u ui s: .2>0-: to +1 o 2T- CL UI OuaLQUs Up-c u.1--1 U. oUI cs o"ZS1 to- <uau0as0::ii to .tn II 00 f** .-- Xx 00 r1- CO .r-- CM +1 ro co it QO f!" #--r XX CO CM CM f +1 .r-!' f*" t1 OO jr*-* p- XX ct'cb toco CM i -H to in i1 00 r** :X X O *3" CO.* to.# CO CM *1 *r 00 11 OO r-*.*-- Xx 0 03 .r~ tO^t* +( CM r 11 OO I-* r--' XX 53T CM to .r>* .rrk i-- H CM 0% -H CM 0 CO CM 00 . CL O --* CCOC to r^. f*7 +t O it * - co ; *-* 75 ;l 1 s '^1 'g i i .^-5 -"'T-i 'rS H i=|5 -yi * -ll? *:3 .j 3 =y "3 -pj# **59 I] - *5* DUP0400115S2 S3 D *<5Q3J 0% Jwtr ua. 0 o o -<c r** CL P O Cw3 flJ O 0 $* CQ .+> *U J o +to* 0a* i-co Ss> t<-S oLOt eO .1 4- {.m O- CL to :=3 S 0 ,u o *soz s/i as p nJnrSJ* -LM ; (0 O o f-" itS*3 -I *-- *--t .44 m rx > 23 4* O * +J o Ul M-- ' o o* b >** U2 <0- o = b t/> Vt- I to S3 n* J3 0 to O V* vf S3 >- o. o to -OO: CO LU: c o UJ a: <x uj CM O CO O .04 *? CM J oo O to to 00 oo to <* CSJ V) >- <C CM X> <C E t/i c o ct: <C +i SI R3 > o SI Vo LU UJ Q_ i- cvr I o _> cs u o to o z: ul l 03 U) CD o CM 00 <n CM & CM oo 00 U. tu ui in 4( o PO r" 'r* tP X X to v> coto to 63 UJ CSC -tO r~* o UJ M a: s: to o .z: +( t-->- t/i _j oz a. UJ J--I UJ o ui cc <D UJ O Q QC CO to LrJ ac CJ Ul GC 00 CO .1 1 O CP * r** XX Oo co p> pi CM 4t i1 or--. ro-- xx J CO r- CM 00 r- +1 CM * <c *?5` On +1 tn CO CO DUP040011563 :i Oi HZ .r-- IX :a C13 t.1 *3 /) '45 C *m CO1.0 -Q L. jCL 4ph ?0 *s >-* 4- .cn <S E *u Sq c 3O * + <2 w *r* -<y 4<-TJ J4C> 4> m 4o O "O >> i/l rtj si S O- EE S3 O c/> u QJ JD fl3 CO to tn Q vf css CO Cl CM o t/> CO US cel CD LU cc Q LO CO in CJ *< es: < COo </> to in CO a* to co t/> _} 2 <c ; 4*o n *?* o c cc Q < lxl: <0 <L? a. a:. v zo> cr o to O s- 3*r so N .00 ss' UJ .*--4 CD *-* u. LU into LU O oa o XX to o<o ocn to. UJ cc r- to o *H UJ d UJ CO os: +1 to I-- oa. 2 ..LU fc--t U4 CC CD UJ UJ ao CD I COt oo XX cCoO fo>* a: DS i--* x: >O-< to sUoosJ t3 LU 401 CSJ CM It oo XX <r> to CO to +J it'Coj7 o , ** o VO to o vo to II oo XX -oCO tos to po +1 co co ir -O o CM ?sfr- CO 04 CM 1I oo XX CM tf> CM <0 vo u> +i u> O; +i cn o - 77 - o CL. 2> O CC CD DUP040011564 S<* Q 13 0 * ux s *5 tn c: * " -Clw SI o Cl *3 u *r' 4^> 3 V t/i u <<StJ CuQ. 3 O T3 -Q <X. oc<Uooe 3 >s. 4- rti VI S *r-- V} *-- *-- UO CO *4--.. E CLI o.3o 44-S 1 C0 0 s CO in CM *3" in o 03 Vj - <c 2: <c 4- 13 r- CM GO of f-{ *3-C*1l c ,>If. U-i Oj Uij uOC1 ZD I Of tn\ <iEi--n r-- r0-- ifnJ S-. Oftl.j = <Or cr-p" >m Q S~ o us_ UJ - 78 - * GO </? .o o ;Z o UJ sUJ ttoo LU Q O UJ CC ss:- o o o. cc CD UJ 3 O CC to in UJ cc. CD UJ QZ CO CO i. i op r* i-f XX oo CO CO -r-- lO t +1 r>> ii oo ,r~ i-- XX r'~ .CM r>. co cp CO -H in i> oo XX ^ oo co m r>. oo +i to CO o. o o +1 CM o o N o o o CTS.C0 l1 oo * r* XX oo o cn co in i GO i1 op XX CO O r>^. *-- r>- cn so ii OO r-- f-- XX CO CM op CO CO -H cn co o* o o ri in CM o o GO OZ3 S CD DUP040011565 *o tv* toco to & >* cn *e 2: r-- .3,10 i*~ / :0 O > I <id t--< *- nHJ CL 3 *ii 2 imx*cp its fiS ' O p-- T- O +J X* fl3 4-* v:sa-- ooo v? ,c; 1 ,o> -icV*;i-' O3a. .3 U T3 CD Ol G -. rr- o j -G C XI r-- 4-<2 O as ^ JZ 5- 4-> S 4~ 4- 0'"0 vt U<u) til S- 19 & O cu <d <9 o cn r- G 44 ir* .v: o. T3 4- <3 4<->0 tJLJ. .UJ PU -v>+* S~ V Sid t - co "e6 4M-> ;Orr- 2J.4P 69 /i a. 4 o* p .P id ID o vf 1 a CD LD .</> to Ui Q CD CxC va .0 04 oo CO CO Ui u> C CM <c O ,5- O CO to O co CO .0 o to CM r--* <0 IH e to G o a: <C p 4> r<--d > O fd P uO tu IKS to a. a: O ID s_ O 5-- CO UI 1 in 3 04 pp c CM co X to m to CO 0O us --1 o *-- U. to to tp t> ui 00 `oo Si XX O OO . P U> Xx 0.0 .. GH *3" CM-^f -H f>. in * +| UJ. CO s: o *df" ^ 11 OO 'r-- p- to 0 XX o Q. MJ *--c o oc CD lx. UI Ui1 Q O* O a O' r-*. 0 00 to N* H CM CM 1. 1 OO -- r*?* CO <0 CD UI DC CD Ut QC XX O'lN 0 cn CM CM +1 CO 15f ij 0p XX 0 co *4* p^> CQ rH CM CM 1i OO r-- r-- XX 00 in in is co +1 0 to cO to O0 +1 * d* <T* CO t-- CO <0 CL CD Q CD 79 .! I i 1 I i x DUP040011566 ec) ri* o%. JaQ. ^co #9 Q1 S (U 'pr* ew 5? * o^-o I flj +~4 * . 44 3a. O SJ i--rc* <aD <=9 C r1.2 2 4-* tW iV-a Sp r-- <i? P *-* cn SS-:C. 1*30.oS0- o> s: ^ ,t JS c +iO4 .3r-t. qj o U r-- JC3 >*? 4~ &OO 9 CX r-- 19 O CU r- <C S . U p) r* C 44.-rtO CL r- 3 +> o <tJ .* M CD CO r" 4- *a oo >> u yi (Q *r + g fS O -O ca in o vf I p p" i o v> CO: LU - cc CD LU C CM IT* i. .1 C O O <c r-* XX !>. 'S* C\ -Xf* in CO Ui c_> 2 1--( 04 x: <c CM Oo r** r** XX o.to -* to VI r*> Ps CM cn <71 in to >- to r-- --i <c z <c 4" ; *o u> 54" ,s to cc .> a_ o o . iro o. <x cc c oo to c 4- <9 > CM in co ii oo xx oo CM -H 4" -9* cs Ps- : CO co *H CM CM Io Io in rs. r-- CO CM I +! OO +s +t in CO CO v> G_ Oi nc CD AA ? i { i DUP040011567 B -W & <S*- *M3t.O* *t;3 O <M V e > X O c; a. co o; J3:"0 &. c 4fl fl3 U - tO-oS- <*C . -cc3n-ooj . a 3. <* o~ o CsS- <uts -aa> o*j jps CCnO~ f- *t~ CJ ^+- -123 H- + *U *<4- ^ 1! VI </ O S-. >s io. OS:. GU id *-<C ta uw iA O. V 23 *CJ U 4-* XLS 0 r-r O UM- -73 p * f>c>-W- i.i m 4Jf f 3 O CO CO 4. :u j a: ts *.u or os' <U1 uo. *r CO .CM 4 O ... *S* X co *& -- CM 1 o r~* X CO VO M3 CM 04 O O co in 03 ID 1>- ; <c 410 a r*> <*- G oi a **-- -C *s .. s- ui OJ Q- .02 I oO: CO c o c; o >ai JD so u u ui co CO to co co CcOo * CM in o $o co o o oo CO .CO Ui c C5 uccj CO 7? O +( CO H- o 2T .a.; LU XX. C3 UUi UJ oo o Q 32 oo CO Ui aC3: ui ..a ii oo XX mo coo +t >s Cs. ti <0 o XX .o o CO is* IS.|N* in m 41 oo . Xx cr> o ?r.C3 CM -H *1? 1 ro-^.orr- XX VO lO CM S. r- r- +1 CO CO I-or4* Io XX *-- o oo CO CM +1 c1ooc1oo XX t>* TO CO CQ coo+1 <r> o o +.1 CipM O co Cu 2D' S o CNj un O o +i vp o i l - DU PQ40Q11568 Table. T2 -'Summary o f s ta tis tic a l analyses o f number o f breaths to IXI I nitrogen data fo r S ta tis tic a l Grouping A, comprised p f the follow ing: Group I ^ Control ar.d Group - 0.51 mg/m3 PbCIBr, U) O CO ,o 1--4 q UJ i0D5 UocJ CM CM X.*0=j5J O O CM f>ctoo cfn* MUJ ac CM oo o CO xn GO CM .in pss co CO CO >-CO| CO CO <** GO "S' <oct o.c <14 3 ou_ flj <u L<d- O a. s. gO 5- CO CO GO O :<M CM CO CO 01 so &GO H* xn .22 UJ u. Lul .1 O C? GO GO <U035J 0U5J Ui <n +1 in O CL UJ ocUJ u. S3 IoU o05' uUi-; oGP a:-** to GO U05J ID 0U5J in in oo r--* .f*-* xX oo e-- <vl c-3 tn +i cio coi Oo XX CO GO O CM CO +1 CM i-- i- * OO XX ctop cq y co co +t to in inm *oo XX -dsr ros CO -sf M CO CO .1 I OO GO GO r- O * fN- +1 tI oo xx fG--O CCFOG CM CM -H CrtMf o<X> co CO +i tf coin Is*- fv` C**M5f GO C50L 0Oo5 4 :: DUP040011569 *^j . - s. l a ic t s r Stati PbCIBr. data fo mg/s# aonxdygGeronupb r IeIa t-h in0.g5)1 {daring Control te - ra I Summary o f s ta tis tic a l analyses o f respiratory Grouping A, Comprised o f the follow ing; Group Oin <A >-vj Qi Q. *O3' tCoO LU PC. CLUD cc c.l=uc?: O OCM r*~ r-** XX .CM tO Cr>Ms CcoO oUi <ccc o oCM -sf o <t/> t>/>- to/> CM t>* CM CM fS ^3co *2=aCC: to St <c vEi 5O <cc 2QZJ +j ,r--Its Q>J Uco=>ci .to0 a.U1*. .zCo: <--1 *ouUUi so CO CLOM CCMO CM <n CM CO 0 rr- CO PUi to CO Ui CCDC LU CC Ui <0 o +1 u>oczsc-c. fzt--o UJ LU *o-* LQcUUni a Qas *4-4 uULOPU O3 t--4 uttoCooDsi CUXJ in to i1 00 r^* XX CM U> Ch CM +[ to in < .1 O0 *-!".*** XX O CM -d* IS. f>. CM +1 CO CO t- 00 -- .**- XX ; *n. cn ; 1 -H cr> co 11 po r-^ *-*- XX to CO CO 'p" CM *3.1 +1 r--" r-- 11 OQ ffP*- XX o> to . CM +1 r--- f1 OO XX r--' p--? 01* rs IT* +i *-- +1 to s* CO <0 =otax3. <D 0 Oj.r -- +t CO CD CD CD 3 : .. DUP04Q0115T0 - 13 Table iti U 4"IQ* V) r* rO 44 JD .t+o4fcCoL' <2f 44 tn *9* p4* CI <y ;Q E~ cM** CiosL s 5HS O f!- O = 44 <0 <3 r-- EO 3 r-- 44 OC =*5 :<0 > o X > a<3i t3 ** > aus at 3 .. HO ;3 C Q O -Of-- o o 44 r- .it/} t> -4IT4- CHL il3 O -*4 <J M-- C 0 01 > rdt CL S g 00 CD 1 oO as to O vf i a s O-- to to l u; OS O LU CC cc xc Oo .r-L ?-- LU 2: XX <g to CO CO u. o LO . ** * K r" LU o 2: <c IH pc ?=C ro i o 5>; U_ O to *-- to to *" CO N. 00 xn ; to >__r 2CT, <, <i* to *3- as <c nj V. Ui o Cnl j a; O c( oto o .2: cr a > -' to HoZ CL LU w ui O ui as u*> m* I1 oo r-- .r-- XX in Wr* r-- CM 1 4! <s Ui LU aO o ooc St -* o CO CO t1 oo tc --t I-- to t/> CO XX LU OC O at tn ! cn LU as in co * +i CM O to to ii oo n-- -- XX oo CO r** f-- r* 1 H <111 OO r-- Xx cn o ON CM r- +* n 1! Oo i-- 'r-- Xx U) :U> ir> a *?M>. +1 <jft o o 4t tn to * r-- to GL O o QC O rv. o o 4* CM tn --e J J i: DUP040011571 rtS U. 4 t- s -> co JA r~4J XI <mPoo o a> o-- -m in m . oo x: **M3 3X CL* O S- M -P CD 4Cr *ctJ O *J > X *--o Scn-M e: q *S*-- oo ,<y ,E ex. ;3 .3 r-- O S> CD * ** O CD fC i/l o *<** U) 4-* ns H- O Urd 3O3l -r- t/J 4-* *t V> 5*r* O. M B fll O P U tn Hr <C - O Cft >> P t* *r* f CL 3 O 3 V. .</> CD .in r* <W XI tn o vf a. oo cn in\ LU CC CD Mi cc Ca CM QO cc <c Ui O tn tn CM co UJ U>\ CC *CMO O*0* > Xx co co O tn * T-* Cp CM S' O' 4- co -a -3- o *-- -a:- X <c OJ o ns . ns o o. C Z3 s*z OO CO SC o 4~> nj > <3* o u uo CUJ o OO is. to CM CM OO 00 o CO CO h- </? sr z Ui CD CO CO LU cc CD Ui CC ui CO Hi </) t-- o .JS a. LU Ui X CD LU UJ LU <3 O . CD O CO in ui cc CD LU a: 11) to ii fomm Jo-- XX COrtOOl spVOO" +1 oo oo 11 oo c--r xx *tv<M tn oi to to -H *i oo r*" XX O f>CM xj* CM SM .........h 3* \o co' in tn ii oo -* ^ xx oo c0 CO CM r~ OO +1 oo oo tI OO ** XX cp cn co +r .r-' ff QO r~ i-- XX IN. f>v so f-r CM +l * CO to +1 CO o CT> CO r>. CM -H cn CD oo cn a. z> occ CD l ii I> M 4i DllP040011572 Table 16 - Mean values t (S.E.) ana summary o f single c la s s ific a tio n analysis o f variance fo r hematocrit (Hot. - percent) fo r male and female monkeys in S ta tis tic a l Grouping A. Kot <SJ too oi>-* fS7fi> vo* CO vjO CO o is U3# Oj-S^ CO* *o3* Vl .03 03 isr co too i'Js.o to <r> co o co>.^ CO p> ro> co>- ** o C0"W op JOr- cocci tf> o cn*^ dio US ni. CO 03 tin. Q so o COv-r 'cOviOo Q. X HI 0 I! i- O. ion vl o. co VI v so cuLu> c: o*3* fd (Cl. <y<W. 5 - i + f- ' ' j- 03 -X .u* *L0 c o VI f-- s- 03 <9 l CL 8 s Vp) ; X 103 2 CL. to ,3= <3 to jas | 3. 1 .5 DUP040011573 Table 17 - Hfe-aiv values, (S.E.) and summary o f single c la s s ific a tio n analysis o f variance fo r hemoglobin (Hgb. - grams percent) fo r male and female monkeys In S ta tis tic a l Grouping A. *3- NC1 <0<O -Vo od CtoO n V> xt'pj oo o o **'*>"** 5o*" OO --CM oo O O i--**-*' 3<0OH1Ui W CM 3* CM r^-O o`d p CO *--.0 CO,CM cn o 3vt 0 in co CM CM , oo OO CL X ai i- v> -aos.r +J oO:C tLo. v CQ o JQ a. nE tn O in o VI - p- Q0 V) p 4-> u <*- UJ 44 Co S cf 44 3 H VI <CUJ tts -pC! SO-i CL ,X LxJ O.4- -C0 V3 r-- S#0- 0I0 OQO. Ja3Uj v0 CL Xaaw1>i la. *c-o4 CO o 4* to C3 V) o toi -i VI cClr 5 CO Table 19 ` ! Mean values Cs..) and summary Gf leukocyte count (WBC - per own) fo r single c la s s ific a tio n analysis o f variance fo r .to ta lt male and female monkeys in S ta tis tic a l Grouping A. P X?rC?O Cc\aJ<r\s1 CTi r~ spf* CO r-- rv CJn -* pCO cCaJ iCnO #*- if> cCaOtSo-' CfCtwO o53* i$<<OCAUf Z3Z ccvOaao 'cic--noo' Isis to co cCoO--co' can* c'Oa tcoosr>-- Ctoiawrt * r--a rrss--oca>* 5o*- otCoO CO ef5** 53* CcO^ tCoO 0 o j co cr co rs**> co>> GX<0*121-?L a. o at5VaouoJr 4fZ4 cup - CJOut CO .een. M) o > ui . sf*` p tCoSC P vj I? CO tn r 2S o ,p c <d </ <<1y1 4nC4; 3: to i Itr- <c11. cXa v> 5? to .2? PC (L9 oIo oCOL to VHorJ. 2* P .2! fa. <zXy oe in > * f -3 .' ^ jit5'!--~ ZoJ pc Pp> pa* 4p0 t:3Pp-c VJ ZC3L Ch P tarl -4 vPOc<.9: 9 .> P -C I--* * DUP040011576 tbtAL'rcSPUAlCSY S Y S tt'M 'i.0 * K S lH A H C t* iN S P |S A iiO ^[|!ii(ij-,miH20 /n il/i.c ] t Figure 53- Third degree polynomial regression curves for Rrs(l) prior to and during exposure to sulfur dioxide and lead ciilorobromide singly and in binary combination. Each point represents, the mean for the 'animals tested at the indicated time for the various groups. - 186 - DUP040011S77 T 0 M 1 WSPHAtOHY SYSTEM FLOW RESISTANCE- tXPlfcMlON' Figure 54- Third degree polynomial regression curves for Rrs(e) prior to and during exposure to sulfur dioxide and lead chiorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 187 - DUP040011578 f' / TIDAL VOLUME (V , l.)- Figure 55 - Third degree polynomial regression curves for Vy prior to .and during exposure to sulfur dioxide and lead chlorobromide singly and in binary combination* Each point represents the mean for the animals tested at the indicated time for the various groups* - 188 - DUP040011579 HAZLETON LABORATORIES. INC. 3.3.1.4. Respiratory Rate (RR) Analysis of variance of regression for RR (Table 8, Appendix C) indicated non-parallelism among the groups. The third degree polynomial regression curves.are shown in Figure 56. Inspection of Figure 56 indicated that RR values for Group IV were slightly higher during the pre-exposure period and remained slightly higher throughout the exposure period. 3.3.1.5. Dynamic compliance of the Lung [Cdyn(l)] t Analysis of variance of regression for Cdyn(l) (Table 9, Appendix C) revealed non-para!leiism among the groups. The third degree polynomial regression curves are shown, in Figure 57. Inspection of Figure 57 shows that Group I, which was considerably lower in Cdyn(l) during the pre-exposure period, had a marked increase at the start of the "exposure" period and increased slightly thereafter as did Groups III and IV. Group II, on the other hand, started from a higher pre-exposure level, increased at the start of exposure but did not increase further. The difference between the pre-exposure adjusted overall means of Groups I and II was not significant (t = 1.87, d.f. * 1.5), The pre-exposure adjusted differences in the means Of the first year for Group I vs. Group III and for Group I ys. Group IV were significant (t - 2.69, d.f, = 16 and t = 2.30, d.f. * 16, respectively); however, the large jump between the pre-exposure values and the start of the "exposure" period in Group I renders difficult any interpretation of these differences. - 189 - DUPQ40Q11580 t ESP!RATC(rV RATE ( M * S 'M thi/m l,.) Figure 56 - Third degree polynomial regression curves for RR prior to and during exposure to sulfur dioxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 190 - DUP040011581 /i DVNAAiiS COMH.IANCSOF THE LUNG [(M y* (!) - m tftm . H jO ] Figure 57 - Third degree polynomial regression curves for Cdyn(T) prior to and during exposure to sulfur dioxide, and lead - chlorobroniide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 191 - : \ <. DUP040011582 WCJrW'',MWiUTriL'..U.|a roms.h a z l e t o n l a b q b a me. 3.3.1.6. Pulmonary FlowResistance (Rl) Analysts of variance of regression for R1 (Table 10, Appendix C) indicated non-parallelism among the groups. The third degree polynomial regression carves are presented in Figure 58. Inspection of this Figure indicates that the trends with time differed among the groups, but that the R11 values were generally similar for all groups, except Group J, which did not decrease as much with time. A t-test of the pre-exposure adjusted means of the first nine weeks of exposure indicated that Group IV was significantly higher than Group I (t - 2.39, d.f. = 16) as was Group III (t = 2.66, d.f, = 16). 3.3.1.7. Work of Breathing During Inspiration per ml Tidal Volume [W(i)/ml Vy] Analysis of variance of regression for W(i)/ral Vy (Table 11, Appendix C) revealed non-parallelism among the groups, The third degree polynomial regression curves are presented in Figure 59> Inspection of this Figure indicates that both Groups III and IV had lower values than Group I throughout the study. 3.3.1.8. Work of Breathing During Expiration per ml Tidal Volume CW(e)/ml Vy] Analysis of variance of regression for W(e)/ml Vy (Table 12, Appendix C) indicated no significant slope differences among the groups. The third degree polynomial regression curves (Figure 6.0) also indicated no observable differences among the groups. - 192 - k DUP040011583 Figure 58- Third degree polynomial regression curves for R1 prior to and during exposure to sulfur dioxide and lead chlorobromide sing)/ and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 193 - i DUP040011584 WORK OF BREATHINS OlSINa WSfiaAJlO'N PEIimrtIBAl, ViXUME [W(l)^ml VT^ a,..Mij'(iii VT] Figure. 59 - Third degree polynomial reg; ei$ van curves far V(i')/m1 vT prior to and during exposure .to sulfur dioxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. -194 - DUP040011585 WORK O f MEATHINO DURING'EXPIRATION 'ME.nl. IIDAI VOLUME [W M /m l V j * jn.m i.fW I V j] Figure 60 - Third degree polynomial regression curves for M(e.)/ml V-p prior to and during exposure to sulfur dioxide and lead chlorobrpmide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 195 - DUP040Q11586 HAZLETON LABORA TORIES. INC, 3.3.2. Diffusion 3.3.2.1. Diffusing Capacity of the Lung for Carbon Monoxide (DLCC) Analysis of variance of regression for DL^q (Table 13, Appendix C) revealed no significant slope differences among the groups, Ti.* third degree polynomial regression curves (Figure 61} indicated that OL^q for ail groups increased with time, 3.3.3. Distribution of Inspired Air, Nitrogen Washout 3.3.3.1. Number of Breaths from 80% t, 1% Nitrogen [N(T% Ng}] Analysis of variance of regression for N{1% N2) (Table 14, Appendix C) indicated no significant slope differences among the groups. Inspection of the third degree polynomial regression curves (Figure 62), indicated that N{1% Ng) values for Group I were somewhat higher during the pre-exposure control period than value; for Groups II, III, and IV, During the entire exposure period, N(l% Ng) values for Groups I and I.I were similar, but values for Groups III and IV were at a higher level. Separate t-tests of the pre-exposure adjusted overall exposure means were made to compare Group I with Groups II, III, and IV during the exposure period. These tests indicated that Groups IT, III, and IV were each significantly higher than Group I (t = 2,77, d.f, - 16; t = 4.55, d.f. = 16; and t - 3.26, d.f, = 16, respectively). { m t/m ln/W * tig . STM)) DtFfUStNO W A C itV O f ttfU U N G fO ft 'CAWON MON0XIBS ) Figure 61 _ - Third degree polynomial regression curves for DLgo prior to and during exposure to sulfur dioxide and lead chiorofaromid.e singly and In binary combination. Eacn point represents the mean for the animals tested at the indicated time for the various groups. - 197 - it 3 l I 5 %jl f i i i iI I DUP040Q11588 table 37 ** Continued KIDNEY - t nfcersti ti a] Nephri ti,s Epithelial Vacuplatipn Tubular Dilatation Loss of the Brush Border Nuclear Vesiculation Tubular Hypertrophy Pyelitis Focal Mineralization Glomerular Degeneration Inclusion Bodies Vasculitis Congestion Focal Fibrosis Peri renal Abscess Protein Inhibition tntima Thickening Endothe.1 ial Hyperplasia HEART Focal Myocarditis Endocarditi s Epicarditis Myocardial Degeneration Vasculitis Suoendocardial Hemorrhage Thickened Endocardium Focal Hyperplasia in the Endothelium Intima Thickening Granular Pigment I 0/9 1/9 3/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 3/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 CROUPS 'r 11 2/9 3/9 0/9 3/9 0/9 0/9 0/9 1/9 0/9 7/9 0/9 .0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/3 - 109 - DUP040011589 HAZLETON LABORATOMES. INC. IV. STATISTICAL GROUPING JB - RESULTS OF THE CHRONIC EXPOSURE OF CYNOMOLGUS MONKEYS TO 0,51 PPM NITROGEN DIOXIDE (NO2), 0.51 MG/M3 LEAD CHLGROBROMIDE (PbCTBr), AND 0.48 PPM NO2 COMBINED WITH 0.54 MG/M3 PbCIBr Four groups of animals comprised the second statistical grouping * B. One group was maintained as the control group exposed to filtered room air, one group was exposed to nitrogen dioxide alone, one group was exposed to lead chlorobromide alone, and one group was exposed to,:nitrogen dioxide and lead chlorobromide in binary combination. Group designations used through^ out this section are presented in Table 11. Table 11 - Group B designations Group qnation (No.) Agent Nominal Concentration I (1) II (2) III (9) IV (10) Control no2 PbCIBr NG? PbCTBr 0 0.50 ppm 0.60 .mg/m3 0,5.0 ppm 0.60 mg/m3 Mean Analytical Concentration 0 0,5! ppm 0,51 mg/m3 0,48 ppm 0.54 mg/m3 1, Exposure Concentrations The chamber concentrations for Groups II, III, and IV as determined analytically throughout the study are presented in Tables 1, 2, and 3, Appendix B. The mean and standard deviation for the group exposed to NOg alone after 8? weeks of exposure was 0.51 ppm 1 0,06, The mean and standard deviation for che group exposed to Pool dr alone atcer TG4 weeks of exposure was G.oi 3 mg/tvf 0,27, and for the group exposed to the combination of these two materials, 3 means, and standard deviations were 0.48 ppm 0.13 and 0.54 mg/m 0,24 for NOj, and PbCIBr, respectively, - no - DUP04001159Q HAZLETON LABORA TOmS. INC* Z. Particle Size Determination The mean and geometric deviation of all count particle size determinations for PbCIBr converted to mass median diameter (MMD) were 0.550 u 1.57 and 0.845 ji 1.75 for Groups HI and IV, respectively. Composite size versus distribution log-probability curves from the pooled count data are presented in Figures 33 and 34 for Groups III and IV, respectively. 3, Biological Measurements 3.1. Body Wei gilt Inspection of the growth curves (Figure 35) for these groups indicated a trend toward increasing body weight values in all groups. Analysis of variance of regression for body weight (Table 4, Appendix B) revealed no significant difference in slopes among the groups. 3.2. Survival No deaths occurred in Group I, Group III, or Group IV during the 104-week exposure period. Similarly, no deaths occurred in Group II during 87 weeks of exposure. Daily examination of the animals revealed np signs of toxicity or abnormal behavior attributable to the exposure atmospheres. 3.3. Pulmonary Function Tests 3.3.1. Mechanical Properties of the lung and Respiratory System 3.3.1.1, Total Respiratory System Flow Resistance During Inspection ftrs(i)3 Analysis of variance of regression for Rrs(l) (Table 5, Appendix B) revealed non-parallelism among the groups. The third degree polynomial regression curves (Figure 36) revealed that Rrs(i) values for Groups III - Ill - DUP040011591 Count Diameter microns (>o-)- Figure 33 Particle size distributions (count diameter) of PbClBr, - 112 - DUP040011592 Count biometer * microns (>*>) Figure 34 - Particle size distributions (count diameter) of PbCIBr for the group exposed to the combination of PbCIBr and N02 - 113 - DUP040011593 I yl !, i IO 0 Y VrtlOHT Vs'>( Figure 35 - First degree polynomial regression curves far body weight prior to ?.r-d during exposure to nitrogen dioxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various .groups. - 114 - DUP040011594 [wwiVtA^w-ftlu^NOnwusm 35NVISIS3HMOUvmsAS.M.oiyaMSM-ivioi 1 \ f I 1 t i 3 Figure 36 - Third degree polynomial regression curves for Rrs(i) prior to and during exposure to nitrogen dioxide and lead clilprobromide singly .and in binary combina tion, Each point represents the mean for the animats - tested at the indicated time for the Various groups. - 115 * 4 DUP040011595 "SpifWB ^tyttAZlSTON LABORATORIES. INC, and XV were slightly higher than values for. Group I during the first nine v.eeks of exposure ar.d that they thereafter were similar to Group I. Separate t-tests of the pre-exposure adjusted means for the first nine weeks showed that both Groups III and IV were significantly higher than Group I during this period (t - 4.33, d,f. = 16 and t = 3.92, d.f. * 16, respectively}. 3.3.1.2. Total Respiratory System Flow Resistance During Expiration [Rrs(e)] Analysis of variance of regression for Rrs(e) (Table 6, Appendix B) indicated non-parallelism among the groups. The third degree polynomial regression curves (Figure 37) indicated a similar trend with time in Groups I, III, and IV, while Rrs(e) values fpr Group II remained at essentially the same level throughout the exposure period. 3.3.1.3. Tidal Volume (VT) Analysis of variance of regression for Vj (Table 7, Appendix B), revealed no significant differences in slopes among the groups. The third degree polynomial regression curves (Figure 38) indicated that all groups exhibited a similar upward trend with time, with Group II having slightly higher Vy value? prior to exposure than the other groups. 3.3/1,4. Respiratory Rate (RR) Analysis of variance of regression for RR (Table , Appendix B) indicated non-parallelism among the groups. The third degree polynomial regression curves (Figure 39) Indicated that all groups except Group IV exhibited a slight decrease with time. RR for Group IV remained at essentially the same level throughout the exposure period, - 116 - DUP040011596 tfja.w i/**] lOitt.'mrtuitoiy i*ntMnow MsisTANce- ix h u j io n Figure *7 - Third degree polynomial regression curves for Rrs(e) prior to and during exposure to nitrogen dioxide and lead chiprobromide singly and in binary combina tion. Each point represents the mean for the animals tested at the indicated time for the various groups. DUP040G11597 TIDAL'VOLUMt Figure 38 * Third degree polynomial regression curves for Vj prior to and during exposure to nitrogen dioxide and lead chlorobromide singly and in binary combina tion* Each point represents the mean for the animals tested at the indicated time for the various groups. - 118 - DUP040Q11598 I S TIME-WEEKS Figure 39 - Third degree polynomial regression curves for RR prior to and during exposure to nitrogen dioxide and lead chlorobromide singly and in Binary combina tion- tach point represents the mean for the animals tested at the indicated time for the various groups. - 119 * DUP040011599 / 3.3.1.5. Dynamic Compliance of the Lung [Cdyn(l)] Analysis of variance of regression for Cdyn(l) (Table 9, Appendix B) revealed no significant differences in slopes among the groups. Figure 4.0 shows the third degree polynomial regression curves for the four groups which all increased with time. Although the pre-exposure adjusted means of the first year were significantly different between Groups I and-' III (t = .2.69, d.f. - 16), the fact that Group I showed a large increase at the start of exposure renders any interpretation difficult. 3.3.1.6. Pulmonary Flow Resistance (Rl) Analysis of variance of regression for Rl (Table 10, Appendix B) indicated non-paralleli.sm among the groups. The third degree polynomial regression curves (Figure 41) indicated that Groups 111 and IV increased slightly at the beginning of exposure and decreased thereafter, whereas Groups I and II remained nearly the same after an Inff'al decrease. Separate t-tests of the p-s-exposure adjusted means of the first nine weeks indicated that for this early interval the difference between Groups I and IV was not significant (t < 1.64, d.f. - 16), but Group III was significantly higher than Group 1 during this period (t = 2.66, d.f. * 16), 3.3.1.7. Work of Breathing During .Inspiration per ml Tidal Volume [W(i)/ml V-yl Analysis of variance of regression for W(i)/mi VT (Table 11, Appendix B) revealed non-parallel ism among the groups. The third degree polynomial regression curves (Figure 42) revealed only that Group II began the study slightly lower than the other groups and increased slightly to end at the level of the others. Values for Group III were lower than for Group .1 throughout the exposure period. - 120 - DUP04001-1600 H jO ] DYNAMIC COMPLIANCEttf THE LUNG [CJ)M (I) - .. Figure 40 ~ Third degree polynomial regression curves for Cdyn(1) prior to and during exposure to nitrogen dioxide and lead ohlorobromide singly and in binary combina tion. Each point represents the mean for the animals tested ;at the indicated time for the various groups. - 121 - i 1 .t DUP040011601 TUI MON ARY tO W RESISTANCE Wf ml, ike) Figure 41 - Third degree polynomial regression curves for R1 prior to and during exposure to nitrogen dioxide and lead chlorobromide singly and in binary combina tion, Each point represents the mean for the animals tested at the indicated time for the various groups. - 122 - DUP040011602 [ V> |/(|)m ] Swn.TOA -jyflM I" 8WNOtlVSUS.NI ONiaifl' 0N1H1V3W JO SSQM TIME - WEEKS Figure 42 - Third degree polynomial regression curves for W(i)/ml Vy prior to and during exposure to nitrogen dioxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested ar the indicated time for the various groups. - 123 - DUP040011603 HAZLETON LABORATORIES, INC. 3.3.1.8. Work of Breathing During Expiration per ml Tidal Volume [W(e)/ml Vj] Analysis of variance of regression for W(e)/m] Vj (fable 12, Appendix B) indicated no significant slope differences among the groups. Figure 43 shows the third degree polynomial regression curves for the groups, 3.2.2. Diffusing Capacity of the Lung for Carbon Monoxide (DL^q ) Analysis of variance of regression for DLC0;(Table 13, Appendix B) revealed no significant differences in slopes among the groups. Figure 44 shows the third degree polynomial regression curves for the groups which all increased with time, 3.3.3. Distribution of Inspired Air, Nitrogen Washout 3.3.3.1. Number of Breaths from 80% to 1% Nitrogen [N(l% f^)] Analysis of variance of regression for N(l% N?) {Table 14, Appendix B) indicated no significant slope differences among the groups. The third degree polynomial regression curves (Figure 45), however, indicated that Groups III and IV both exhibited a rapid rise during exposure, whereas. Groups I and II remained at their pre-exposure levels. Since Groups III and IV remained relatively level after the initial rise, their overall pre-exposure adjusted exposure means were compared by t-tests to Group I. Both Groups III and IV differed significantly from Group I (t - 4.55, d.f, = 16; t - 4.07, d.f. = 16, respectively). - 124 - DUP040011604 x s' WORK OF BREATHING 'DURING EXPIRATION fM in l. TIDAl VOtUME [W (*)/il V * - jp .e W m l V j] 1 J 1 ! m* ........ i m 1* ___,__ i-- A ..a a .m ' ^ .................... Q a [`enow i -cON!*6Cj B am .. .......................... 9 ' j ____________ i.......................................................................................... .................................................................... !B ......... jSfogp ir-o/sip^ Npz | ............................ 1.5 1.0 ^ 1 | | C ROW HI - 0.51 ngA? RbCB.j ---s*}/ Rt ....................................... B t - mB * .n,j"; b~ ^' 1............................................................................................ - ..................................... 3.0 . 1 1 I 2.5 2-0 " 1 a\ 1 . ................................................................................. . ......................................................................................... ....................... * J -SOUP IV - 0.<8'ppm N.02* 0.54'iASrra^RbCiBLr j "- * " * * - 1.5 ..... i*' I* 1.0 i . . t - y ... * ................................................ J --------------- ---------------------- ------------------ j1______I_______r -_ _-__--I,,-:-.-_________----L-l----- --L-----1 --;l*_--?_i1.- y1-- 1__`________________ --tt--; i--------------------------J-------------------- 1 T --i ---- ------- i---------- -10 0 10 20 30 40 SO 60 70 80 90 >00 HO Tltofc - WEEKS Figure 43 - Third degree polynomial regression curves for ti{e)/mi V~ prior to and during exposure to nitrogen dioxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 125 - DUP040011605 arartwaswaw'-s m l/ W TM . H j. STPO) BtfFUSINO CAPACITY OF THE UIN'G FOR CARKSN MOWOXldf | B t ,, - Figure 44 - ihird degree polynomial regression curves for DL; prior eg and during exposure to nitrogen dioxide and lead chiorobromide singly and in binary combination, Eaeh point represents the mean for the animals tested at the indicated time for the various groups. - 126 - DUP040011606 !! ij i ?* NUMSM OMttAFHS tO 1%MlTtOSCN [ N ( l* N2>] IIM -WfEKS Figure 45- Third degree polynomial regression curves for N(l% %) prior to and during exposure to nitrogen dioxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. J i - 127 - i i.* I DUP040011607 HAZLETON LABORATORIES. INC. 3.3.3.2, Respiratory Rate Measured During kure Oxygen Breathing (RR') Analysis of variance of regression for RR' (Table 16, Appendix B) showed significant slope differences among the groups. The third degree regression curves (Figure 46) indicated that RR' for Groups I and Tl was similar prior to exposure and through Week 50 of the exposure period. From Week 50 to the end of the exposure period. Group I exhibited lower RR* values than Group II, although Group H was decreasing consistently through the first eight intervals prior to termination at Week 84. A t-test of the pre-exposure adjusted means for the time segment Week 53 to 84 indicated a barely significant difference (t - 2.15, d.f. -- 16). A similar test of the overall exposure means of these two groups, however, was not significant (t = 1.90, d.f. - 16), Further inspection of Figure 46 indicated that Group ITI, when compared to Group 1, had higher RR' values starting at Week 45, A COSUM plot of the time-paired differences between Group I and Group III (Figure 47) indicated that a change in the differences of the mean RR' levels occurred at Week 45 of the exposure period. RR* data for Groups I and III were therefore separated into the following time segments, 1) the pre-exposure control period, 2) from the beginning of exposure to Keek 45, and 3} exposure period from Week 49 to the end. A t-test of these pre-exposure adjusted means for the last time segment indicated a significant difference between the groups (t * 2.94, d.f. - 16). The earlier time segment was not significantly different (t - 1.65, d.f, - 16). A similar test of the overall exposure means of these two groups, however, was also significant (t = 2.61, d.f, = 16). - 128 - DUP040011608 * S ftg A rO *Y RATI [( b u r in s bu>< 6)'SIV Irw th irrs ) US' - trW H w M in ]- Figure 46 - Third degree polynomial regression curves for RR' pr'or to and during exposure to nitrogen dioxide and lead chiorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. * 129 - DUP040011609 \ 4 i Figure 47 The time-paired differences between the cumulative sums of RR' between groups I and III (control and 0.51 mg/m3 PbCIBr), - T30 - DUP040011610 HAZLETON LABORATORIES. INC. A t-test of the pre-exposure adjusted overall exposure means between Groups I and IV indicated that Group IV was significantly higher (t * 3.69, d,f. - 16) throughout the exposure period. Similar tests comparing Groups II and IV and Groups III and IV revealed that Group IV was significantly higher (t = 2.22, d.f. = 1.6) than Group II, but was comparable to Group III (t = < 1,64, d.f. - 16), 3.3.3.3, Cumulative Tidal Volume from 80% to 1% Nitrogen [CVy(l% Ng)] Analysis of variance of regression for CVy(l% Ng) {Table 16, Appendix S) indicated no significant slope differences among the groups. Figure 48 shows the third degree polynomial regression curves for the four groups which increased with time. Values for Group III were slightly higher overall than Group I throughout the exposure period. A t-test of the pre exposure adjusted overall exposure means comparing Groups I and III indicated that Group III was significantly higher {t = 2,24, d.f. = 13.7) throughout the exposure period. 3.3.3.4, Tidal Volume Measured During Pure Oxygen Breathing (Vy`) Analysis of variance of regression for Vy' {Table 17, Appendix B) revealed no significant slope differences among the groups. Figure 49 shows the third degree polynomial regression curves for the four groups. 3.4, Hematology The group means and analysis of variances of the various hematological variables measured are presented in Tables 18, 19, 20, and 21, Appendix B, No consistent trends were noted in any of these variables which remained within normal limits throughout. Random statistically significant differences were seen, but were not -.onsistently related to the exposure conditions. - Ul - DUP040011611 rvna / TIOAt v a m t TO 1% NITROGEN fCV, [ ! V N j ) - r if t a ST P ] Figure 48 - Third degree polynomial regression curves for CVjO* l^} prior to and during exposure to nitrogen dioxide and lead ch 1 omprosiide singly and in binary combination. Each point represent* the mean for the animals tested at the indicated time for the various groups. - 132 - DUP040011612 x T10AL'VOtUMEi(Dvrii'a'Pw 0*ien B?othJh9) V j 1 BTFS]- Figure 49 - Third degree polynomial regression curves for Vj* prior to and during exposure to nitrogen dioxide and lead chldro.brgmide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various grouos. - 133 - DUP04Q011613 HAZLETON LABORATORIES. INC. S-. 3.5. Clinical Biochemistry The group means, standard errors, and the results of the analysis of variance of the various clinical biochemical variables measured are / presented in Tables 22 through 35, Appendix B, Scattered statistically significant differences were noted; however, no trends were seen in any of the variables. Throughout the study, the group mean values fluctuated within tne normal ranges.of these variables. 3.6. Arterial Blood Gas and p.H The group means and standard errors for the blood gas variables are presented in Table 36, Appendix B. Examination of these data did not reveal any consistent trend with time. No apparent exposure-related changes were seen in any of these variables. 3.7. Terminal Body Weight, Organ Weight, and Organ Weight as a Percentage of Body Weight The data of the terminal body weight, organ weight, and organ/body weight ratios for Groups I, II, III, and IV are presented in Tables 37 and 38., Appendix 8, for males and females, respectively. Single classification analysis of variance revealed that the brain weight for the males in Group IV was significantly lower than the males in Group I and that the adrenal weight for the males in Group II was significantly lower than for Group IV males. Adrenal weight and adrenal weight/''body weight ratios for the females in Group III were significantly higher than for Group II females. Adrenal weight/body weight ratio for Group III females was also significantly higher than Group IV females. The liyer weight/body weight ratio for the females in Group II was significantly lower than for Group IV females. - 1.34 - DUP040011614 HAZLETON- LABOHA TORIES. INC. 3.8. Histopathology Summary ^ A detailed listing of the microscopic alterations seen in the lungs, traeheas, livers, kidneys, peribronchial lymph nodes, and hearts from the animals in the Control and exposure groups are found in Table 39, Appendix B. Microscopic alterations related to the exposure to PbCIBr were seen in the kidneys of the animals exposed to 0.6 mg/m of PbCIBr alone and of those 3 .... exposed to the combination of 0.6 mg/m of PbCIBr and 0.5 ppm NOg. These microscopic alterations were characterized by varying degrees of degeneration in the proximal convoluted tubules. The epithelial cells of the proximal convoluted tubules were slightly to moderately vacuolated, and there were varying degrees of loss of the brush border and of nuclear vpsiculation in these cells. Acid fast intranuclear inclusion bodies were seen In the epithelial cells of the proximal convoluted tubules in seven of the nine animals exposed to 0.6 mg/m PbCIBr alone and in nine of the nine animals 3 exposed to the combination of 0.6 mg/m PbCIBr and 0.5 ppm NO^, No exposure-related microsocpic alterations were seen in the lungs, livers, peribronchial lymph nodes, traeheas, or hearts from the animals exposed to.NGg alone, to PbCIBr alone, or to the combination of NOg. and PbCIBr. A moderate amount of brownish granular birefringent pigment was seen in the macrophages lining the sinusoids of the livers from the animals exposed to Q.5 ppm NO,,. A similar type of pigment was seen in two of the nine animals in the control group and two of nine animals each in the groups exposed to 0.6 ihg/m0 of PbCIBr alone and the group exposed to the combination of 3 0.6 mg/m of PbCIBr and 0.5 ppm NO,,. The etiology of this pigment was not demonstrable in the sections examined. - 135 - DUP040011615 HAZLETON LABORA TOfllS. INC. *V 3.9, Summary The inhalation exposure of male and female cynomolgus monkeys to 0.51 ppm NQ2, 0.51 mg/m^ of lead, chlprobromide (PbCIBr), and the ' combination of 0.48 ppm H02 plus 0.54 mg/m PbCIBr resulted in a de+arioration in the distribution of ventilation in the animals in the two groups containing PbCIBr, The number of breaths to 1% nitrogen measured* during pure oxygen breathing was significantly elevated in the animals in both groups exposed to PbCIBr, Ho increase in the number of breaths to It nitrogen was detected in the animals exposed to 0.51 ppm N02 alone. Respiratory rate measured during pure oxygen breathing was significantly elevated in the group exposed to N02 alone during the latter half of the study only, but was significantly elevated throughout the exposure period in the groups exposed to PbCIBr alone and to the combination of PbCIBr and NG2> Microscopic alterations related to the exposure to PbCIBr were found in the kidneys of the animals in these two groups. These histopathological changes were characterized by varying degrees of degeneration of the proximal convoluted tubules. The epithelial cells of the proximal convoluted tubules were slightly to moderately vacuolated, possessed irregular luminal borders, and in several areas, had lost their brush border. The nuclei of these epithelial cells were yesiculated and many contained acid fast, intranuclear inclusion bodies. - 136 - DUP040011616 HAZLETON LABORATORIES, INC. Body weight measurements made on both the control and exposed animals throughout the exposure period indicated that the animals in all groups increased in body weights. Analysis of these data did not reveal any significant differences in the rate of growth between the control and exposed animals. Terminal body weights, organ weights, and organ/body weight ratios for the control and exposed animals were compared. No meaningful differences were detected in tbess variables between the control and exposed groups. Hematological, clinical b xhemical, and arterial blood gas measurements were made on both the control and exposed animals pre-exposure and periodically throughout the expo ffe period. No trends were detected in any of these variables 'n the expend animals. No meaningful differences were detected between the cont.'o1 *.;.d exposed animals. - 137 - DUP040011617 4m>/HAZLETON LABORATORIES 4k Appendix B - Data compilations and summary of statistical analysis for Statistical Grouping B, comprised of the following* Group I - Control, Group II - 0.51 ppm N02 Group II.I 0.51 mg/m3 P.bCIBr, and Group IV - 0.43 ppm NO2 + 0.54 mg/m3 PbCIBr. ! i - 138 - DUP040011618 Table 1 - Monthly means and the grand mean for the analytical concentrations of nitrogen dioxide for Group II. Date 1/12/69- 1/31/69 2/ 1/69- 2/28/69 3/ 1/69- 3/31/69 4/ 1/69- 4/30/69 5/ 1/69- 5/31/69 6/ 1/69- 6/30/69 7/ 1/69- 7/31/69 8/ 1/69- 8/31/69 9/ 1/69- 9/30/69 10/ 1/69-10/31/69 11/ 1/69-11/30/69 12/ 1/69-12/31/69 1/ 1/70- 1/31/70 2/ 1/70- 2/28/70 3/ 1/70- 3/31/70 4/ 1/70- 4/30/70 .5/ 1/70- 5/31/70 6/ 1/70- 6/30/70 7/ 1/70- 7/31/70 8/ 1/70- 8/31/70 9/ 1/70- 9/11/70 n xppm 20 0.4875 28 0.4843 31 0.4997 30 0.5343 31 0.5277' 30 0.4790 31 0.4855 31 0.4813 30 0,5090 31 0,4842 30 0.4787 31 0.5023 31 0.5264 28 0.5093 31 0,5077 30 0.5147 31 0.5365 30 0.5113 31 0.5339 31 0,5116 11 0.5073 N * 21 X = 0.51 S.D. * 0.06 S.D. 0 0477 0.0813 0.0561 0.0710 0.0553 0.091T 0.0721 0.0471 0.0575 0.0828 0,0734 0.0794 0.0670 0.0468 0.0439 0.0324 0.0336 0.0251 0,0434 0,0288 0.0210 / - 139 - DUP040011619 Table 2 - Monthly means and the grand mean for the analytical concentrations of lead chlorobromide for Group III. Gate 5/11/63- 5/31/68 6/ 1/68- 6/30/68 7/ 1/68- 7/31/68 8/ 1/68- 8/31/68 9/ 1/68- 9/30/68 10/ 1/68-10/31/68 11/ 1/68-11/30/68 12/ 1/68-12/31768 1/ 1/69- 1/31/69 2/ 1/68- 2/28/69 3/ 1/69- 3/31/69 4/ 1/69- 4/30/69 5/ 1/69- 5/31/69 6/ 1/69- 6/30/69 7/ 1/69- 7/31/69 8/ 1/69- 8/31/69 9/ 1/69- 9/30/69 10/ 1/69-10/31/69 11/ 1/69-11/31/69 12/ 1/69-12/31/69 V 1/70- 1/31/70 2/ 1/70- 2/28/70 3/ 1/70- 3/31/70 4/ 1/70- 4/30/70 5/ 1/70- 5/ 5/70 JJ 20 30 31 31 30 51 30 31 31 28 .31 ... 30 31 30 31 31 30 31 30 31 31 28 31 30 '5 X mg/m3 0,8570 0,4743 0,4565 0.6022 0,5773 . 0,5074* 0.4286 0.4638 0.4752 0.6154 0.5677 0,5147 0.7770 0.5503 0.5597 0.5010 0.4737 0.5352 0.4930 0.3871 0.4052 0.51 DO 0.5561 0,3070 0.1080 ft = 25 X = 0.51 5.0. = 0.27 S.C, 1.0552 0.6379 0,3048 0.1088 0,152.6 0.1497 0,1944 0.1819 0.1339 0.7173 0.1515 0.2131 0.1710 0.1740 0.2216 0.1545 0.2049 0.2722 0,0363 0,1065 0.2503 0.3669 0.2526 0,5232 . 0.0295 - 140 - y DUP040011620 Table 3 - .Monthly means and the grand mean for the analytical concentrations of nitrogen dioxide and lead chlorobromide for experimental Group IV Date 5/11/68- 5/30/68 6/ 1/63- 6/30/68 If 1/68- 7/31/68 8/ 1/68- 8/31/68 9/ 1/68- 9/30/68 10/ 1/68-1G/31/68 11/ 1/68-11/30/68 12/ 1/68-12/31/68 1/ 1/69- 1/31/69 2/ 1/69- 2/28/69 3/1/69- 3/31/69 4/ 1/69- 4/30/69 5/ 1/69- 5/31/69 6/ 1/69- .6/30/69 7/ 1/69- 7/31/69 8/ 1/69- 8/31/69 9/ 1/69- 9/30/69 10/ 1/69-10/31/69 11/ 1/69-11/30/69 12/ 1/69-12/31/69 1/ 1/70- 1/31/70 2/ 1/70- 2/28/70 3/ 1/70- 3/31/70 4/ 3/70- 4/30/70 5/ 1/70- 5/ 5/70 PbCIBr NO? n X S.D. mg/rad X s.o. PPm 21 0.6938 0.4009 0,45.90 0.1525 30 0.5313 0,2659 0.5293 0,0818 31 0.4229 0.2202 ' 0.4538 0.1253 29 0.6069 0.1938 0.4386 0.1197 28 0.7018 0.2171 0.3900 0.1651 31 0.6332 0,2762 6,5052 0.1337 3.0 0.5513 0.2039 0.5007 0.1230 31 0.5655 0.1176 0.4726 0,0.624 31 0.4755 0.1776 0.4890 0.0638 28 0,671.8 0.6879 0.4711 0.0686 31 0.5558 0,1991 0,4606 0,0657 30 0,6893 0.2610 0.48.26 0.0579 31 0.6881 0.1563 0,4771 0,7721 30 0,6783 0.1021 0.4770 .0,3911 31 0.5455 0.2489 0.5132 0,0768 31 0,5739 0,1936 0.5206 0.G479 30 0.5007 0,2448 0,4850 0.0730 31 0.4135 0,2207 0,4690 0.0927 3.0 0,4223 .0,1588 0.4597 0,0653 31 0,4326 0.1230 0.4619 0.0769 31 0,5581. 0.2428 0,5187 0,0726 28 0.4925 0.2157 0.5182 0.0502 31 0.7639 .0,6775 0.5100 .0,0486 .30 0.2280 0,1403 0,5203 0.0335 ,5 0.1760 . 0.0279 0,4980 0.1743 N ^ rIL.-J X 0,54 S.D. - 0.24 N 25 X 0,48 S,D, = 0.13 - 141 - DUP040011621 J4Z1 4-> *fxii >JnZs uf! u* rtco sBTo*~ U jQ a. 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Cl o* U5 3* o Oo o 0O o fVU) CD *"T* H4 O M --1 s-- 03: l-r< o; tr DUP040011623 a ta N O gj nd ppm a tio ,5 1 It & m # in g up Ie xp - ir 0 I LO * n uu 3 CQ - *o U *-- j Q L O CL (TJ S+J> +JCO w r: E *r O -"v, MO O) af s- .11 3* * * tn o .* -r-- 0.0 4- o . o+ B S4K3 CsJ 4-> O c/s z: >> -- tn c* E G EX >*r- CL S- 3 O O CO +*>~- ^r SSii r- . s- o o - ai tnndj .ux >. S-, 44 I-* I-!-* CL UJ a 13 +* O OT3 L +J OJ CD 01 -r- XI O 5- C CL rt* <n E r ^ca idCQ'J C .O RJ 0)0. c: r-- *n*CO j o. e O 3 -N -r- o in +J s~ u tn CD r*' 4*> *-- LT so rj +> o o Wi?r* 44 ( 4- V) O rrr *- M >} S-4-3 03 S/> O. Eo E i- O 3,0 L V>: 4~ LD ( to Q> 43 H* 2 O sM tS) /> LU 03 CD LU. 03 .03 <C iii 32 M U LU O LU O 32: -< M .03 >*. Lu O xn 1-4 co >* __ 1 <c : <: to o *A vl - Q. i O*. U_ CO i 4 toI Oo X CO CcMo CO CM in : oo CO M Ii oO XX to CO r>* s*3f* to o o\ CO 4- CO ~p O -*-4 H <C *--l (/> 03- < LC > O <a CM o\ 00 CO CO co co 144 IN. xO in in oo 8 *2 o o Q >1 to > o o o o LU CO co COCO' CO CO coco 14 1f 1 1. * 1 0.0 0-0 oo oo r-- r-* .r-'-T-- r^- r -- XX XX Xx Xx o CO o o o o o o O O SO o w CO *-" cn co :co in .LU a: CM iD rs .r-- **+-*$ LU. .1 +1 -H +1 +i oi *oto to to to to rs.%to .UJ ii iI I1 i T coo2 *o*-- o(*U o ,r i---* oo r* r-- .0.0 r-- - >- X x X X X X X X so_J O a. CJ f- Kj"lN ro at to N. ,cn CO CD CM to to u> O) l u LU r~ IS to CO IN to to \o W0co3 --i o +t +1 -fi +1 LU Q 03Q o ^ *fS" o 1] 1 1. t 1 t. 1 oo oo OO oo r-- r- r-- r- >-! r-- r-- o M CO >co CP LU XX r* to O dM XX ittf* r-- oo XX ego o IN XX O VO o co .03 CD cM co CM CO to ; CO CM LU t 1 :i I 03 +1 44 +1 +1 CO f\| C" to CSI CM CM CM oQoo oOoo o o o o <x. -N +t . to CM "Cf <o *3oooo oooo to CL. ID -1 H4 > o Hr *--* CO03 4-4 DUP040011624 .4<5u - +4 <1- . o To?j "Oc: (A AS *r- fol.l s<-? CQ Or- uo a 0>3CaO- ' Cft E C^ r? 1 C1 3o>.i.e' O*-- - GO O* ' ' O iAt 5 | O ' *T +4 M .C/I `HI *rr. +4 O. ' * 3 3 4J O vt sco .& o* 4-*' CM O S 21 4# Xxt*f iEQ. ' : ni Srr- 3 lO # ** k o > o . CiQ, *-- O <9, m XI :'O .M Q* L> O-CO 3E Mo- oy- Eos giCO- p*3 Wfr-.io :> O . i--<0 4s-. o fi= = + AS O .r-r O OCM os ?r u *-< E 44 a, 3t.to' ; a. 44j *4 ; iO- 0 *0**" to o ' o :o q> <x 3 0 SV> '4- p I rs. a> XI ns ..if) o v| 1 1 CL oz >-H GO cn 1 LU tx CD LU DC D : Ui --< ' ' U1: O I1 LU O .2T C cc <c Lu O GO *--< 00 >- <c Sr 'S!: |M U- 43 O 1 fw 0 r-~ CM O jT" XX GO s -^4* to fS- r-- CM CM tf) !p O cn X X GO CM 00 ** *4* CM 0 * CM CO 4- 00 LO T3 CO 2E O *--4 f-- E T v> cc r O - <>=4: V* <D A3 u. f-L > 0 J 01 L- Q UJ A3 0 Xu -o. Q 0 1 -c P 0 O 1 00 2 LU Mti3l <7 r>* in OO 0P COCM CO CSl cn CM X CO VO O LO GO *4- p CM .a: CO n p co CO Ui -< CJ lu lu Ui. into LOGO CO L0 * co tn 0 0 i . 1 i 1 -1 1 1 OP op PO -op r-* r*?" i-" r" *-- c-- 2: 0 1--( X X X X Xx X X 0 GO CO*#* CM CM C>*f 0 LO f-- CO Q O cp co vo p .UI C* rr* CM p-- GO CO CM r>, ; CD 1 LU -H +1 +1 rH QT . - --. -J < ST O 2 D--1 O A. CO <0 sf.co CO co CO Ui 1 1 1 t 1 cn OP 0 0 PO OP rr r" IT- rU r-p pH .r-.f-* +i 00 (U XX VO CM 54- XX .00 CM r>. co XX Ch . 0 co r~ XX O KT CM LU Csi .d* rs. n q ^4* .r-- ^ LU as. CD 1t -H +1 +1 Ui Q U. LU .0 O ex HH -O rp* r* CM r- CM -- j~ 1. 1 1 il i 1 1 |. CE 0.0 O O OP O O h-- * *--* r* r'*' .!*? r? r-- q cn CQ Xj J CSL CD LoUc XX ; ;; n CQ CM r-- +1 XX .O r~" fs, c>i +1 XX CM co rs. P-- Xx rr* VCT> N. p^-f-r 41 - 145 - CM -P AS M' fs <0 CM CM CO -H co r." . M* CO to CL E3 O !--a 0: CD n VO rr- t. t ! O. O r--~ CO r-* do CO CM -- .*-!* M' D> M DUP040011625 0.51 nrafnvS PbCIBr, and. - 0.51 ppm NO,, Group* Group PbClBr. Table 8 - Sunwary of. s ta tis tic a l analyses o f re s p ira to ryI I ra te data fo r S ta tis ticIaI Il Grouping B, comprised to O v'i >V<*Ui a. *r a> co IS. to # P o - P CM to o Csl co cCMo co oCM\ U ontrol, mg/m3 -C 0.54 l-lo0.w i4n8g :ppmGrNoOugp+I O oco itUnni oUcci CC. <CC NO Op*. Ui c?nsr ctoo CM tn UCi<zcJi C<Cc coo o in in wV> IptSo >- to <<zcc. H*o- CO CO in .00 z O; <c o--c :*ca: 5=* ai r-- oU- t-- *3 UU>J iQornDi t_ *3 ai_ coz jrr 0 i" (0 ** aHI so~ u u. UJ ~ 146 to. X cn CM tn CM 0> <o to 2h UJ v> CM *-- CO co Mto j u. u_ Ui UI to tn in tn to to to o 1 t i i. i i 1 i o OO T"" oo r"^ r-- po f-* fW op f-- t?~* X X XX XX XX VI p CO to IS to Ok VO s. o VI to 00 to f-- co r> to 1-- Uiosci If} jr-* r~ CO r~ CM r^co LU .cc +i H +i Ui ro co CO <o CO CO CM co ti 1 i< l\ o o P o .0.0 oo -VI r-!* -? t-*- r-* f-J- r*^ X X XX XX XX Hoa. VI u> oo co cn Cl s. CM coco O CM tn co CM co ui Zu j 0> CM CM CO ** ?r I 11i oOUJ H *1 +1 UI Q oto0 r~ r-r CO ii i1 ti ii z O o O o P -O p o .o .r-* r-?* r-- *-!" r-- to VI ca Ui ctoc UI cc Xx vo co .1-- CM CO -H XX co to CM CO "d" FI- +1 XX NO to co CM +1 Xx N> r- O iO CM to CM r-- f> o =M* to +1 CO a? o *tr to Q. :o *-* o -- CO* co CO o * r* CM +1 +i m GO <P GO ,o% CO CO t-- M *--1 o f she fo Group IV DUP040011626 u CL as .O' . ir- 04 m o D w +* G ns a. +* a. m os4--io0* ns I .*I : --t *u^ ^ c ; co c: 3 r:j ou . r~ S--jQ . CD CL c: *< *3 4J rn- = O -x 4- &*. Q> +c * E oAf oo'sinfr iiGs I O CL E D. O] 0y; 3o- 0z'- O LD S r- CL CL US * 55=p*OsC.*Or 30 5*^ O Or- I . 'r-- U) Q> <y ih- *-- M-i: r>-*xq:j 3CL O CUJ m05* .ToO T33 o .or ns r* !.</) +J .* m u s~ s~ CL CD +a*s1 j Jo rr- o a. M U xi 4o-XcOnfOHx >> c c> ns5-"- s ; S r ; o in .in3 :CD|:-JL- o* i o - .co U. CO o\ O o> a O : . OC < rr- CO oo o CO co in o fr-* CO IS. in O' CO >- z: -<C 00 AO CO o I-- iA<c *--< ' .<aC: 5) '* o in AO o in <o o. CO p"-- 0 tU1oMu-4. LOOU to to AO in ID AO AG AD I oo op rj o io. p r-* r-? r-- r-i- /-- r-" .r-- r-- XX XX XX XX in in o o cr pf<0 cn r-- O .c0a-r0s 0-0 CM p LU QCD1 *-- AO CM t--" AD..CO fOP>. o:LU +1 -H +1 CO COCO CO CO CO :sro Ui in li PO 1:OS p 1 1 .1 1 0-0 p o -*.!-!" r-* <?- p~f r-f* >- +i: X X X x X X X X LOUi .2: 03 pv. a? p pco mro * CM CO r- -- CO > r-- 1UI LU r~-- r-- CO M- r-! LU --i ;i i1 ac O <D 1-4 LU LU +1 -H +1 +1 a U. LU Qo rs o JM CM . r~ CM CM CM CM CM i i. I 1 t. 1 11 oo O.o P O Oo r" r1!- .r* .r* AO X X X x XX X X in UJ CO AO O CO ; m in r-- txL to in CM P CM AP p IS* Ui< r--* f-- si* AO r in jr cc +1 +1 +1 +t 547 - p ccno pinn . VD vt opO o +1 ii +! +i t-- .0 .o.a> PO t-i. AO ID in AD in iOCSocncD3. DUP040011627 CO & cp gt OS' .13 *r*. r- LTS a. # aa 0 &: ; t! M *" 10"** 0 *i~> CL 4-ft:: nj Vlt 0 i +3 C3 m* 4* m CO CM s,, -<z4Qz ,o.; _ B . CL pl G' L *faflijn- o01-' CI US 4Jm w<*r.t!,:m :C.!<O VJ Cl *-- oi ns O S- O JZ s- a. 3:0 o <0 r* ** Es *s >iO!-2> JnTMs -Lc*: <* c0 oOin Bo r~ I =J + CLm CM <Of- 'iCjSLtOe wau'.. t/j is*.. E= o> a., <A CL. r>r--tfV c*n_CMO* c c: ' r.iO-m"*' -- c> <0 *??* Or- rQ-tm>* 4- +- C/ i~ <51 .3X 4-> x: o ITS -frS> . 4-> O V? V O X3 40*0 C3 Cl: t-V- u ns cQ S S-r-- S so i3n OuaJ3 1 O .0 . 03 CO Q v* vi os >. a. u. CO 22 o &> *-4 </> </> a:CXl CO UI a: If a: o o <c Ui 8CM 8CO 1x1 O z< *- 02 <c < tCO r*- 10 a u. t/i V) IS CM CO tcoo as zc; :<c. co to CO c0 cc < fp *r* uJ its i- > a0s1 o cc o CO a3. 1 c o Uos5S4--- eCMo tOo J*#O* tl"o#* 0 0 -O Q CM <0 CO CM OS CM 148 M3 SSf is. 1% XO O 0 O H* , cp CO to at 0 a? sJ- 0 CO o.Ui ca *-- to r- to co in to tp *1 1 Ui a: -H +1 H +* ui IS. tO to to is to to to 1 .1 i i . 1 1 1 . 1 CO OO O O O O 0 0 r--.ri- r-* r--* r- r-- p-- rr- a.a X .x X x X X X X o **-04 Oarr- CO 0 CO r-- ss is. CO tO is fs.-^- .os tn 0ui U4 . .* UJ coco toco Is % r*- cr> .OS' l CO UJ U. +f +t +1 H Q U- .Ui Qo cs: :o to 3- to i1 1i I! 1i OO 0 0 OO O O t*-- .r* 1-- -?- *-- .r--`.r^* to to cd ui az CO US OS XX .^HCO cow IS CO +1 Xx q on CO <3\ *J*CM t +1 XX 5T CM a* co co co +1 XX to ^ 01 0 co*t 1 41 0to CO to CM os CO cn CO O00 0O 00 pO 00 cC +i fl +! 41 -to in as CM CM CM CM 0 P .O 0 0 O P 0 00 a. ' O C t5 DUP040011628 u ai i cd 15 .r"* 3U rrm w J3 >O' o.' <X am r* O S *OC3 D1 p("4 H r- a UfJ H s- . W.& <a o& ' + au Al SZ I o O z. s****,*"""! S o.i. j. 3 a r* 'Q . ' mCL 5~ KCOt )G >. r- .O Ocr os= t *i -- 3> Jn-> 3" t o #-!* n. . r-- 33 D O O 3 *t* ST- CU a> +* ; :-o r s +*> q o its J3 O * iM" *0 CO O CL?-- V3 O -i<: *i- ^3 s.. s- a* .O' O- ,43- S(oj *S o cm ** tM>a/tik Ic<X0J)1--0 I--fl'j a-r- Q C3 I (0 O s*. >- r(-1$C3>M- ,o>-- rr RS 13. M U 3 in <*- Q r- -M ** V> <3 ftf 4#'-** * to AS .CM 4J O U LO 23 O 2- H >* Q Oi- Ci. <a g 4 .u> 3 to itO "53 O o t/i Vi QJ >* CL o fc-4 <n GO LU 03 CD iii a a: 5C UJ UJ -O a 'St' O* -r-- CM IN CM Q- 03 * * m < O Q> o. in m .<3 .04 </> -CO CO M CM GO >_J <c z <c CO *- LO T3 CO .s c VI p r* *- r~~. ftl 3 r- I-- I*.-- ' > .10 QJ 5- 33 UJ o a_ t03 > O to c u ino o sLU to C\j \Q SO CO *3* { I 0. 58 29 t\l co >* <r> CM CO 0.51 ?0l 10" * x x -1,06 4.30 2.91 x 10 * 6.83 X 10" 4 1.81 x 16" IT) to to oi to & O *o -Q UJ o o CO in UJ 03 CD UJ .03 O z >o a. UJ LU 03 CD MJ Q a 03 to CO m to to to t( ii 1i o o 0,0 o o r~ r--,rr- XX oo ,ch to Xx f>V O CM O XX oo a> r j * to f>. to +t +f +* UJ sf <r> CO J1 ii (1 in OP o o o o *-- +i XX in r>-.o iO<NJ JOT CO o o :IX> tO to rs r--T>. r-- CQ +i -fl +1 Nl 04 04 CM CM CM OO oo OO r-r" r-- r-r .r-- r >S H XX X X in in o r>s Ifi.r- Cn . ^ UJ O C!> co to in in 03 o 04 04 CO Csl fN.cn LU 1 J t .03 -H +i +j 149 o CM to P co CM CO CM oOo O H +1 +1 Kf CO o o co r-r- m io m XT in a. 33 O 03 CD; -8,65 x W"; DUP040011629 0 a. s a. o 1-0 id O9 > l4 * ?* ,* a It* CCI a CLp~ p- 3 O r-*&3 ' S CO *H S'r- N, mom tt :sz^r o o in 4-U +J o S 8 a+ xCX aoCM ' .O. . cii. g ca a w ' i O. a T3J C*E*<COr 0>r-- O E 3; r*"0 I XZ c-- 4-*r~ is* (9 Q M 01 4- J- ' Q. Q 01 3 -E O 4-> $- O .( ' ^ 0*0 ac OS; T<tot3s rtf * 4- f- a o a co wguCXp-- o j o .a w u a. >nr-i d*>^0 Coi,cHn <-- r^r <CJ CL*-** U 3 W> r O * (A Cs5- o i* 1 &B* V,<Q tm---44 tfi *4~r*> M 40-- *4P^->* 3COL iat>s*+i<bjo oa || a <M tsn* 4o--Osi f9 F-*- to o Vi a. r>. co .s: o -- </) (/> Ui a: O LU tX r* 14 a: O O <C r-- n- XX CO to LO LO o <3- Ok cO CO LU o s <c * --< cd CM <c O oU~ X t>+ CM CO -o o .r-r CO c zz <; CO 4- LO TO CO 2 O CX -fe* fd r-- > rtj 01 ua UJ as o CL a DC I o .oo c o aa to at to 05 <o w d CO Ok CM CNJ ,UJ aa> Ui o o zz -H CO tn LU or CD LU ix. --J 1 <c M is: o 2 >~ __1 O a. ai ai or LU r*-x cn CO CO CM CM CO &0 O 0 . to to to to to to t>.vO I I I it l1 o o oo o o o o r'- *-- p-?- rri- r-- r-- r*~r~ X x X x X x XX ao O'-flS* oo CM * 0.0 p> m so co t oo CO #-- csi i oo oco >1 *3- CM +1 +1 +! -H sf,0 O r~~ r-~ *$ a> *? Oo *0*0 it oo rp-.r-- r-- rr-- .p- XX 0 to r> in oo Xx O to O co N M* XX o> r>co co XX oco f^" 3* 41 41 41 H KM CM CM CM CM CM CO CM 1 t. i i I :l 1 1 OO oo oo OO ;r~ .r-- I--- ` r-- .-- r" XX XX XX XX to 0 to to CM r? 1 +1 *a- co CM ^s- ~" i- t 41 Lb r>p-^ to CM i--* 1 4f tn co m co Nr^ i 4! 150 LO CM LP CO r-- r-- -* a Ooo O rl 41 -H 41 to 00 CO CO rv r^. \a .m p--- to CL o.. or is. * OUP040011630 fo r S ta tis tic a l Grouping B, composed o f the fo llo w in g : Group I - C ontrol, Group - 0.51 ppm Table 13 - Summary o f sI ItaI tis tic a l analyses of d iffu s in g capacity of the lung fo r carbon monoxideI I data N02, Group - 0.51 mg/m3 PbCIBr, and Group IV - 0.4S ppm. NOg + 0.54 mg/m3 PbCIBr. W> o vi QJ co co 0 wvaCiU--/Dz>J< 0LU1 0I4 0I4 -<C 'r-- r-! LU XX OU. r-- CtoO VvOo co to svi U*LscUs- *<o--c: o CO C>O- RT VO oto =C co CO r0--% o -o<5Ti ,u. O LCcdUJ; atIo. rotoo1 -c '2oS Ca oy u o I co rt>o* VGOO tVoO P . p CCOO CcMn CO CO 0C4O {Lz2U CM X too C>O o LVOQ :0 . rs GO m P GO oCO 41 O w CJ u*-.* u- LU vo vo rv !>> f->. O . opo fi ii Oo ii 11 ao PO r" ,r" * * r* .*-! Q X X X X '< X X X 7.50 7.70 CO o CM CM Oo VO vo vo ,o o o> o ccLU ,r-- r- cnvp CD ocLU -fl H +1 -H l o in ^4* m to LU ti ii 1 -1 ii VO O o p O O O pp r1!* i-" ** i--** j -- r-- +t X X X X X X X X t--'CO cn o ro o vo vo O co P *}* co CM r- -CO 25. LU ; *-- r-- CO O'3f CJ i 1 +1 +i +1 +i OLU. QQ LU .8 O CO .00 #b?"* bH-- CO CO foim1 . ot . CO CO Iof* f*~* coco -rO- Oi-- * 4 to Xx xx xx XX CO UJ CCD Ua4: -o<r "po->s* CO CM +1 O CO P to N*t H CO tcoo tot ''*54* +i rtf*-00 o co CM *0 1 H CM rpo p tn o P pPoo H -rl -+i rri CvOM in P (Ns, vO Cr>M- bbb CD- 151 DUP040011631 ,C5 - Ol c A. 3 *N. O Ol s t r-- tn t oo 44>' I 4^ w S --* oo a. 3 *0- VQ 4- C9 AS * 4-4 CM o# O22T S01= o. cn L r~ CO TH5 J! :C# * 0'>>4 ~ +* CO . '-X#p-- utf:i o.3 jOa ftJ <.t5- a. fl> co S. JO 4- r3a--- -s- a> O -L* j O; #' a- ooin* jo o I 3 * C *Ll CM 4-- 0.0 0 02 4W1.s0O-' a__ tf> CL > i-- ^ --oo j oisr C C,; * rtS t w O .. 3: tf-- O I fd r-V ! <>*-- O'*-* l-> 4t/t Ol - 3 0J-PO LO < 4- O; OT 4- C 0 tJ 3 01 2>> VI idu *(f.-CQ K CLrE" 0 :r Oj :i C/J O L 1 ja U> O v| Cl o r>% to (Si LU oc CD UJ oc oc '!< LU . 2 U. o LU o a: i *c o -{/> 1/1 >-. X izr. X CM CM OO o O <d cn co ; to oo tn m CoM o .10 <31 tO CO r- CO op o itn3o1 to *r .ttcon-** No tn LU o to to to to in to to m I I I4 4 I I I o 0.0 0.0 00 o o o2 M XX Xx X X XX o 00 oo oo o o o o ,40 ! - CM x tn 3* r>v CO CM LU . CM tO to to <n n* -- M> o LU OC +1 +i G +1 o LU <Si CO I 1--t OO cin co i qo co <n >o io co 4o Io. 2: rr* r-* r-- r*. t--~ r-- +1 o r. XX XX Xx XX coco o co CcaO CO ; VO to o rt--- n -.cr LU LU .f--Crv r-- rv *s3" Cn . CC o +iCD +1 -^1 +1 CM.r-- p. ^ ,p~ r-- ri*vpp t I t i 4 J. t t 0.0 o o o o O o pj - r-- pp- r--p r-- >* P-. (Si X X X X X X X X cn LU to to r-- O PP- CO CM oc CO CM CM Ol tn oi co <n o . * LU co <n CO CM CM CM CM CO be +i +1 +1 +1 CM *cf VO CoO CO sf oo CM co CO +1 -H +t uo co os tO Il>S*p, CoO CM OtoO sr .K. cb CL o oa:. <o DUP040011632 tti <o oz;s** u *O|L. HQ- o. ,wl *-- *0' * * o cSn- Osr^rTwI .*~* uQ +C* J3u o cum S- 3O "E**. jr.i s* cn c:W e <CuTTr-- U> x>J -oiM- o c* co 4* CU M ^3.**;:,;i Oz; ^3 - S w' 4laf-*a?-<iQ=03-i- cx ; 0=3}** '" ' O ii l +oj so>r> ' *"* t * O Q. 0-*-- =s VJ r-- o o o 5S* u. 4oi/-l.'-*<Ncu oc*9: /ly O 0&3- 1-T3r flSi.CU CJ C(0 Tif-, jaQ. U <--M dSfOS Uo r- a cn M s C/1 f* Cut r^1 h - m >S0i* t~ri 5- 0 if-- CL <tf t3 wo 3 *r u Ui # * CD I lO -O <0 to o v`i a. zo R *--* fSi vj LU a; CLU3 .os CM r-- Oo L2U. & in rc^n. in cn -CO <L_U} nc >< fCVOl -5ot Lu O Li--0* L/) co o> $o in cn ;w --i a: <n f>% co CO c o 4-fr /a its LU i1s0* o Ou .ooo- I e o ju o w L- s/> in co r> ,CM LO r- in aQ Q o svi CO CM CO CM CO CO 153 isi :X 2^ ' cWo cf 03 CM o o <M 5S V> p* C0r ULU O o i r . in in t* in in ii mm ii m in tt o o o o O CO oo "!" r-- r-p- X >< X X X X X x V? CO LU Q a CM CO in * in O CO rsi .co -O CM 3* IS* CO CO coco in rr* :CM CM S CM LOCO CD LU . +f +i -H +1 G CO CO CO M oo to CM.CO 11 i i 1t COO z 0r--1.r0-- 0.0 l^* ^ oo r?** -ri- OO r* rf* >~ --i H X X X X XX X X o a. }2 fs, *3- CMr-. lO 03 coin 2= ; m O ID CO r-- cp iu LU CC CD LU i^ p\ csi csin CM ^ r-- m 1 t1 O --i H -H +f +1 LU U. a U_ LU QO CC LU CM r-r i-- r-- r- r-- .25 O M 11 11 11. t t OO oo oo oo -?-- r^ r-- r-^ r*** r* r-- r* xCO CO X XX XX Xx LU CC CO CTk VD o cn r*? o o ; cn VOID a> LU CC CM CO r^- i--" r~ in ; .1 +1 +1 +1 +i r-- <c 4-'! o CO CO in * r-- CM 4-1 V0 CO CO 5T in CO Cf l> m *a CO CO ro co CO S3CL. h< O *--< M >-- Z *--< CD DUP040011633 0.68 31 0.19 -2.50 x 10" " 1.70 X 10_b lO 'l 10" 4 I its j mOT n3. i- O -iMe Ct3- in * 1.0s1 <2 = rO S. -M CL ref *a.** tfl lEcuJ, o...- at b; i u ;= s. O.CO V* 3 r-\ UO JO3 O CS> IX. W-. *co e !g'& r>o- u4ok-*wsEa=* r . TnJef: f' O 4if4f m: + CL eg < 3 O > O ZZ IS*' So. 4U-S*CJ3 SCL ra*ii Q. IS u -cjs- c*osoF *1- Q Or- i * O > <!U M- W <'u a. r-C 3 J 44 IS . SL. m l - o rrfi TO <513 C O 0> <8 r Vt 4:4,: r-- * .Cirri L L r- O.CQ 4 * Srr:l O C-> 4-> U ID C9l 4ILI COCO O f= -s* 5`D C CD 5rs.E ligE i3noS- o* tu r-- .<s in ,o vj a. r o2= ip co v> 1x1 nc <3 U4 a: oc o o < Ui *c X co CO Os! in U- rs w o flC. i ; c o o 5* to to to CO p> to in 1-4 CO to to >- u <c <: r-s co co o --* h* <C :C v O QC s O i- a txl 3 L (X o 'ZD G t- o to o sUJ o N to C<M0 0o CM 03 CM CO CM .CO - r$4 z txJ to r** CO o P> * CM pu * --1 +i X x X X X X o to co in co Cl . vCOjr-- m.i>. PS , UJ UJ r-- CM CM CO csif-- UI *--< 1 oc o to #-* +1 +1 +i LU u. O Q cc: CO CO <OCM <1- CO ii o .f-- f-- 11 op 11 o r^*'pp" to X X X x X X 50 UI or. o a\ in C0r- ,m m r>> <y . co in txl in op CO r- 5*T>. ac I -H +1 +1 cf a% CTI p-- PS o r-- O Oo 41 +1 41 in Ol CM co m >. p-- o- *-r .*--i >-r x x 2*78 2.60 -1 .1 6 x 1 0 "; T.09 x 10"^ K44 i 0.112 DUP040011634 o -- 44 a. o a - 44 aj - iS er . 44 tn CM psa-os 's .p aX. m* a r-- " 4S>" a>o. JfZ: JS 4- I <:* c. J515- ' Q.CO 3f* O CJ c: s- xt <j i o cu a* > *co !6 0Cfo-SM- gc c: c r-- O 3S-UU) a io H+ --f3ElK, a3a w"0ss. als^3 Ea, r* X -*' i 43 POP -c-- nC i5f 4-* i- . 3:0 If- O Oi1- 1 VI > > <1> *f- +*4 VI >, a. r1*0 -i:Js 3o cu flj ~ 0: C; 3 40 <T3 *V. C U C.> rtj r- ug. 44 *r*- .. .*> .VI S.. r- C2-CQ 44 S r-- itf O O *P U J2 v> a. v-cciro C.4 >lC Ol Q.S 1 off 5 pra I :r-* -a A5 m o vi a. VO in CSJ o- o <c un wp in CO UJ o a:. <c ; .** oo oU- an on CM VO ..rs on >* oo -j c z <c r* 0 CO V) oc <c VLCS t- UJ ooc ^3- c: Oo CO 2S ;C o Cl - 15:5 oI*. p* CO m CO in * ,p- CSI CO CM <o CM CO CO CO X * CoO r> CO * Kj* VO oao\ UJ to ch vp co co j--4 CO. mm o* in in co in m o o |i i i i S 1 i .< Op pp r*" r-- OP r-- .r-!- po <r r** 5= o XX X X X X X X VO con^- on in CO CO COCO CO LU vop CO . vp.cM CO P 9 ec C3 tu DC Kt<O #-** on i 44 44 in oo ti -H +1 M5C'- co.co CM CSJ CO CO CO CO UJ 1 J t 1 i r. 1 1 Qis on go op oo O o * rim r4- r- r-- ! -- r* p~ >__r -H XX X x X x X X -O CO CON isf- COP * P'T CO pj p in UJ UJ tnm UJ co^r i^iri PC o CD -4 UJ u. a u. "H 44 4*t 44 Q pc t i ' :i i i i j i z QO op Op O O -O to CO X X X X X x XX UJ a o; r* p ;p NJS r*p VO CM CO CO CD * * UJ CSI<M i-- CM CM CM a; i i +1 44 44 44 CO co r> P in r co CM co CM CM < +1 +i -H +1 a? CM P o g r* P in p o CO 00 co sr ro uo cu o , -4 o P~* .1--4 1--4 --4 CD DUP040011635 table 18 - Mean values hematocrit (H (S ot, .E - ,) and summary o f f percent? fo r wale a c to ria l analysis o f and female tn&nkeys in Variance f S tatistic o a r l Groupings. r*K os .-** ; ; cy o\ *?r vi3 * .* Uc>i'SO" .9 . cCOo>r--- ' Ooo-Ow to d V** 2.*? </| V,I* ^4 CXI *7# 0* oo^J <* r- S ISjr '* * 43 N S CO r-- LO too 07 PIS' o vf /i. 68 o VI <Si 4CO 2: 0 u w* co Os- toot <ftr> .jemo.^O-> rco* >r* ccoo>o-' >n*#- o 4<8-1 t4t**. o t/> CO *f-- V> z s: V .<Lc>u X > VO V? o o( to v> o O ro rv co q oi .tr> as is* o too too CO'--- CO>^ rOv-- co-v-* cOaJ "t--r SQJ, CXL ,LU CO 2C 4O- G :0 VI 0i0 i- QJ nt '|S-- a<r Q3 ro co <o co rs r*> 0 oCL so a o-o ; o ^-o Q. o 0Xu0I41 co -s^ ro>--* co w- r^ w 1o CL *-* X V> oir 01 c. as to a. ir- o -fj c: o o v a. o3. CS3- CM O s: s Q. CL f-* 'to o .f C_aJ a. co B H to p 'll + joo CMOO STfO _S E >>* CL O) Q-E CO *** y4 to e ao 3 qo r" ftt?- > qj M t. cco - 156 - p,s oCM u*3 v/ ,/ DUP040011636 Mean values (S E .) and suirenary o f fa c to ria l analysis o f variance fo r hemoglobin (Hgb. - grams percent) fo r male and female monkeys in S ta tis tic a l Grouping is.co *r'*r p tn tv co r C? <M O O c5 O P kcj>- *** in V) in CO to -.VXD m NCJ * .. OO in W CM <3 r-- ?f CO 0.0 CM fO i OO QfO >!-rsi CM; .r-- O f'- O rfO O O CSJ CM * r-O CM CO . 1-^0 r--*!-* dvcsi ' pO r--" 10 co . OP p-- O CO CQ CM CO CM -csi O p p orl O -p Q JO 0 vi co to O a. p *-ie to to -r to Vf <0**) c oitf. *t*o3* o ..to fli 4-* V) efd <11 in So 2D CO co adu> Q <taxI-uu. a. to CO r~ CO CM CM CO CM bo i-- o oo op fS .ae. oo S> 3<0i/-S g_ xa. -!* 00 <Os1u-f a. 5- fc. ca CQ r-- r-- O XX CM Q- 4- O XI ; a. O CO e & O2: co .S s s* c 0 rf- O. cn Cl Ol +J P Q- fcs a. D <a vc M r-* co =r J- 0 n in m O' to m f-- 0 . .* 4- qi p p O 0 0 CM *** 4~ -P O s \o o 0* r-- c **:*" 'r--t4** -CO r" CO CM nw o vd Q to > in a in o .3 <3 rr m S 3? U -?< ' CO CD CO y is- 4/1 (O tu1 ;4J -W r<- ^ atj , >? -4- u> S t/i < ** <**tf (O 03 -C<. * *- * fe 4J*"S Ps <0 <4- <2 O 03 IQ O -% *-s co sin p!> A-O .Cm -5J* #p*? in 0' in 0 cn co ; .<** cr* cn toco CM r- .iO 1--- i-- <r~~ <jk .r-f* in o 3- o w o 5J- o O CM ,f>* '* r>* ; 0 *- u-i 0 to Q> Oi'o* CO .03 to c? in co p-? ri*~ in 0 sf.co co -*>r - <y% o - sr 'jf r- CO r-- CO CM IQ wo <3- o *i- .0 <3* O c: vi CL, to +1 u ar . CO CO 10 2c 03 32C to zs o CO ** CD .>0-3* in 2? ts 0E3 4-> eeks fO s4f c. H- to 03 03 OO *1 *3 & s.3 VO> 03> X 2= f CD 03 l at .k to &O +1 O au & tA (U QJ -M co CO 1-- Pf* 0 4- O 3 >, J3 ^3 r- 0 CM a. ; a. flS 0 O0 *> a 2: CO 2ZC0 c Jt C 4-i E E "N S 0 *r-- u >> r-" a. C7t Ou cn a Sw :>S Gi 1 0* CM O a p a 0 0 in 1 U. m 0* 1 E r1-- to 0 1 a. co icr rcr u> a a0 1 3 w a I. *r< 4--* p>- O OJ * QJ `-Q 0 .*-- 1--1 >- O a S- *--* s_ 4- c 4--1 H- -CD 3 O 03 158 - DUP040011638 Table 21 - Mean values + (S.E.) and summary o f fa c to ria l analysis o f variance fo r to ta l leukocyte count (WfiC - per cmm) fo* male and female monkeys in S ta tis tic a l Grouping ca OO 0^> .O >N <1* 'SfO wo ro* o voco *5j*p> ; <d- cn crv .CQ.Q3 i>> to <n 2: 0VO3 O gr /> f0l1i oo oo CM CO CO CM VO IN*. IN* CON--' NV' oo -- vo -- CO <1>s> oo <M*f CO to ,,0>?n OO CM O VO <3- VO o o O vo vo .00 co o O CQ CO -- CO CO IN* VO 0r>. r0-- .0co 0cn oo o co Oco <Qd* M3is ro co r>^<j :<m ,*r CQ*--* CJV**^ 'fN.*--- to o4 . vf a. co V? VO 5K 0 to to .0 > 2? ^ / hMoai O to o CO 4-cJ JBT 6 2? <*0y s_ i0l1l VO VI <d +J o .*x VO oO i-s.cn I-- 04 r>* S--< OOoo vo cn *d-vo oo \Kjr CO 0 .0 co co o ' ,r~ CO VO VO ia-> a. X Ui ca c>--o c o 0 r* <D fc im .za etsi OO oo oo o o 0 oQ. d* -^r in ; co to in CM CO CSJ VO CO IN* CO o X l-s-w* Q-w CQ v-' CO *s-- OJ 1 01 [aL.. CO Zi-3 0 8. C<uX)ul Q* .to r-* o4oiOeJ. o.voe3_xi -I . ozCM OBa- OXcrur*oI* a. co N.sOs^ Vr--O. r-- to oo 1I t*--!*i M *--1 CsQ_ O2+C:McoCoQL. ,C_XU s .CST co *oT< oV* O 4 * frc4C~*1 ,s~3 'CrQ-* H 01 -aa_ 2oA=M +ia--j >c--i tOo - 159 - DUPG4GG11639 Table 23 - Mean values s (r.E .),a n d summary of fa c to ria l analysis of variance fo r blood urea nitrogen (BUN - mg percent) fo r male and female donkeys in S ta tis tic a l G roupings, CM e-r <x) p CO r- CO N CCOSrIW* OCMsr-^ oJr^ CCMM*^ CE!_>. tSO.S** ZCO;* C.O . * IS in <3i .3<<iUu: Jcp 01 </>* o a. X * vo in ..* COO r*r*' r Or* .CM'S-*' r> r** -* h*0 rs. ; * :W)rr in O vi a. 4u-? O O *-*f Ixi 0 CO tor* *-* M to o to to*!-* z op - t>o rr- "L-* oi ^i* CP r** CO oT . cop cp ' . in r-- ; sf- O r* co to cp m cp d ' * '# Ulr- UO O ^ r-- as <u fU , h* tu UP *T *--1 <3 *-* CO .<u m 4J r C<11 to to u to to to C<uL ? 2= UX4 cp coo * SO r-i** ; % 0* r *3* .m * qj- O a^ * . LT3 -- *r in-j f XP ' Qj <3C4a C3 M m<i5 to to sc j--i O- m-!O s_ co o { in G nM o L CP CM o z E CL CL r~ LO a o iCp t-> Jp Cl co E cn CO .* Q - .M 1--* Sm 4* ; JQ CM CL O -ico e E ""ss Cl o > q -.E Ui "?ar 3* ti> * OO l P M G P 4- RJ j- C P .T3 4J> CM U XI O 03 o .4- 2 k XU 0> 4* u ff S- ZJ o to - 101 - DUP04001164G Table t i - Mean values i and summary o f fa c to ria l analysis of variance fo r blood glucose (Glu. ** mg: percent) fo r male and female monkeys in S ta tis tic a l Grouping O CO Z;aolS>i to :sQ>, CO (U i3V0S CL XQ1 01 a. . <**> US * ; p *. CQ>-> . /**> CVIfSi * CM * J-N. co i>- co to ,03*-** <-< .* CO O cn>~ ' >-> COCO * ip *-s6 . * SO CO Mf-LP . . > CO CO to C3> w p<- ko co ,i^ r> co ^ va co *c3n*^*i* <r> xixo* CcsOi--rV^> CO r-- CM 0ip0> <oT>s'Pv OCO?; s> -CUO?C' O ipa CO cp j?* IS.* CO M*' CiPTs ^CO-' VP CO CM CO so co IP-*-- ip>-^ co rr> vo as c> q> .--oo <T> CO O CO CO CM O.CM IP's-' 00>~> w -* C0-- Kj- CO V) V* P-5 2: IP . vj Q. CO ip CO 2= . vi -Z: *-* CO u-- C t-T5 ro CJJ o u 0 CJ M3 J0. CO E .6* . E ,--i IP o Sca * * f y M3 CMCL. O SZCO. cs E^. Cl Oi -a.--- Q a- R3* in . v3 O vs 1 a *-- p S_ CD 1* M 1--4 M -*-- M 1 S> *--i O i~ c4M nj i~ P U fC n- ja oCM omL-J t- o Cl . 01 2 sz u i- 3J o VO - 160 - DUP040011641 Table Zi. - Mean values glucose (Glu. -andmgsupemrmcaerynt)o f f f o a r ctori male a l analysis and female o f variance fo r blood monkeys in S ta tis tic a l Grouping B. *3* ** tn O .* fO cvi r>. ; Cn'rr* > N CO O cCOM>F-->,' CCOTS* --l-s* C'O >U-O* *j- V) o -? co 2S CMO> o<3* S<c1uz1 0&t) in CO CO -.to ?cflO - CM.Pn !>> tf> CO CO CO CO sit- to qn^ .o>>--I- ov v! a. CO 0 AO CO .CCi1-OD* .<o co w oo ?* r^co cr ; j>* cn>-- r*-w ipw co-v-*- o ^ COf- oCM ON OiOS s'M>* COOifw- QDCM^ iCOOCsOv u> co . 00 tn^-* CO CM .* in co f>--w OO * CM <TJ lf)v> >-s CO nf * <0 co u>>-> CO CO ao co UV tn <T> oc co CO <J r-r- oo co ; .coo *cvi u--Di CO S- CO Of ka; a. O iU C O C_5 cSa3O/>-, 1 --t CM O Z Jr Du q _#-- u . 0 * .*-4 . .*-4 s- i- ca ca r* -cj + CJ J3 -Q O. CMQ. O co -SCO . Q. D> CL S CQ ir XO ** 0 OO 11 1-4 t--4 2S *--< C O 4M t ! .0 ML. p- 5> t*~ P Xa.I CM o2: 4J 01 O 3O_ CO 1.60 DUP040011642 Tab-lie 23 - Hean values s (r.E .) and summary of fa c to ria l analysis o f variance fo r blood urea nitrogen (BUN mg percent) fo r male and female monkeys in S ta tis tic a l Groupings CSJ r- to o CO r- <T> IS Q CO i CM- Off-- i0-!^*S--/ WCsWl- w v> </> 2 2 CO 43 O*J* .</) <5i 07 -2ie LO i I- c$o &W<tUJ1 0 CL X<a1ui 10 fs* CM O .CVI-N-" U)Ol CM O r--' to so <M r~ CMS f*s wfr O r4- .CM---*' iC--Q 1O"^- * OCM "* r>* r>- is. ; f*.*-0* U>*c- 9 M3 fs. O ..ov'tr 00 -- co o>' coo oin*wjr--i. ; sr co m co m co <3* qip- m #*- in o ^ r-* no cncM O r- cfl r^- u> oqf <b tn^- in o Vi du Oor-ot in oiHnr* 4iIuSuJ) o Ml in ^ oo , =s 2t ** <d 0u1 jf-- -000X13 10 ir o*- 00 *c--h in oO 3: 4ca4i *Ir-" e i- .00 .Q01_ 2 uXi 4- o oc CO v *c <y po 3 V) a x ow00 40oI11 Q- 00 2 in 2: -o v LU* o o t in j Cl , 2 M O oi_ CM O 2? E a. CL r--~ m . o M >-- m o i *-4 .1-4 cun r~-- +o 43 CM CL. O' jsco wE o-.cn a- s ui -=r rj* u> * oo 1 > ir o *rr 4- ifI--B t_ 153 *1-.* O 01 u J- c o r-- 4-* CM 07 43 O a. 2 ,rtS k Q> +J C 161 DUP040011643 OtO 00 r- (O r* ilO UJO CM r> <r> o co r" * * . . * r-. OO OO <3 0 oo hr v* to 00 o 0to0 r-- co oo FCO- CoM OCO rp- O3- CpM IC*M> O op o. p- o. o.* o* o.* VO CM CM CO CM CO r-- CM O coo |CM O CM O OO OO OP op VO CM NO OO CM*CM CM O Op 00 CSI CM O op OP CM P OO oto vj CO to VJ CL VO * 25 o o UJ o v> CD CD * --i 44 2: CO to e V) rtS JVC 2 a to <0 O >r-4 X =r 2S CO L. 5- CQ q JD CM a. O co +0 -Q CMCL OZC1 CL o CL tx cr> a. E L to to C0 sr *3* 'O o o CM WI m CL r-- 3 f3 O o S_ CD O Z> CM t* O . ra a. ST U (U 44 C - 162 - DUP040011644 Table 25 - Kean values + (SvE.) and summary of fa c to ria l analysis o f variance fo r to ta l serum protein (grams percent) fo r male and female monkeys in S ta tis tic a l Grouping B. tino con CIO O'* r-- $12 oo ps i>. o mj a rC o i** o Jw W K Vw<5? IICpO <n CJ 3: to i E<L> *-o*- *inr .<* --p O CO Qf*>.Ci--Mo ,r>* CD PN. O 0.0 o* o o cr> ; to a 0 CM LOr" .r-- i-- rtrf r* o r> o -ps* -O *cT O CM r-- CO O w inCM CM r--r oi*s r>LO <si ; PN. G> >--> CO co.f-- O'fs. o to CO CO O *i* 0> <00 *-- !>- *- VO rr* P> r-- CO -- r>- 0 O r^. o o cOO ^co in co CO r>v o> cvi ?-- ttoor-"- r-- r-- O NO r* ,o K. o Oin Vi a ioao UJ CO .00 2 C/J 2 u4! U4 4G-* O C0 1--4 CO CO <3 pC~O4 S,QJ Rj nj V-r 2= 00 2 .0CE* r* --4 co .-+--4 L3. O<4Cu3aiO~Ot - 163 - *crp-- ajn. o2<v 4#50--UCt-d^i DUP040011645 Table 26 - Mean values {$*.} and summary of fa c to ria l analysis o f variance fo r serum albumin {grams percent) fo r male and female monkeys in S ta tis tic a l Grouping B. uno n 4) a\ ko otci o ,l> O 1S.O tf0 l>Q CViO CNJO CsJo <V1 Q V5 V> V) 22 s0o0 o VI <a 3Qi:l a. 01 s2~5 V) a o. XOi. 0.11 cCL in at o 10 vo o xsi 45TW* r-- ' iO Q CO rr* .04.0 0^0 <4o oSo {>.00 00 < -00 o rr- < fc>o uoo fsir*ooo> wo coo wq wo -ao too* an* ooco o 01.0 isT o U3 o CO O <VI O N O 04 .0 COOQm JO>> c< Oo j uO> apioO 04 0 04.0 04 0 COQ 0*3* o cn m ai in r-- rv. o f& xp *s* o NO .04 0 <M Q 040 LH O Vi a .</> 0 M t/J o4--/) aai O^ *5f* *-"4 ^ V3 o wco mai vi J<V2C> i- .01 > io an 2 tD X o M CD *J an VO xn =5 tXu o Gvo> co> rr* J- 51 t 2V3 PO & X CD an 0r1j U a. *-* O -V* sr o o VI i o2Oco3l: w 04 O Z E XX q. FrlO o i #-- M cua jcpi a. ro e nj : f--!* LO o t-- r-4 cco + o-Q NX O zco. S'^n . a. o CL co*^ *r m *> 0:0 ) 5* r-- c o -- FTj i*53 <*O -01 u tscooi: 164 C q r- O 0*4 Oc a. 22 Cl q c W* DUP040011646 Table 27 - Mean values (5.E.) and sumary o f fa c to ria l analysis o f variance fo r serum sodium [Na - m E q/liter) fo r male and female monkeys in S ta tis tic a l Grouping B. n o vo fo ui in vo <v O co o ui o co O to o <3 Q t*O-* 0VO0 .<xa CO f? ino r< o -COo rr* cri o <sT-^ .*** p v| ix 0M30 *C-D*- <o *C~D4 CO *o Ss f>. LO cfr LO O <M fet f> CO o to o CO O CM O >L>* CM VO VO O co to CcnO*O!-*' 0<03'>i o ro o ^ S--* - CO O SO in CO CO O rO O .to o O CM cr---- CO'w' o to o to r-r*. c*3o*o*^ r>. o ^r*f.'Wo *#*<o-* p .<* O 42? CD sf .*-* +e* toCO *-< to I tn P a; u olO CD CD T t~4 *r-t #-** Pe 40CO CO <Cu uCJ CL CD CD to *4 M CO X La Sf* o c lp/l *r-- i. p .253- E -O CJ Ontr.* C^O* a4j P to sz . a. o +* or o o O3Va-i 1 w u- CD XM O 2? s CL CX r- to o M (--5 c. co o X) CL co E *% o> ts r*- to * o l IH .* --4 i03 + ,0 JD ; a. o' 2CC0 s E ''S. ex n> o-.e co *r <r to .. O Ov f c. o M n3 *r~ <9 *1^ O P -o i- Coo X5 a. - 16b - co pf9 +C-J* .C DUP040011647 Table 23 - Mean values (S.E.) and summary o f fa c to ria l analysis o f variance fo r serum potassium (K-mEq/1iter) fo r male and female monkeys in S ta tis tic a l Grouping B. jUufs ,r*o* oicOn r.0-0- CcMo Oto CM P coo coo <*>o *ro o CO CMO3 Ow v\ 43 2OJ I <U E CO 41 l. -u3) Oaxa?. 41 aL.. eg o O # * * '- ^O ; o JlSr^ CO o to tn CO r-- # CO O o r-? CO CM *a -Vp o ; m co r-* cn *-- tn e .COr- M3-- C0*"* PtQ coo wd <do coo sVl CL MCO3 CO* oflj U4 +* oftr to *tp4*:Cf--g coo v* o O 43 co CQ r*- CO r-- <oo cd o *>> V--< y--s ro o 'v*' fs. o toco eu to <OCSl j-r- o r-. CM UJ r- nq *3* o coo coo to *^r i>.-; cq r-- cr r-- eg oy to o l o rv O COO coo coo ?f O <o X o XU u H* M to 00 T CL 2t MXJ *4- O tCo/l r* co t <34 oO U3 0V* 00 Q. XZ 44 414 40 2K C3 >t-o** to oo 2 OO CO z G. O O tft A o'3. ou u ca o zOCM -U A. CO Du CL 0 O s- .ca + OJ3 CMOO *1% s:-^ *cccf--t^Or OO co .r- X >3 o 3u0c-) o to - 166 - sor i OCM dm DUP040011648 Table 29 - Itean values (S,E.) and summary of fa c to ria l analysis o f variance fo r serum chlorides (Ci - m E q/liter) fo r male and female monkeys in S ta tis tic a l Grouping B O CpfO <X3 %0 <*>*? ,-C0 -C4 j f . ' * CM go CM CD Mp ,C3 o cp Hr V3 XO w <m op <r> tn co tp crt CO O d CO CD r-- o CM o r<* n -' -- " in o vi CL co ^2 *S? o *r VI D-<00XCiu11 . ,i>. co tn co rs i* co *>i" f">~ o r*- d *r d r--d .p:v- 2'"' p"-' 9- o r>.r>> a> so toco co i o> cn o .55 O d d 4V0JI Of 4CV-Ui 4J S01Z M xu o o--* t/> LC-D4 to -i CD H-t to yp CO to 2. : ccu so ip r-^tp ; imn ocn<c->* cod CO CD .C*Df SO-* s- .C01L X ; CD to z.l-ri V) to G f? .c0n u<ZU3 OiA CL o r~r ; co a> to tsr cn CM i-- g O CSI O O P J-rs" riJ & oo X 4OtJS s. ;3 VI OX<o01u. *to* o 60 to *t--o* i- a. Q_ CM O 2? r-- CL a Q. t- L> fr-- G O -tf> t_2 o */ : p 3 O LCD U CO f-- o jQ CL CO 6> jtn . .p a *-* M L cp +o JO CMCL o sz cn 'B CL>O-*S. CL ..fcs cu ^r * tn oo i >--* c o *r~ 4- ra r-- c 4-- Opf-- D* 4-> 0 4O CM *3 ,.Q O L CL 0 XU o J- C *L 3 o to - 167 - y DUP040011649 Table 30 - Mean values (S.E.) and summary o f fa c to ria l analysis o f variance fo r serum carbon dioxide (CDg - m E q/liter) fo r male and female monkeys in S ta tis tic a l Grouping ** o 09 CO o xt in .^c 01 z M3 i 0) E ff- 54" 03 0) (3 tA O QX 01 Ol u a. CO M3 ir o CM^-* *S. NO ** -** iO *1" wv Ch M3 CM-w #^*s *j-P> .* * <43 O CM-**-- CO^ a - .03**CSJ>--* ** in in * too CM'*--' >rs csirn , M3 O CM w <o U) . f>S.O CM>^ r>. in *TO CM~*-- itq cn r-- CM*--- in i-- .* > r~ CM'*-' a* r-- - . GO o 04 w N r*?" : * tn.v~-- ,04>-- ^r* er r** >* CM r-- csiw **>s T>* O * Ml O CM<- 03 CO *> O 04*^- CM O* in a (Mr-' i><n mo csi*s- r-- rr> in o CO o ^ f!** 04 v-' CO o r>* f-iCM-*-- r-* ub M3 O CM-*-- CM f>* to d CM>-- *a o V) cn cn 3= 2= 25 in o vl C3l (/I u 41 4-- <4- Ui 4-> .tz CO cn to 1st cn cn 2 .a :z o as CO *--. i--4 .</> cn .a cn . z aS <V u frr" (0 43 c & & JG> O. X U4 HO c o M snj Q. E o o in .X CJ CM M3 S f-- o H4 03 i St 03 Z ca i a> .3 1/* P3. 'X ci ni c sx. 9 cn a 2= m * z .* cn * St cn .* z iO I--I .03 > cn a z .a cn z P-* o i4-> rr P p t | *-4 Po{j H o 1 1 CM O Eo. a f--* tn O tCQ O -a a. ro H cn r-- in . O i--a --t #-- .f-* s co +o -Q CMCu O ZC3 -- 6*S* cx o> P-E GO r=r LO .. oo I 5 C o r* 4- <o *r* '0vis ,- u~ O <U u L 33 O .03 - 168 - c p r* Ci CM rtf -oO. O' z .-a .C / DUP040011650 o Q (S,E.) and summary of fa c to ria l analysis o f variance fo r serum - nig percent) fo r male and female monkeys in S ta tis tic a l Grouping C<O0 o<r i/l 0a3. ~7 a<D 0 CL Xo o ; ,<M -53* oiw Csl jr** avo o o 3>en co o cn.in O *d .O #* * .tor- 0*0 OO OO in o v| CL u0 c aid co r-- OO e* ; r-- CM oo tn; tn CM cn o oico T *-!- a> o m*- 54*-.tn ro.r-^ tn fTj cn CM f*l r- LD -- <0*0 oo oo oo <y . ,H<cLu** *.0*4 -* uxai. is. ; *Ct* CM Oo cn *>.<n CO CM 1^ f-- cr> ,o cn o in o\ r-- rr cn a c yo> r-r i- S ao. o Oo -* tn HI LO CO <3 ur> tO O V3 *to--n* C3 *-* tn to o in o CD tn to c4o fll os/-! 0 cn ;* oxs si 01 SQ .in * fa o 4. 4J *c o c> v i ct 13 --I o to CM O 21 CL CL. <n * o t * -- tco o aj O. <n . O E ra in o i A-* H* u ca r" 4- O JO CMCL O 21 cn a E ^ ; cn EL E oo <* Sj" ul . OO 1 fr-- oc 4J to ;c r-- t- o|M vG 4J> O CM n3 #-. D -Q o CL z: s 4-i 41 qr o t-- i -3 L. tn - 169 - in Dll P040011651 * Mean values calcium (Ca 31 Table Table 32 - Mean.values (S.E.) glutamic Oxaloacetic and summary of fa c transaminase (SGOT t-o rial Ku n iatns )a lyfsoi rs o f variance fo r male and female serum monkeys in S ta tis tic a l Grouping B. S3 0&0 <QU) u0) is t0o ax03. 1 .0) i- a. O.isi Oi O %o^r 'm t co u> t+i-*** STL# CO co in M3 * rcsn.;r- cvirr in w m Lf>>-- CO tO CO r-- tp ai ocsi ; tp <coo*c*o** icno w; r>s r> co* CM co CM f** ON rt CO o o co to r>^ o co to CM-P- jnv tf) e*" CO>> St *-- to C, to CM to CM O 0> I-- to 'r- CM CO .r-- tfl?-- co ' fOs> 003 pCO Wr- CM O to o en o ; to co 04'--' in'--* n-s--' co w oStfl r-' V7 m *-r* to O r~l CO m o vl a. 0iO3 ^* <5 to aui LxJ CP O s* (1rptj .s (4 <<ly> tp C/> 5E 0*<-0* CO t<oH3 ca i trdE-ri XCL * o v> CO IcH/> 2 ,zc LU 4O G O CO Gr* I a* % oo .o4i#3 G CL KD P-4 to r-~ O L 4-> oc p 1 o o5- CM O 2= E CL CL r-r . tp o O t *- , J-H G CQ O J3 CL CO E cn E r- U> o ! 6-- *-- G CQ O -Q CMDL o -SCO ^E S >>% CL Cl a-E 03 <? mm O S3 4 Co *1-- 4j 3 S- C0t rt3 CM s-l_ j O O O CL 03 G03 4-> U .G t.oo3. 170 DUP040011652 flj u =r n p m iZ rt su fS oo M3 o E cg ri 2 -a * c: 4- -- <2 v> = ,5? s- *"* 'O' " '+- '0>*. J___ U) n +* .V) tu Ss t o E o(0 g? 00 MS in msMS*-* -OP* *.* .# * -. 4 - QfO 00 00 CM 03 <a*.--> CO**-" ft)*** 0 00 CO 2$ 2T z: Vt.CO. CQ f*> -^. Ps#.' CM f> * r-- CM ^t- oo f-> o r>. ,o pT>--' .Q3.r-^ St-?--' co to co to *-- co ; o t .s> LO r-r wo pip pirn CM s> CO U) O vj to & CD CD cOQ. lu) w --* * ^ CO 00 U 4Ul CO V? (/) ss S? 2;' fi- N CM O LO CM CO *?f .CMn -* Nr- CM O f>. `fit* o.co LO CM wv j p->Lv *>0 O CO CM?-- CM CO* CO CM cos-' t*^ to p^f-- CM?--' co P di ; cM^ V? AS P ai i- <a *-!* SO i o 1--I CD -- CD t^4 as <00 V5 40 rQ r* t-- c St* iSl CD "!* CD *--i (/> CO o Ck<D >>V? fO Pn . co lO <r. o row0 o. X :u-> ; OVCM CO CM CO CM <T rr C\J^ .41 1 P \t +t -3 s- W >v * u? 0.03 3 '' r- U cn Sv- C > e^1 3 CX c: p flJ 3 O 0J r - V S OiCD 1 CO CO as . r-- XJ ia r-- O t. M E Q O t <A G 3 !-- o CCD CM O 21 E CX CX r~r* c*> O i *--* tca r-- U -O a. co E X 03 S f-- Ml * o 4 >--4' J03 * *p" + <-! JD CMC!. o 2:eo _e E ">. CX oi cx.6 co ^ Sr uo * oo l .is* .--4 c (Uo1 CO t as 3 o o UI a 00.* CD +-< O --< K 2: CO < 0I1 L a. c p (W AS *r-~ C v. -O ftj r* <<- CM O' -'"0 .Jjj V/. a- 0- P p o e U j. 13 o i/> - 171 DUP040011653 i . If CO jd G. T* cx 3 a r. ID *? a *-* * r^.co -.'Si' r- O CO r~ cn cn to an St* co to to^--* oW u 4-> VI <0 '-M flS 4- to Of ^ y ** gI US LtU *<113: *;jr-j So CO so o <3" v> ..a;: <j j lo c*i l o or> to o FVtO ; :*r O CM I0.r^ fO^ fOl-!* l-f-'*S-K* o in co at *JVr-- CO O CM fv CO CTS co rd* CO CNi coca o CO tsbosV-O^ COj*UwD i^cp cao CM r> o n<VJ O N-VO CM CO o XCi U)W yo I-- CO *-p SO >-* vo co .cn no ; :f>> co *r5*T***3-*' .i<no>C--O' O>C0 OcoNs' JO o W X/5v| Q. tcrny m *5 CD *-ri CO 0 01 a v> CO CO -M 2C 2= ft (A (O jw: CO to Tas :22 z: E ,c 01 -r-- X :<L> *T co o. X 2E <*- +VJi O *r~ G (0 ca Eo Eos 3-3S V> 1 -a C DC ns 3 UJ +t os o vj Sai -a r=--s ->C> ctt as > -a .C T3 xa-i-- as u s: $3 t cr CO* 01 r-- -O n3 H- 00 ,1 G o w as 3 ,V Cl , B Q .X ca cn co r> O vo COCO r--<Tl rs**cf* CM tO o a o X ins> CO-wOS1 f>v?-- s--' as x CL co c# v> . o a. 'HC-D4 <A </) X V7 as i ai x X | VII aj 3.} aj J-I O. j 8~S34-> G o V l --4 CM O z E a. > r-~ tfl -CT 1 M '*-4 s_ ca o O -s a. co \E . a S' fvui . o 2 Sm +o jQ Nix o ?SiO E a. ; .iX e= co ^r u%- a 0.0 1 M 2^ *--i *-- G O *c *1-- ,x R3 .4O as u X 3 O V/ -C Pr~* +J P CM ra jQ O X a. 2S- as 4-J .c fr--4 \ ' j - 172 - DUF040011654 Table 35 - I4ean values (S.E.) and simrnary of fa c to ria l analysis o f variance fo r alkaline phosphatase (Aik, PO4 - KA units) fo r wale and female monkeys in S ta tis tic a l Grouping B, O Ktdi *3-to o to * > COCO r-s *-- r> T>*tO C<O0 007 fopS <m *r ; **r?- P*. sf ip pW?*0--6' Ulv^ o vn -oX 204: p .a04 O <r)cc Xc?o*t*d-* o?stc*wo iinoS p r* or 0 10 r* ' ** *- eo -* <Jt o\ Ip CO CM O Pspl CO-p CO 03 r--- co lp>-* .10 .1-- oIO-Nnt ^ A; O *c*o-- CO I u<11 1/1.3 CM CO NO sf p r-*? O > * o. 01 X P CO ipf co ; to IP -- IP r~ m 10^ J & J- o. pi w vj 2: as .i0n v| CO <* to v> (X 2? .2? VI 4u0"1> ?*-- *Ut O V) 4-1 ^ss G E 44 Vf rrf -ii: 04 u 5h" to p to to t/> r~ JZ"T r-- OJ 55 .2: E 4~* p GH QJ B ?d- to v> 07 a. X z :2= Z o G *.0 in a. E O O .04 .S- 3 1/1 = O to Q. to to . X z: 'SE .04 1 01 fc a_ O 1 I ctf 3] of S-j CS 1 1 fT C5 O *--* SCQ r-- < .* -O CM a. O ; co E e & 5E=i'* r-- iP u> OP 4 -4 t-~i 1-4 < ica +0 XI CMQO ZCC*1) _E -E ">. 0. 02 0. E co tiV O .O 1 ;> r--* G O r* 44 G fG O r^ t. 44 <0 r_! CM tG -a 0 5- li-r 0. z P P 4-> G <y -- u 3 0 to - 173 1 / DUP040011655 7.36. - - CM O B Cr* JC3L- l/t r*i>jt> O > 2C CL a D. _C 3 "TT 4-> O r; sJ 4~ O tA "O *a c cn a> to wry *r" a *- sC Cl CQ -2C-- E C-- OO y s. a. M*. CO B *c Idil *r,: S * CL LO 3 r-- ftin Ji: * fl o Wf- 1 *-- > </1 j V*' CL :C +-> 3 3 to .O ^ -*-> L. S' .1 CQ <y 3 7.34 7.33. 39/1 36.7 C3L S> o 4~4 s- ICDO ro~ is.. pc*o. *o *- K o *r o NO o CO O IS. iCflOO IS. COO r*., CO coo fs r-. o co p > Cl 3>-4 'OS- *--<< rc a a. 3i Oi L C0 <o o r> o tn r- CO o rs o !C>O. . is Nto r*^" p*. ir*. COr-* p* <LG0 0O p *.q 40 #"! to o CO CO o o coo fv r*.. p*. <f i-- pv t~<o o r?* r* <o I** -.CM <0.0 t*>& CL 3 CO o CO O JtNo..oO O u r>. o is Pn . o to a COir CO !>* .CO O o r-- P*.. pc>o*o~> -!S O CL 3 > O '--* s --S. CM r1- <\J r-- St>-^ CO o Kt^< r>. co o. *-- sr ' O r-- r-- co>^ o : :r-- COw o t>. o f * fJ*!. r-- St**-* r-- CM tops. Q. 3 O --i c\ o o CL CL 3 t~-< O ?"* *--.o avo Ofs-. CM CO r^* * Or-^ar>-^ cn f~ rs. i-- ?w <0.0 -- CM r rCOS-* f>. CO co^ ____ . ! CM O **>* in o it . JN r-r" <n>-^ |>* ... * CM r * *r co !>. O I I-- r-- r** '--' . * . r- .* ? O -Mr*---* -CM ** -rr.f-- CL 3 O *- ;S- er> r>> o COw CM *> fs -- CO^N-^ st o % <0- *-- S--r . -m rr- csi O rr"sr s--* o-. O P-- . . r-- m sfrt <VIH ^"S. CM :in>--* CL . 3 3* o * *- 5 LO rr-- *--' o >*. CM -.^ s ^3" O ^4* CVt-- >-r CQ<~> r-* .r-- ^ ^^ 4fO SO it Of-- s-> fsCPl <-CM P>w 1** . # CM .>-> CL 3 rM O *-*: 4- 1--4 CM O a. CL 3 -< O -- 4ar.r>* r*. p-- n -' rois i Cj- o P% r- CM *--' r* r-- CO r^ O r*,w LO <t r-r ^S-r oo r-- CQ Pn . .* r-- >--* J>* o K vvl ->-> .--* r** . p-- >-* r> r-- CQ Vr" 1 y^. P> CM >-r tn aP CM w V* - to r-s. ^ CM . . <t f-- ^ CL 3 O - i-- O ___^ CM cn CO * . Px r~- __4 CO . p^ p-- ^-r cn . - > P> o cn w CO ^ * co ^ CM . t-- .^----- ____ > LO p-- LQ * r--f- {.--* L> .* '. CM 3 9 .8 83 k7 8 7 .2 9 6 .4 > Jj SO. OCDJ m rs cn r>. - 174 - *sr - DUP040011656 ill 'i :\ 4-3 .O e** JTr-U Cflr-- -Q O !-? O CL tn ^ co *- m E to >*xr**a 5^X5 4-> o> *-y <3 <0 43 <*- -% Or-- ns c: tn <0-a * sz as <y o o i- V) *<- O V* I 44 S- <0*0 o.-* uc *-- <0 o >-h M- O .**-*. * Q. (/}.*-- '* 3 m oa c J- w tn J- co OUDi-- U CO 44 -r- f JO Qi _C5 CL CMO. r c3 0 OV-f- O ZfO . c v' e v* S <23 -S ^ cn o. o> c ^ a. s <*- .m <a O OS Or-'t i- *- in in &>'0+. s*. in o o 10 g,r--v44 1 + & <0 3 0*44 i--i Oil in ^ (/> *" o z *o 4-> i- a. . dJZ Q 3 s <o cn4- o a. ,f~ i- CL <D in CD 2 >1 Of) a i0> *r : .r-- * tn t j c c o ' o o s- .43 E 44 1 +1 c r-- 01 o s> in S *-- O-*-* u c <0 = - E I a. >-- a 3 <0 ' :$> ~ -- O > O' p X- +4 Ifi cuts C3 0'Vr>:6:*O CD: o ^0 S~ G s: <4-^o s 1 n> <o -P <0 i-- O r* 44 tn <0 r-- c~ <0 CD c* *o 44 * o, r- tn 44 > <0 OJ u c *o r~ . 44 s cn ; trr O OO 0.0 >!-' S coco 10 r-* OO uO LO coo 41 : ..* 00 in 10 '. i* 'i. 03*0* r--4" CV| CM r-- O OO OO v--* CM *cT in 0 00 v-" -4-^. 0- tn .co.o . ^ > 00 0 rv * ' in r-- o **"* 44 S- to GJ i> r* . 44 sn uo CO CM . . *--,0 %-> r-- CO 1 :* CO <0 CO r- CM CO to CM : .* r-- O -Mhu^ CO to . CM CO P>Q O * r* --S U3 ; m 44 CO 0 co sp <0 . < . 44 V 0 0 O ;<p: X<0 a"*-"* O DC 0 to a COCO 44 to 0 0" r-- ? (-- s--< f4 S-' o *r-- 44 CO Xo c O' --i 44 00 00 Cn 0 a .0 o> r>. LO .r-- 00 CO 0 *.* fsi U5 CSJ>--' 4T1**' r-- in ' vo in PJN4 O r* 44 T5 *o r-- V o c > xz h- * 44 5 O -0* <--"O 0 4 0> 00 CO 90tn co 00 4--< COrrOO OO l: .0:-0if ^ 1 CO 0 00 r*r ,* 00 "V O 44' cr 3 r-- ns i03 *4 3f +4 .r-- X5 <0 cr 5 v*55 P S3 u01 > #-- TD: O cn Ps.r-- LOCO * f4- O w* CO f>. B ror% 00 CMr-i cn *0" *0-4-- '*TN* CM O in 00 ' ,4-K co rs fs is vo<- tn in CM co tn tn 0 CO r--O OO - OO ^--, 10 in r>.co OO in uo f-O OO O0 cn r so -* i. OO 04 co CO to ' co 2= 25 :25 to co to to *35 z; z as m co 0 0.0 'S^ ' CO to 4"1 OO'N p" w O <3 *0- jr* * O CP -4?S 'I-- > CO CO ir-- - *' V) to co to z: '2 st z ' , co toa to CO -izz .25 .25 CO Cv CO CM r-r 0 *U> CO 0 <0* O CO CM inr* co o PO *--*h .-0" *0* * -* ID l>v r-- -w--+ CMTs so 0 OO S CM CTl * . cO ch CSl>4 cn CO 00 00 * 0.0 ^O cn ^r r-O ' co tn to :SZ 0 cv CO PV OJr in r-- fO O ' '? 00 o> 0 * ' '* U5ts r--,n -> CM r-* SO r-- OO **4* 1, CO CO CO ^ SM^ CO CM OO OO OO co i . 2: " in O- v| to a. vs 3> ' CO i; 01 St Xp' <4- V7 O 22; 44 ,er CO U *r>* co tfr* zr C 'Pr-- in co 2: CO 2; . CO 25 CO .35 to 25 to z . <n 2: ; CO 25 . co 41 .2: CO st > <0 to 2 to 2 V 4-- CO coin *0- f-- CO O 00 . O O co to CO -:2= 25' 2: 0 tn tn a- > . i-- 0 > *!. co co sn 4 .rr* O . to to 25 25 co uni !>. CO Pv* O C-r 0 CO VO *r-p CO to 4C^D4 rz* ,ZT V* # to '25 to `25 # to 25 .a CO St to 2 ' .* co 25 . to 25 . :tO Z CO 25 to O CM CM LO CM .0* CM 0,01 co cn co 0 0: CM a to to to to .a '2J z z z ,a vi to Z' z CD M .to CO 2 . to to z 25 .* to CO :25 Z a CO to zz to to z- .25 , to to z ..z .a co co .z 25 . to CO zz CO to z St a to to z Z to to 2 25 a to to z .2: , to to 2 as 4 0 to a St .-tr / The variances o f these groups were heterogeneous. CL in ifi vs 3O >> .> > I--r *-h * DUP04001165T * O r -M t/i cb *--* s,.. CCl 10 O CM -- OO -O P ai U. t? | <c -M 1. i to Ol fN-'Csr 00 .*--* ai to - "o o o o> c i? e >d 8 -M f- 5 3r > .S-- .i* O S~ <s m x: OvO **r a> 4- xi O ** CL. <tf ft* to 3:j CCO *- +> E to >> ** >>*0 4- c? r-f a 0 S * XI I2-X-0*-- (d 1: aj in fl5 to * c bi**" 0 ou*-' r- O CL I 4-* , E <T5D 0*h O .3 U *-* f*~ *-r 4- *-- rio a to >-** 3 jo * cn 0 OJ EO C Sr-- CS <J ix. M3 ai Jc 0 ; s; s- cn i- 0 *-- 0'r*CJ2:u _C <0 _ Xk- r* 3Jj -- E Qu. to <0 CL. C u :QTO 4- .flj 'r- B a OV-M r-- \ </* U> .0* >> O *** E 5- *J O 3 '* <0 S-^-v-M * U> E * t/> * 3 OV ..-* O W '-*-' S- *-H 0+ "O *M CL tZ St- 3 W CO tz>,r 3 0 *1" ^ 25 .*^U<1K3 ^ c o e *; ' > .O r-- CL p ~a = c__ *-- 0 U- CO M QJ *M <J" +* 1^- G -f-- CO O O wi E <J <11 c a? 1 1 J-- E ,; 0 SI O > ft* O PH-aa G -3 3 m 5-.v^ 0 O fO 0) iG *3 r" -M :3^ Kf P OO ' ]* CO ri-'w 0 JO .INr-- -pH* +4 .* S- CO f-- ,^7?v a-l cO <f . > M -to ** 2 CO >--' O M <0 M S3 ftJ 5C * 4- 3: co -O OO cp ' a 0 O fM <0 $>. a c 3 * M 0^ rs 0 Pp V' CO r?* * r-- CM CSJ ^ <0r-- 44 ? u *r-- O L > J= I-- n M 3: r-^ a 00 * 00 S-*" cocn ^3* O O0 O r* G ns *r* t. <0 S..cc -M 2 co 01 - . O U> r-* *> <T^ CO CO CO 4_> {--; jc; >k jfb G3 in co t-- G r^. 0 a# > O CM 1-f T3 00 0 00 >-s. tfl r* O OO 0.0 ' 1' in ; CM 0 op 00 * * p CO 2- .O OO OO 'W O r-- in 0 O0 <T CO tD r*: OQ s-> Wtt * > PO CO CM . co ***.,, .r--' O in m.O OO ^ipw J>- .C O CO r-- P O) LO Q OO #i-*S CM <M in .* 00 v 0.Hr ' 10 co r^->-1* , v> z: > in .2: * 2:. V p ,2 co r^. O < CM O ..iL?-' .CO "SC .* <00 <Or- ** 5M OO CO 0 OO 0p " . O Yr~r r--b IS-*" CM P r--' O O O. CM CO CM V-* *-- ?sr ^Q 0p ' p0 st-^'* CM;P: 0 r> ,. '* a> cn m --^ Cn . in co 0 00 ]>% CM l>S * . -i ; 0 csi intn !l>. O *t O O--:* ***% co * O CM CM>-> *-> r-r- 'M* *-- O OO . OO *>* V-*!* CM * :* ..CM -O to > `2? >s> CM --* . * in jer r> w - . - ' *5f<M CO.O u> 0 * vj CL to!* <n 0.>0w> P CM > 0 .* Pr^ CM U> * 00 sf rv CM CM '*--> **"N CO cPr p 0 O0 -2 </> cu u c 1--1 O co 44 2 G CJ U *r- . 4- to Z 25 a> 1^ <n > xA -2S *3- .r1CO r- . OO Q rCO p-r OP O CA ^3" p OO to in CO r-r- . 4> rr- O CO--- 1 * TV^t in>-- U5AI r** CO . CM O P.fO * CO AO ip^--1' O CO 0% r" . -r- O w*" in en OP tok 2: 00 2S 0 .co <3" CO CM ON m r*^ co CM'-- ^s in 10 CM O fj- <M CO'--^ 0 00 2t --1 ; IO to ;2: - 55 ,* v> tO . to to z 25 . 55 z * * to ss V} to .25 35 a to to z 25 .00 to 25 .'25 ,* to to z 2= to to 3: 25 to to z* .25 to to 2= ' 25 tSi to f 35 to tO 35 to to z: 25 w ,2> * P *--t P to .Z: P 1-4 P ja p M P P to :35 25 . . a to p P 25 Z :2? . , to p - P f :35 25 25 ik to z. P *-* CO <0 to 35 . te: _a P P 25 a P 25 P to to 25 25 3: . `a to P z: 25 P 25 . .a an P P 25 z; Z5 .0 .a PPP 35 25- -Z: a , to P P z: 25 > a PP P 25 25 325 . PP P Z Z: 25 P P to 25 ST 25 aa P to to 25 25- ' z --< 5> p > w to >> to V> .v> :> :> > v> > CO! 176 * The variances o f these; groups were heterogeneous. V > X* DUPG40011658 fable 39- Histopathology Incidence table for Statistical GroupingB, comprised of the following; Group I - Control, Group II - 0.51 ppm NQ? Group III - 0,51 wg/m3 PbClBr, and Group IV - 0.48 ppm NO? + ' 0.54 mg/mS PbClBr. - s LUNG Focal Pleural Thickening Peribronchial Brown Pigment Artifactual Emphysema Alveolar Duct Fibrosis Thickening Bronchiolar Wall Bronchiolar Epithelial Hyperplasia Bronchiolar Epithelial Hypertrophy Pneumonocyte Hyperplasia Peribronchial Lymphoid Hyperplasia Emphysema Focal Necrosis Focal Hemorrhage ; Parasite Perivascular Edema Pulmonary Edema Bronchial i ti s Bronchitis Monkey Pox Vasculitis Granuloma Pneumonitis Abscess Lung Mite Infestation Adenomatosis Bronchiectasis Purulant Pneumonia Epithelial Necrosis Thickened Alveolar Wall PIeUriti s Crystallin Material {yellow) Mucous Focal Fibrosis Pleural Fibrosis Alveolar Nall Fibrosis Vacuolated Media Endothelial Hyperplasia Stenotic Chronic Pneumonia Eroded 8ronchi Emphysematous Bulla JL 2/9 1/9 4/9 9/9 0/9 .0/9 0/9 1/9 1/9 0/9 0/9 0/9 .0/9 _ 0/9 0/9 1/9 0/9 . 0/9 1/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/S 0/9 0/9 0/9 0/9 0/9 0/9 GROUPS it III 0/9 1/9 2/9 3/9 -9/9 2/9 0/9 2/9 1/9 2/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 1/9 1/9 3/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 D/9 0/9 . 0/9 0/9 0/9 0/9 2/9 3/9 0/9 2/9 1/9 1/9 2/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 .0/9 0/9 0/9 0/9 0/9 ' 0/9 0/9 0/9 0/9 1/9 0/9 2/9 0/9 .0/9 0/9 2/9 0/9 0/9 0/9 0/9 0/9 0/9 IV 3/9 0/9 0/9 3/9 2/9 1/9 1/9 2/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 2/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 2/9 0/9 0/9 0/9 0/9 0/9 0/9 - 177 - DUP040011659 Table 39 - Continued LUNG - Continued Atelectasis Congested Extravasated Blood Collapsed Alveolar' Wall LIVER Pericholangitis Bile Duct .Proliferation Focal Necrosis , ..... Sinusoidal Pigment Focal Hepatitis Focal Lymphoid Infiltration Nematodlasis Thick Capsule Granuloma Abs'ceSs''"" ....... ' ' Hepatocyte Vacuolation . Greenish Granular Material in the Hepatocytes PERIBRONCHIAL LYMPH NODE Phagocytized Pigment Lymphoid Activity Lymphoid Atrophy Adenitis Granuloma RetiCuloendothelial Cell Hyperplasia Lymphadenitis TRACHEA Tracheitis Increase in Goblet Cells Exudate in Lumen Necrosis of the Epithelium Inclusion Bodies Epithelial Hyperplasia Cilia Atrophy Spuamous Metaplasia Focal Hemorrhage GROUPS I II m 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 Q/9 0/9 1/9 r 2/9 0/9 0/9 2/9 9/9 0/9 0/9 1/9 1/9 0/9 0/9 0/9 0/9 - V/J 0/9 0/9 0/9 1/9 0/9 0/9 3/9 3/9 0/9 2/9 0/9 1/9 0/9 0/9 0/9 1/9 i/9 IV 0/9 0/9 0/9 0/9 4/9 - 3/9' 0/9 2/9 0/9 0/9 0/9 0/9. 0/9 0/9 2/9 0/9 6/9 7/9 7/9 8/9 4/9' 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 1/9 1/9 0/9 0/9 0/9 0/9 1/9 1/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 n"/irp, 0/9 0/9 e/s 0/9 0/9 0/9 1/9 0/9 0/9 1/9 . 0/S 0/9 0/9 0/9 8/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 Q/9 0/9 0/9 * 17:8 - DUP040011660 Table 39 - Continued KIDNEY Interstitial Nephritis Epithelial Vacuolatin Tubular Dilatation Loss of the Brush Border Nuclear Vesiculatioh Tubular Hypertrophy Pyelitis Focal Mineralization Glomerular Oegeneratlon Inclusion Bodies Vasculitis Congestion Focal Fibrosis Perirenal Abscess iotein inhibition ............... Iniima Thickening Endothelial Hyperplasia HEART focal Myocarditis Endocarditis Eplcarditis Myocardial .Degeneration Vasculitis Subendocardial Hemorrhage Thickened Endocardium Focal Hyperplasia in the Endothelium Intima Thickening Granular Pigment GROUPS I II lit IV 0/9 1/9 3/9 0/9 0/9' 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9' 0/9 0/9 t/9 0/9 1/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 .0/9 0/9 6/9 ` ""0/9 0/9 .0/9 2/9 3/9 0/9 3/9 0/9 0/9 , - 0|//99 0/9 7/9 . 0/9 0/9 0/9 0/9 T/9 0/9 0/9 2/9 7/9 1/9 . 5/9 4/9 .0/9 0/9 6/9 0/9 9/9 ... 0/9 1/9 1/9 .0/9 ~ 6/9'0/9 0/9 3/9 2/9 0/9 2/9 0/9 0/9 0/9 .0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 - 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 - 179 - DUP040011661 HAZLETON LABQRA JOfUES, INC. V. STATISTICAL GROUPING C - RESULTS OF THE CHRONIC EXPOSURE OF CYN0M0LGU5 MONEYS TO 9.70 PPM SULFUR DIOXIDE (SO2), 0.51 MG/M? LEAD CHLUROBROMIDE (PbClBr), AN0-9;93 PPM SO2 COMBINED WITH 0.50 MG/M? PbCiBr. Four groups of animals comprise the third statistical group!ng-C, One group was maintained as the control group exposed to filtered room air, while the other three'groups were exposed to sulfur dioxide and lead chloro- ' y. bromide singly and in binary combination. Group designations used throughout this section are presented in Table 12. Table 12 - Group C designations Group Designation (No.) I {1} - ... II 5) HI 0) IV (18) - Agent Control ,S02 PbClBr so2 PbClBr Nominal Concentration 0 10,00 ppm 0,60 mg/m? 10,00 ppm 0,60 mg/m^ Mean Analytical Concentration 0 9.70 ppm 0,51 mg/m^ 9.93 ppm 0,50 mg/nP 1, Exposure concen trati00s The chamber concentrations, as determined analytically are presented in Tables 1, 2, and 3, Appendix C for Groups II, III, and IV, respectively, Tire mean and standard deviation for the group exposed to S0? alone was 9.70 ppm t 1,10.; for the group exposed to PbClBr alone 0.51 mg/n? t 0,27; and for the group exposed to the combination of S02 and PbClBr, the means and standard deviations were 9.93 ppm 1.03 and 0.50 mg/m^ 0.27, respective^ - 180 - DUP040011662 fp 2, Psrticlje Size Determination The mean and geometric deviation of all count particle size determi nations for PbCIBr converted to mass median diameter (MMD) were 0.550p t 1.57 and ].]30n t 1,84 for Groups III and IV, respectively. A composite size vs. . distribution log-probability plot from the pooled count data 1$ presented in Figures SO and 51 for Groups III and IV, respectively. 3, Biological Measurements 3.1. Body Weight Analysis of variance of regression (Table 4, Appendix C) indicated significant slopes among the groups. No significant differences in.growths rate were' found between'Group .1 ..and the other groups. Figure 52 presents the linear regression curves for the four groups. 3.2. Survival Wo deaths occurred in Groups I, III., or IV during the 104-week exposure period. One monkey in Group II was sacrificed in Week 40 due to extensive monkey pox lesions. Daily observation of the animals revealed no clinical signs of toxicity or abnormal behavior attributable to the exposure atmosphere. 3.3. Pulmonary Function Tests 3.3.1. Mechanical Properties of the Lung and Respiratory System 3.3.1. ]. Total Respiratory System Flev.< Resistance During Inspiration [Rrs(i}] Analysis of variance of regression for Rrs(i) (Table 5, Appendix C) revealed non-parallelism among the groups. The third degree polynomial regression - 181 - DUP040011663 Count Diameter microni (m-)- Figure 50 Particle, size distributions (count diameter) of PbCIBr. 182 - DUPG40011664 Count Diameter - micron! (m-) Figure 51 - Particle size distributions, (count diameter) of PbC.TEr for the group exposed to- the combination of PbClBr- .and' - ' * 183 - DUP040011665 O YW tlG HTU*} Figure 52- First degree polynomial regression curves for body weight prior to and during exposure to sulfur dioxide and lead chlorobromxdr singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 184 - DUP040011666 _- ,, V -== * = -7.'*-'rr*C*t,i#v ` **5S?i3j5srs ^aS^sSsEtr&iw'.s?- r-ri j 4, --.*rf".. K4ZU TO* LAGOM, OA/f$. WC*- ~. ^; M> jr:-.~_ -f' ~ t i V* v%r . ,. -M'--f~ -C' curves (Figure 53}* icdlce^ed jciiat^firs(}.Ys1.tf^.lf0r Group III were slightly / * * *r - ~ -*1:- *V- ^ . jir*s 1 "C'' "'*7 r ->*" -MT:yi"^;V- higher tter, Group I.during the first rlr.r weikprof exposure, but thereafter 'V ' v'.,5 ' - - ,-; ' were similar to Group-I.'l-A t-lesc of the preriexpdsure adjusted titans, for . rw thisf'early iiwen'.l_>as`s'lgnifiMit' (t *.3'\~1ihf. * 16).. A simiian-- lied a significant t value - - a During Expiration prs(e)] (Table 6, Appendix C) .indicated -non-para ileTlsip nmobg the grouser The' third degree polynomial . regression.curves.(Figure 54).indicat'd chat Zvoup 1 decreased with i/me slightly more th/n-the other grrups, starting from higher pre-exposure values.' A t-test:of pre-ey.posure adjusted overall exposure means indicated ' ;Si vf- r- . ' r- -w? ^ that Group IV was-, significantly higher throughout (t ~ 3.63, <l,f. = 16) and indicated a significant difference between Groups I and II (t = 2.83, d,f. = 16). Group III was-not-significantly different from. Group I by this test (t = 1,92, . 3.3.1,3. Tidal Volume (VT) u'lysis of variance of regression for Vy (Table 7, Appendix C) revealed no significant slope differences among the groups. Tne third degree polynomial regression curves (Figure 55) indicated that all groups increased with time, 185 DUP040011667 roTAiTtesnuTOisY s y s t D m i Figure 53" Third degree pol.yn.6mia] regression curves for Rrs{i) prior to and during exposure to sulfur dioxide and lead chiorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 186 DUP040011668 TOTAL MSPtSATOkY SYSTEM FLOW LEStSTAHCE- EXPIRATION [X n ( K m . M jO /m l/ijs ] Figure 54- Third degree polynomial regression curves for Rrs(e) prior to and during exposure to sulfur dioxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 187 - DUP040011S69 TIDAL 'A3 LUME ( V j m l.)- Figure 55 - Third degree polynomial regression curves for Vy prior to and during exposure to sulfur dioxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 188 - DUP040011670 HA2LETOU LASQRA TORIES. INC. 3.3.1.4. Respiratory Rate (RR) Analysis of variance of regression for RR (Table 3, Appendix C) Indicated non-parallelism among the groups. The third degree polynomial regression curves are shown in Figure 56, Inspection of Figure 55 indicated that RR values for Group IV were slightly higher during the pre-exposure period and remained slightly higher throughout the exposure period. ' 3.3.1.5. Dynamic compliance of the Lung [Cdyn(l)j Analysis of variance of regression for Cdyn(.l) (Table 9, Appendix C) revealed non-parallel ism among the groups.. The third degree polynomial regression curves are shown in Figure 57. Inspection of Figure 57 shows chat Group I, which was considerably lower in Cdyn(l) during the pre-exposure period, had a marked increase at the start of the "exposure" period and increased slightly thereafter as did Groups III and IV, Group II, on the other hand, started from a higher pre-exposure level, increased at the start of exposure but did not increase further. The difference between the pre-exposure adjusted overall means of Groups I and II was not significant (t - 1.87, d.f. = 15), The pre-exposure adjusted differences in the means of the first year for Group I vs. Group III and for Group I vs. Group IV were significant (t * 2.69, d.f. * 16 and t - 2.30, d.f, = 16, respectively); however, the large jump between the pre-exposure values and the start of the "exposure" period in Group I renders difficult any interpretation of these differences. - 189 DUP040011671 lit SPlfcATOW * * t ( M - tn K itb / ml.v) 8 8 8 8 8 8 & 88 Figure 56 - Third degree polynomial regression curves for RR prior to and during exposure to sulfur dioxide and lead chiorobroroide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 190 - DUP040011672 C O M m X N tS O f tHE'iUNO jcdyn (IJ atom, H gO ] I TIME-WEEK! Figure 57 - Third degree polynomial regression curves for Cdyn{l) prior to and during exposure to sulfur dioxide and lead chiorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 191 - DUP040011673 HAZLETO/f LABORATORIES. INC. 3.3.1.6, Pulmonary Flow Resistance (R1) Analysis of variance of regression for Rl (Table 10, Appendix C) indicated nonJparalleiism among the groups. The third degree polynomial regression curves are presented in Figure 58. Inspection of this Figure indicates that the trends with time differed among the groups, put thi.c the Rl values were generally similar for all groups, except Group I, which did .not decrease as much with time. A t-test of the pre-exposure adjusted means of the first nine weeks of exposure indicated that Group IV was significantly higher than Group I (t - 2.39, d.f, = 16) as was Group III (t = 2.66, d.f. = 16). 3.3.1.7. Work of Breathing During Inspiration per ml Tidal Volume [W(i)/ml VjJ Analysis'of variance of regression for W(i)/ml Vj (Table 11, Appendix C) revealed non-parallelism among the groups. The third degree polynomial regression curves are presented in Figure 59, Inspection of this Figure indicates that both Groups III and IV had lower values than Group I throughout the study. 3.3.1,8. Work of 8reathing During Expiration per ml Tidal Volume [W(e)/ml Vj] Analysis of variance of regression for W(e)/.ml Vj (Table 12, Appendix G) indicated no significant slope differences among the groups. The third degree polynomial regression curves (Figure 60) also indicated no observable differences among the groups. - 192 - DUP040011674 "0 ' PUlMONWtV FLOW RESISTANCE <RI on. HjO/WCfac)- Figure 53 - Third degree polynomial regression curves for Rl prior to and during exposure to sulfur dioxide and lead chloro- bromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. ~ 193 - DUP040011675 ] WORK OF SREAIHING' DlSINC INSPIRATION FIR rat TIDAt VOt-OMI [w(l)/rat Vp 9 ra .t* /1ml V j ], 7tM-WEEKS figure 53 - Third degree polynomial regression curves for W{i)/ml Vj prior to and daring exposure to sulfu-" dioxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 194 - DUP040011676 ViOSK Of ifiA IH IN O 'O'JMUS EXflfMION H I. tlB X tV O tU M V j . 1 J .3.0 i ' ' i jj--j ; s*2*0 . * 1.... 1 3 1* ____ .____ 1__________,___ l | -B---ai...... , a 1 *i .. r .5 r* 1.0 . . i .i . 2.5 , { ` ,,n! ! SIJ " J* . a. - ------- .. fa . t i 1- i i 2.5 f !--------------- S------ ------------- 1 1 ---------- i-------- : a! 1.5 "-- aj u...... !; i -a a L --.__ _J____ .________ n 0 Q B A m ff m n. O 0 a A A ' a "* a 0 [CK>UP ~f- CoVitepn S " -- 4 H j GiaUr tf a .a - a m a -tr a a a j GftOUPfll -O.H.jAft ftCle. * S' "................ * " o' .* | <58PW IV - ?. S3 ppn SOj . O.M PbCiE. | a 20 a B a '' 49 i TIME -WEEKS a 60 BB .B ,, ... B' a " B 30 M SO ioo h o Figure 60 - Third degree polynomial regression curves for W(e)/;ml Vj prior to and during exposure to sulfur dioxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 195 - DUP040011677 \ l I % * HAZLETQfS LABORATORIES. INC. laapfi! 3.3,2* Diffusion ^ 3.3.2.1. Diffusing Capacity of the lung for Carbon Monoxide (DLq q ) Analysis of variance of regression for DL^ (Table 13, Appendix C) revealed no significant slope differences among the groups. Ths. third degree polynomial regression curves (figure 61) indicated that DL^q for all groups increased with time, 3,3.3. Distribution of Inspired Air, Nitrogen Washout , 3.3.3.1. Number of Breaths from 80% to 1% Nitrogen [N(l% fl,)] Analysis of variance of regression for H(l% N^) (Table 14, Appendix C) indicated no significant slope differences among the groups.. Inspection of the third degree polynomial regression curves (Figure 62), indicated that li(1 % N2) values for Group I were somewhat higher during the pre-exposure control period than values for Groups II, III, and IV. During ths entire exposure period, N(l% N2) values for Groups I and II were similar, but values for Groups III and IV were at a higher level. Separate t-tests of the pre-exposure adjusted overall exposure means were made to compare Group I with Groups II, III, and IV during the exposure period. These tests indicated that Groups II, III, and IV were each significantly higher than Group I (t - 2.77, d.f. = 16; t ~ 4.55, d.f. - 16; and t = 3,26, d.f. - 16, respectively). - 196 -. DUP040011678 ....... -1 A 'i ' 1 DlFfUSUsG CAPACITY OF THEUING FOR CWIIOMMON0X10E (0Li;o -'<nVmiri/iwi'H8 . Sirai) Figure 61 - Third degree polynomial regression curves for DL^q prior to and during exposure to sulfur dioxide and lead cftlorobromide singly and in binary combination. Eacn point represents the mean for the animals tested at the indicated time for the various groups. - 197 - DUP040011679 Figure 62 - Third degree polynomial regression curves for N(l% %} prior to and during exposure to sulfur dioxide and lead chlorobromide singly and in binary combination. Each point represent'- the mean for the animals tested at the indicated time for the various groups. - 198 - DUP040011680 HAZLETON LABORATORIES. INC. 3.3.3.2, Respiratory Rate Measured During Pure Oxygen Breathing (RR') Analysis of variance of regression for RR' (Table 15, Appendix C) indicated no significant slope differences among the groups. The third degree polynomial regression curves are presented in Figure 53, Inspection of Figure 63 indicated that RR* values for Groups I and It were essentially the same during the pre-expo-sure period and the entire exposure period. However, RR* values for Groups III and IV were higher than Group I following the forty-fifth week of exposure, and remained higher until the end of the experiment. Separate t-tests of the pre-exposure adjusted overall exposure means indicated that both Groups III and TV were significantly higher than Group I (t = 2.61, d,f, - 16 and t - 2.28, d.f, = 16, respectively). 3.3.3.3. Cumulative Tidal Volume from 80% to 1% Nitrogen [CV^(1% N2)] Analysis of variance of regression for CVy(l% Ng) (Table 16, Appendix C) indicated no significant sloHv differences among the groups. The third degree polynomial regression curves are presented in Figure 64, Inspection of Figure .64 Indicated that Group TV had somewhat lower CVy values during the pre-exposure period and generally remained lower than the CVj values for the other three groups during the exposure period. Values for Group III were slightly higher overall than Group I throughout the exposure period, A t-test of the pre-exposure adjusted overall exposure means comparing Groups I and III indicated that Group III was significantly higher (t = 2,24, d.f, = 13.7} throughout the exposure period. - 199 - DUP040011681 Figure 63 - Third degree polynomial regression curves for RR` prior to .and during exposure to sulfur dioxide and lead chlorobromi.de singly and in binary combination* Each point represents the mean for the animals tested at the indicated time for the various groups. - 200 - DUP040011682 CUMULATIVE T.I0A1. VOLUME T O 'I* NITROGEN [CV (m N j) - lilin STPO}t Figure 64 - Third degree polynomial regression curves for CVj {1'1 N?) prior to and during exposure to sulfur dioxide and lead chiorobromide singly and in binary combination. Each point represents the mean for the animals tested at . .... the indicated time for the various groups,. - 201 - DUP040011683 ? < 3.3.3.4. Tidal Volume Measured During Pure Oxygen Breathing (Vj`) Analysis of variance of regression for Vj' (Table 17, Appendix C) revealed non-parallelism among the groups- The third degree polynomial regression curves are presented in Figure 65. Inspection of Figure 65 indicated that Groups I, III, and IV increased slightly with time while Group II maintained a constant level throughout the experiment. A t-test of the pre-exposure adjusted overall exposure means indicated that Group II was significantly lower than Group I (t = 2.44, d.f. = 16) throughout the exposure period. 3.4. Hematology The group means "and analysis of`variances of the various hematological variables measured are presented in Tables 18, 19, 20, and 21, Appendix C. Mo consistent trends were noted in any of these variables which remained within normal limits throughout. Random statistically significant differences were seen, but were not consistently related to the exposure conditions. 3.5. Clinical Biochemistry The group means, standard errors, and the results of the analysis of variance of the various clinical biochemical variables measured are presented in Tables 22 through 35, Appendix C. Scattered statistically significant differences were noted; however, no trends were seen in any of the variables. Throughout the study, the group mean values fluctuated within the normal ranges of these variables. 202 - DUP0400-H684 TIDAL VOtUMj .['{During Pur* OMyg'tn Breathing) - V ^-m l BTf'Sj Figure 65 - Third degree polynomial regression curves for Vj` prior to and during exposure to sulfur dioxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups.. - 203 - DUPQ40Q11685 HAZLETON LABORATORIES. INC. 3.6. Arterial Blood Gas and pH The group means and standard errors for the blood gas variables are presented in Table 36, Appendix C. Examination of these data did not reveal any consistent trend with time. No apparent exposure-related changes were seen in any of these variables. 3.7. Terminal Body Weight, Organ Weight, and Organ Weight as a Percentage of Body Weight * The data of the terminal body weight, organ weight, and organ/body weight ratios are presented in Tables 37 and 38, Appendix C for males and females, respectively. Several significant differences were found between the experimental groups and the control group. The adrenal weight for the males in Group II was significantly higher than Group I, and the adrenal weight and adrenal weight/hody weight ratios for Group IV males were higher than Group I. The liver weight/body weight ratio for Group IV females was significantly higher than for Group I females. Several other significant differences were found from comparisons made between the various experimental groups; however, no consistent trends could be discerned. 3.8. Histopathology Summary A detailed listing of the microscopic alterations seen in the lungs,* tracheas, livers, kidneys, peribronchial lymph nodes, and hearts from the animals in the control and exposure groups are found i.i Table 39, Appendix C, Microscopic examination of the tissues from the animals exposed to 0.6 mg/m3 PbCIBr and to the combination of 0.6 mg/mX Pb.Cl.Br and 10,0 ppm SOg revealed exposure-related alterations in the kidneys. These microscopic alterations were characterized by varying degrees of degeneration in the proximal convoluted tubules. Hie epithelial cells of the proximal convoluted tubules were vacuolated and possessed yesiculated nuclei. Numerous intra nuclear, acid fast inclusion bodies were seen in the epithelial cells of the proximal convoluted tubules. No other exposure-related microscopic alterations were seen in the lungs, liver, trachea, peribronchial lymph node or hearts, Scattered incidental lesions were seen in these organs from both the control and test animals. No difference in the incidence and severity of these lesions was seen when the controls were compared with the exposed groups. Animal number 182L in the group exposed to 10.0 ppm S0g died during the 40th week of exposure. Microscopic examination of the tissues from this animal revealed lesions consistent of monkey pox in the lungs, liver, and trachea. 3.9, Summary The inhalation exposure of male and female cyncmolgus monkeys to 9.70 ppm SOg, 0.51 mg/m3 PbClBr, and the combination of 9.93 ppm SOg plus 0.50 mg/m PbClBr resulted in a deterioration in the distribution of ventilation in the animals in the two groups containing PbClBr. The number of breaths to 1% nitrogen and respiratory rate measured during pure oxygen breathing for both groups were significantly elevated above the controls, with respect to their relative pre-exposure values throughout the exposure period. Cumulative tidal volume to nitrogen was significantly elevated in the group exposed to PbClBr alone, but this change was not seen in the - 205 - DUP040011687 #AZLTON UtBQRATOfVES. iNC. group exposed to the combination of SDg and PbCIBr. With the exception of higher breath to IS nitrogen values than the control group, none of these differences were observed in the group exposed to 9.70 ppm SQg. This ',ne difference was probably due to the high pre-exposure values of the control group. Microscopic alterations related to the exposure to PbCIBr were found in the kidneys of the animals of these two groups. These histopathological changes were characterized by varying degrees of degeneration of the proximal convoluted tubules. The epithelial ce'.is of these tubules were vacuolated and possessed vesciulated nuclei. Numerous intranuclear, acid fast inclusion bodies were seen in these epithelial cells. Body weight measurements made on both the control and exposed animals throughput the exposure period indicated that the animals in all .groups increased in body weights. Analysis of these data did not reveal any significant differences in the rate of growth between the control and exposed animals. No meaningful differences were detected in terminal body weights, organ weights, or organ/body weight ratios between the control and exposed groups. Hematological, cl inical biochemical, and arterial blood gas measurements .were made on both the control and exposed animals pre-exposure and periodically throughout the exposure period. No trends were detected in any of these variables in the exposed animals. No meaningful diffsrattces were detected between the control and exposed animals. K r i LABORATORIES *A Appendix C - Data-compilations and summary of statistical analysis for Statistical Grouping. C, comprised of the following: Group I - Control, Group II - 9.70 ppm SO2, Group III 0.51 mg/m3 PbClBr, and Group IV * 9,9.3 ppm SO2 + 0.50 mg/n)3 PbClBr. - .207 - 1i DUP040011689 Table 1 - Monthly means and the grand mean for the analytical concentrations of sulfur dioxide for Group II, Date 3/31/68 - 4/30/68 5/ 1/58 - S/31/68 6/ 1/68 * 6/30/68 7/ 1/68 7/31/68 8/ 1/68 - 8/31/68 9/ 1/68 - 9/30/68 10/ 1/>8 * 10/31/68 11/ 1/68 11/30/68 12/ 1/68 - 12/31/68 1/ 1/69 1/31/69 2/ 1/69 2/28/69 3/ 1/69 - 3/31/69 4/ 1/69 * 4/30/69 5/ 1/69 - 5/31/69 6/ 1/69 - 6/30/69 7/ 1/69 - 7/31/69 8/ 1/69 - 8/31/69 9/ 1/69 9/30/69 10/ 1/69 10/31/69 11/ 1/69 - 11/30/69 12/ 1/69 - 12/31/69 1/ 1/70 - 1/31/70 2/ 1/70 2/28/70 3/ 1/70 - 4/ 2/70 nX ppm 31 8,2971 31 8.6948 30 9,2770 31 9.5377 31 7.8032 30 9,4020 . , 31 9.7019 30 10.3617 31 9.6352 31 8,0226 28 9.8011 31 9.5323 30 10,8390 31 10,1565 30 9.976;/ 31 10.2965 31 10.4761 30 9.7290 31 10,0545 30 10.1233 31 10.3842 31 10,3281 28 10.1696 31 10.1761 N = 24 X = 9.70 i.D. * 1.10 s,p. 1,8973 2.1871 1.4754 1.1408 2,2104 1.6718 1.9957 0.9926 1,1671 2.1781 0.7511 1.3048 0.4810 0.6112 0.7275 0,7100 0.6406 0.5017 0.4857 0,4409 0.5963 0.61,98 0.5316 0.6594 - 208 DUP040011690 Table 2- Monthly means and the grand mean for the analytical concentrations of lead chlorobromi.de in Group III. Date 5/11/68 - 5/31/68 6/ 1/68 - 6/30/68 7/ 1/68 - 7/31/68 8/ 1/68 - 8/31/68 9/ 1/68 - 9/30/68 10/ 1/68 10/31/68 11/ 1/68 11/30/68 12/ 1/68 12/31/68 1/ 1/69 1/31/69 2/ 1/69 - 2/28/69 3/ 1/69 - 3/31/69 4/ 1/69 4/30/69 5/ 1/69 - 5/31/69 6/ 1/69 - 6/30/69 7/ 1/69 - 7/31/69 8/ 1/69 - 8/31/69 9/ 1/69 - 9/30/69 10/ 1/69 - 10/31/69 11/ 1/69 - 11/30/69 12/ 1/69 - 12/31/69 1/ 1/70 - 1/31/70 2/ 1/70 - 2/28/70 3/ 1/70 - 3/31/70 4/ 1/70 - 4/30/70 5/ 1/70 -- 5/ 5/70 n 20 30 31 31 30 31. 30 31 31 28 31 30 .31 30 31 31 30 31 30 31 31 28 31 30 5 X mg/m3 0.8570 0.4743 0.4565 0.6022 0,5773 0.5074 0.4286 0.4638 0.475.2 0.6154 0.5677 . 0.5147 0.7770 0.5503 0.5597 0,5010 0,4737 0.5352 0,4930 0.3871 0.4052 .0.5100 0.5561 0.3070 0.1080 * $,D. 1,0552 0.6379 0.3048 0.1068 0,1526 0.1497 0,1944 0,1819 0,1339 0.7173 .0,1515 0,2131 0,1710 0.1740 0.2216 0.1545 0.2049 0.2722 0.0363 0,1065 0,2503 0,3669 0.2526 0.5232 0.0295 N ~ 25 X ' ' 0-51 S.D, = 0.27 - 209 - DUP040011691 Table 3 - Monthly Rigans and the grand mean for the analytical concentrations of sulfur dioxide and lead chloro* bromide for Group IV, S02 PbClBr Date 6/ 1/68 - 6/30/68 7/ 1/68 - 7/31/68 8/ 1/68 - 3/31/68 9/ 1/68 - 9/30/68 19/ 1/68 - 10.31/68 11/ 1/68 - 11/30/68 12/ 1/68 - 12/31/68 V 1/69 - 1/31/69 2/ 1/69 - 2/28/69 3/ 1/69 - 3/31/69 4/ 1/69 - 4/30/69 5/ 1/69 - 5/31/69 6/ 1/69 - 6/30/69 7/ 1/69 - 7/31/69 e'i/69 - 8/31/69 9/ 1/69 - 9/30/69 10/ 1/69 - 10/31/69 11/ 1/69 - 11/30/69 12/ 1/69 - 12/31/69 1/ 1/70 - 1/31/70 2/ 1/70 - 2/28/70 3/ 1/70 <- 3/31/70 4/ 1/70 - 4/30/70 5/ 1/70 - 5/12/70 n 30 31 31 30 31 30 31 31 28 31 30 31 30 31 31 30 31 30 31 31 28 31 30 1.2 X PPm 9,0860 9.4800 8.1126 8,1710 9.8820 9.8613 10.1381 $.1694 9.9996 9.8535 10.6361 10,2061 10.0123 10.2297 10.5742 9.9700 10,1168 10.2610 10.4919 10.5181 10.4392 10.4284 10,8520 10.8500 s.o. 1.2098 1,5272 2,3330 1.8994 9.2737 0.9160 1.2822 2,2516 0.9223 1.4923 2,0651 0.6014 0,7646 0.7385 0.6935 0.5091 9.4745 0,3675 0.3204 0.4787 0,3409 0.4740 0,2919 0,4373 . X mg/m3 0.7460 0.6381 0,5897 0,4690 0.4271 6.3920 0.4500 0,4755 0.5825 0,6377 0.5557 0.6194 0,6340 0.4252 0,4516 0,4090 0,3925 0.4333 0,5413 0,5906 0.5257 0.5903 0.2017 0,2417 S.D. 0.6084 0.3021 0.;57$ 9,326:0 0.1582 0,1834 0,1752 0.1776 0,3086 0.2419 0.2620 0.1859 0.2501 0.1405 0.2649 0,1720 0,2516 0.1563 0.2833 0.3867 0.9777 0.2595 0,0730 0.1083 = 24 X = 9,9:3 S.O. =1.03 - 210 N = 24X 0.50 S.D. = 0,27 y DUP040011692 fo llo w in g : Group 1 - Control , Group IT - 9.70 ppm SOg, Group - 0.51 mg/m3 PbCTBr, and Table 4 * Sunwary of s ta tis tic a l analyses o f body weight data fo r S ta tis ticI I I a l Grouping C, comprised o f the Group IV - 9.93 ppm SOg + 0.50 mg/m3 P b tlfir. VoO> r<t7f' cnfr*- vo o> o .0 iOn v] a cl ro 1 ro o ,co .* o tn ictuoc CD O=c' LU oU. LU -O -<'SSI' Mcc 3> au. CtoO to >- CO to *Oo3* OJ o CoO cr aCMO> CM CO VO *o CO CO sc o e oU. 1_ LU ro O: CL ICtT or? c: CO 4<.1a a> C7> CO +1 <Or r-- Ol co -H CO CM .L> O CO +1 rttof* 41 ll. u. 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O! rS LUi ,S~ ta 2oO3il1j DC1> Ot O to I z: soa_ uJ - -224 0is. .03 CO co VO u> .IS 0 0 O .0 c CM ro O CM <r> ..ro r-- co \v_w-' 3. 0 TP to CO VO CM H2: -t- .0 to Ul O .*-* u. ,tL' 111 in us i t in in in O O 1 00 fU. #-T 11 00 `o'o t1 O'O r" r--- r ! -h V^* 2T O x x X X X X Xx to .00 O 03 FT* >-- CO coco in ; vp o 0*^- VO CM co 0 Ui cc <3 UJ co ^si* co r+ CO CO CM i11 +J -H 41 41 Cg. < >-< CO CO 00 CO CO co CO CO UJ -1 -1 11 Jc 00 Q O O O 0-0 O CO r-- r- f--.r-H rH* r-^ rr 2.' S-- +1 X X X X X X X X --J O o_ tO CJ h- CM co a\ VO OS r>* 0 0 TP CO cops 0 Rj" LU UJ or .2: LU m m m *=p co i VO CJ 41 41 41 41 CD *--1 UJ u. .a u_ Ul Q Q Ht 3C 1- 0 0 J1 r^** rr* 1t 11 11 2^ O O O OO OO O O ,f!" rr" r--* r" r--- ih* r-- .-!< to X X X X X X XX vs ca 0 Wis r>- Cd CM CC .CM M' in 0 :r^o 07 CO .1C1D1 CM CM fH. 5M r7 CM CM r-- a: 1 1 1+1 41 41 41 co O r*. CO m r-- r-* * CM CM ..CM 41 41 41 41 CO m Os CM O o- O r*-. OS in CO co -- Tl- 'i :i ' \ J j j DUP040011706 hematocrit (Bet. - percent) fo r male and female monkeys in S ta tis tic a l Brouping C. s* inINiM o O * v|> O l M3 * M3 O (VJP? OlN . . * M3 O CO t -- OON-' Ms -- P)v * P)s / CL 9 (/)9 inp CO .22 25 CMO3 -0oVX>3I CO O M3 *3* r-*- CO-CM r r^- .M3 O U3 r- IS. ,i CO*w CO W rtv' CO*> *-- O CO --* <9 tO CO 01 r- r-* *3* 0 *3* O *3* rr-- Ow OO w CO <3 0 OO COCO CQ*3* MC3Ow irntwp mco**o-- cowco *- MUa-t eM E.at 4aft4t) S. <xt J4<c4u ic.u ax. QtoO (A 't bs. v.i 2: 020: i/> 9 v) i/>9 to ,:a<saisyti 3* CO in ZT s; ICO <3svOiOn. X .01 MCO3 wcOo. ioCnO wro*. C<CMO0 weOo* COM*Cvr*V*-*I VVOSfc--d-i Eco3l o 5- CL f CXa*rVCauoLs*t)tL. <3 fO in 2= .00 I i--* 4OEio4 cio- OmCM ECCLL o4id3. COB SCD <or>?i ion Oc4C<C(_oS*MLucrCCO4oLuBs>LO3*. CoO\ oin *rt a c o JO ocsi act.j cy 4a. CO 03 J---fbd C=OLOJ - 25 - '1 f ij | i DUP040011707 '-'ffJitJii*W- 3*. r*. Table 19 - Mean values + {$ . .) and summary o f fa c to ria l analysis o f variance fo r hemoglobin (Hgb. - grams percent) fo r male and female monkeys in S ta tis tic a l Grouping C P f> CO <7> CM ip M CM3* r^O O O r* ion v! CL sr - . OW to <3 r*:-=S*Z . .#(O i-- *CpO JV 3QBi % ICO 0 <M W ro NW .. ,* . OO r-O OO r-o f^.v/ f--* *-:s--* r-* _ __ _ o j csi r~ csi .1--<n <-d o o o .<? <3 t~*-*~*-r**-**--* r*~**~* fc* H" **- u4 |+>? jj* >- *** on tocj CO.CM r--to r` O c> O *-- o LO r> If) CM CM CM CO CO P O o' P o o r"w >--* c4-> 0u1 Q. MXl o oc JOT *<uo ECL oo Pv5 to pi 'ipx':* zz :zs* v> o * *!-l <0u) .32 v> sf"</1 .O3T O 3 9-~ </5 s: .</} :& s V S- CQ CO >-- o * a XI x> CM cu CMCU Oo to P) i/J S* H-Sh a. cn 0.0 o ex O. +> o cr> O c a UTo o> to . <3 o P^sO 1 >_. --t -4 > -- cc o *X_r~** c: *- o 03 CM o .4O -Q o CO rtj di 4-* 01 o c c. 3 O v> - 226 - / DUP040011708 Table &0 - Kean values erythrocyte co(uSn.tE(*)RBaCn-d summary o f fa c to ria l analysis o f Variance fo r to ta l 10/cmm) fo r male and female monkeys vn S ta tis tic a l C.t ifo tip ln l o CO sa v\ 3C0>J I tt*oT* `**-r e? S, -CO-r*--** in* o o <n Qt~* * UlO <br* 40* CM> in >o> O co rt*r. ?or-rw^ >*> O r-* CO.r4 mo *T CO w40* oCM> m; .*cinv too in o v! A vM> .u0+1tUh4r ; c+ * o m eo ; <n.o io'ro fs<\i a\ f-- ro co o ,ca tn* o> ** q to oi* u>o* *#**" iC-O* o CM 1-- oCOocM ON CVlr- U)p in cp ^*0 in o mC? C/3 C3 t**o*4 Suo * to 3g to S#t tp ^ O CO CO m-* CO g <>> CO i OJ k Jo a oo t/V I t--t CJJ cko ro* Cm a. oCO CO E cc cr> A O rs* N?> in u O I1 MM *** * u CO 4- S <* Ag> a, coo O LO CT O Au >-4 sko.' CO - 227 - CM U X3 .0 Q_ CO V 48 ii Table 21 - Mean values (S.E.) leukocyte count (WBC and summary- per ctnm) f o o f r fa c to ria l analysis o f Variance fo r to ta l male and female monkeys in S ta tis tic a l Grouping Ttnmn-- ! w m;ii i ) o Q 0M33 i3XVP0I1I 0I0 a 3vi-> ap. X<a1>u S- a. oo o o 0.0 oo o* ** rO*- vr*w 0*r0o^o <L3f>0 o*3* LoO vj X ?a* CoMO 0.0 OO QO 0.0 CM CO COCO r~U> to CO CCMP*O--" VO M3 *O--lsC--O con>r-v- a --* oo VOrCM CM *3" r-F oo O CO rc>r%,o>>-^ oo 03 lOoacwn* ro-> oo r* CNl oo f*r-- to oo 1Sfr M3 O -IfO* oN Or-- r-- CO CQ^-> Q*r O*3- CM CO o ;o <7>K oooto j- 03 CO--- <o<oo>o4<7r1 6rt1S 4Ie4tf J ps4aX4. 04oc 4ft 4 <atS. o0E & -l 2: oo CO <or- ,** * v> rP .2<<xIeyy lh S> CD 0-3* o t<-ot ^ V) -sr sc 010 U 4. 3 V0*CL to CO H3 jaX004I11. z: s V) r-P 4. 44 C 0 o 1 o r-< iso_ *c--4a CM o43 a. O4o CO E N. a. PI a. E o -> r>*- U?* o> O tl 4a 4- 4453 CMO_ Oto<o E>>. o. cn CL B co o <71 in pi o 1 r- -4 .--4 co nf (- c t- p ra .2> Mpmu 24o*. 43 a. Gt0o>4 u xt -4 4043 :C w to - 228 - DUP040011710 r V*/ T a b le 2 2 ~ Mean. v a lu e s * ( S ,E ,) and summary o f f a c t o r ia l' a n a ly s is o f v a ria n c e f o r b lo o d g lu c o s e ( G lu . - mg p e rc e n t.) f o r m ale and fe m a le monkeys in S t a t i s t i c a l G ro u p in g i o CO %o VI ssau 3:. &I <y u 3ut 00oOX13J. sO. VO TO CO CM Lfj vo .; is ^-tn bcpiss--'* U) o v'i CO jfO <n O in 55f IS eISn- to bto-two Wat'-M--' CtoO*C-M* 4V->) O03 <4-- 4- uj O Rr ca rs o ; ; o i OV*** t> to o ; tr> to .Ope*-" VO CO /CO to o .o r>*- <inr*-*c-o-* tiso>.c--o iCnMsc-o* *os^sc-n* rtS <y s- 4<->0 G <33 E Vr*. <y Q. X LU co co co to n cn ,co OP r--. < in--- to .* CO fcyl CSJ CM VpN--' <S0_ CL E oO PCO <M003 CMVJOj o </) 0 <03u cMoso OH00 Oi.f 3 V) 3. 2 CiJ 5- |cu s- CQ ca ir1-- <-3 n CM CL 4* U J2 CMCL O CO co O coco EE E SN CL bt a. s CL E OLE XJ C. i .r>- r*^ in o r> CT to * CJ cr O pvo ( > i :l ,e-- --tf .1-4 > *--< H *- c o r* +> T* L 5 qo *L o -Oa- oCSl -00 a *s o u 03 u3 ion - 229 - DUP040011711 *ji V table 23 - Mean values (s*EO and summary o f fa c to ria l analysis o f variance fo r blbodt urea nitrogen (BUN - mg percent) fo r male and female monkeys in S ta tis tic a l Grouping otf CO co .1ft Hi HJ GIO ai30u.i CL X<<1uu t. a. <M**f O CTl CO r-Qi <Si>fO r 0.0 0>.r*- CT.r-- i-- >w' tO o V| CL COMJ !o--* 'CO to VO CiCO CCMM-** iCnM-?i O *-o co cn CO VO T-s O to o op o CO r CM>- oat -cM 4ra-t*ij s- ; co in 10.40 to O CioM<So-- CO o.-o !>m in Ip *3* o SO r-r 00 r~ ar o cr S cu CL X Ui Ho-* c o Vi 'si id CL aH si* p to co co oo ciJ VO ::*~04 <3 0w V) io *- <*--3* o in OJ 3 *-HI O tto t. CO r- U jQ CL. CO s s C7> E to o t -* s. CQ 'r* 4* O JO <MCL O toco fi'sl ,CL Ol a. E CO o c? m r CT O 1 3* EO aS T-- srd. CM O 0u1 -Q O Q_ SO U <JLy C- C 3o ~4 CO - 230 - DUP040011712 / Table 24 -Mean values (S.E.) and summary o f fa cto ria l analysis o f variance fo r to ta l serum b iliru b in (mg percent) fo r male and female monkeys in S ta tis tic a l Grouping C, *o* iQnLoO Oco ro?- -Ocoro-- co foO oo pp qd dp Pin vl a. P t/> tn PMt/1 GipO 2mOsf cd l1*l i. rtf cflj .*rr0--*1 uXQi. CoMp<Pn rCo>M%o>;O*** .OC--O*OrO-f- otPo. POCO. V6O *SCfEdL a p CO C3 ><oLnt MVas) *4:- .0X(A1 *I-D< 30461 H* 3 CD CD . k k-i i-* V> IS) oo CIO 03'U1 <0Qii. X <woo0 M; 0C-O0!* 011 COiLf. L- po poai I -- ooJk i. iu-c--Qa o<C/Sj I Qu E Ca_L o o> ion t--t Mt*---- A1 a *O ot/C>McOo. . h 4= SI ocfnn moo* $ L<3 cp Pa ' 0o3u1 C_aL otCoM 4uOC(L---i3>f - 231 - DUP040011713 iu.w4w few o OS G r* a. .- 3 *2 +*f,e*u* W"'4J m-}2 Ue<0:+4&J4 >fl?.c 0>, . 01 AO^ *v*i Go 4tnz*j i<tiau. 1"** E(M *- ll u ** ns .a M- rtH- G- s G 2? (O E* E* :3 v c0) o "O i. cp (O a. V) Ui * flj G CO P> +1 C v> P Ol 44 3O r*** G O. . c3 G Ci S> s: A>| in CSI p -Q p ,'aa N> ui -X <OyJ CO 0) NrC'OP f P-r IN .rs.p v 05*0 CM**' NO*s--' O** cn rPo .*& <o p~i6 o'co wo *t r* cp O Or-* ift >-<* in i^C? in p #n <t* O nr* VO in ca oo csif-- vpo ; 4 ; GO O fN O IfN O .00 O m 0 V| u> 4- o <y 4HUl .40 G fll -4E4 rtJ L *"* P CO f> r~ r> o O CM CO*-- in f*> i-* f>. o CM -sf Or* coo .on *Orr Kp in ; tn rr- in co:tN U7 r* is. o coco <0 0 r>> o c o r* G 0) .Q* X Ui q-* O G O G a. o o & P .</> 00 s C -34 i/} </> P5 aii 5 CJ M CO .25 V) ? 01 G 3 0 gQ*| 2-* 011 g o 44 C o p t f M Q CM O CO . cx GL r>. o i t--4 *T* u GO j- o .43 CU CO & s O r-- m *-4 M >--f G CO +O a3 CMO. O CSiCO S^ a.o a. a -j\ in 05 O j -> 4-< 4r^0 r-j G O 2G>s1i; <o*~! U A-a- CM owl rGtj <U .o01 uo to 232 - DUP040011714 Table 26 -Mean values (S.E.) and summary d f fa c to ria l analysis of variance fo r serum albumin (grams percent) fo r male and female monkeys in S ta tis tic a l Grouping C to o into co to <y%Ko c m*t N<D OlO U)Q Nr*. o v| <M <3 Csl O CM O CM C3 CL * o v> i/i Z CO VO *A 0013 03 s3 ,%1/1 CL X u01 o. Wr- COtrt tO UO VO tO po o too CM O CM O CM O N O r-- lb *-- a 0 co 0 co,in in * 0- CM O .O sf 0 CM O to co LO O =CM O CO to t tn o cv* o ion ccmo coo CM O NO Nd coo SO to r CM O ST to -:l-- Art ,NrN O NO re- CO in o CM O 4o1 44 s4)r 4B- JOHl .332* "# to CD <L5 <D -<A M </l -to CO a .03 3t sr o <7> CD hs--o4 M</> cto ,41 f3c VI XCf0QJL CzO 01 L. Q. co ^s >-- >Oc +4 c 0 0 1 a3 * oSL O Sca c-Po CM QO sn CO E U 'X CL as CL E O r--. N, 40 -* 04 O 1 *-a M H IH co 4- CMO. O coco CL PI Q- E COO cr.v u> 4 os 0 > J- o iar; "44 oIf** .CM JO o o a. co u e .O-r ** a. k? **~i5 oP>--<13 ncso- t V3*</) > + > 4Q^WM<0 IS >:ti>--o>ti--o S <S03 Jj*IU <C IS -s 3 r o ts 4r> S u <11 45 ^ ID H~ .ic 0 jQ >> v10. f-J-tl 1 3- J<o O lK TJ e-r-* (O u -OJ *'*r" Ui f-- * tO Ov-^Ui s +1 I to E .3 E -ij-b i O ET v> t r*. CM tu o ns H- opf NVp q)rt m to o%*t CO o to o CO o !>. O **W oto vf * p to CD to *~4 CO o CO SI 00 o to SO to SO to *4 QJ OJ 5EI .03 VOi 05 0 Wv-' r-- O *** O AS .i0.) t> co o i*> o to ; oi co o f-- o to O to o s j * ***-' ** W- e tU - i. o xa. Ui ro i co <y i3 IO . 0 0>5. lO) O tO -CO r*-sf -to to *CJO->O> <to3 *0--' O oo JAS- CL E S 1 Cl 1. a. O V) -ic CL O) bo cr CL-S s- 4-> O r*" CO o Co r* in cn tn o <o o d* o .(A1 4 3 -- i i-- i t O KH -H *- c *r( CD C bi-- + 3 L .03 3> <4O as o L. 3 O to - 234 - c o 4-j CM a JD O CL to AS V- <13 c--4 DUP040011716 l : 1. 0411 * o o> .4.* -c O *r+1 CL '.3' S O 4o-0 4u1 j-<0 c: o d *r? ts <Tl *r* 5' 4> , <o 4o- 4to* t/j t: r* </J 4/5 r .fi J:oX>i> rs c O 1 fl> hi ns if 3 %V) O C'j c:>^. hi S~^UJ +1 L V) V-- 0) 3 .rA>r*ll *3V1->* c: ns < 4> 41 :0 s: a. OCJ Osl <11 JQ .H** 40 too to oo i-- co <xo> o tO r--O CO O CO CM COO vf CO O CO o CO o CO o b. Q <3 CsoO to V5 .01 01 3 I 01. E *p 01 i3 /> 0 CL X <D 1 01 S_ b. ; o Or~ ^t*:0 -- ix oo *3- to ir> CO * * CO Q *3* 3* O csi *&rrto CM CO O SO Cp Pi .10 d- Op r4 to O co o <=r o co o co o r*> o o to si* to,csi so -CM r-- CM r->. CNJ CM pi CO O o CO . ; coo CM *4o; o CM pi to o coo r-- CM sr ; *3\o o o c <13 E 4 <a a JL <d +> c ai i. ai CL X Ll I 4O E P V) ** S. cac j. o u ,35 <0 c/> oo u> > z z: 5$ M3 t/) O' Cl J-- M* to <J5 CO CO I Of u 3 ui .. 0 oo CL o M .00 Xai z^ c/> 2S * 01 i- a. O u 4* c O O to a 3 O s_ t*3 u CO ca -o0 o0C0M .CL co 4* o sx CMCL Ococo- E e CL >cnv CL E at O IX to 00 O cr to o> o o> a I -i G -O CM -P O CL. OO o ns L. 01 c V> ns-*- ',<tl +J >V3 i= Pri> wp- >nj cn <n *>f--lj* *OT: <g8 s 01 j Vo xg UT3 4A*S C<o 4- .01 .O fO DE rtf L. I <8 3tflr*N J*o AS * * * cr LM iU *H *S <n i,~ go. csl d oo d in o vj Q. po C3 fcH co ca c0 \>ixi in aj *tco p<5 g*0 *--0 dd U Cl 44* HU4 44 - 4"0 P*r qv.tO o to co ! -- k j *o cn o cn o p-w 0>-- Pw On -* rt* Cl IO p to CM -*c*' u> 4l* dONp- iPr-^-Wd ,cOovd* Odow <0 44 SmZ *nr* L as a. X ClOO o1*4 <n S3 1*4 00 to d *--N> O >> P. o u OS S- Qm S3 1-4 o H CD *-* CO CO CO s. C CQ CQ O +o -Q n CM a. CM CL O CO CO o toco .E .E r- E'^ CL CL ?- u. pi CL CL- 4- o -* CO o c *n 1.0 a> LO o . ,* A p Pi p P o 4 141 H .3* #--* M :Lh c: p* (O c s- a <o CM f+o jo o a. co 4a> 0J ps3o CO - Z36 n i\ ]A DUP040011718 ,3 Table 30 - Mean values (S.E.) and summary o f fa c to ria l analysis o f variance fo r to ta l serum carbon dioxide (COg - m Eq/liter) fo r male and female monkeys in S ta tis tic a l Grouping G. P CO so so tn 1-- jx 01 01 2t l &B *-- co t : O PO SlX-* CM*--' CO P>. o CSl>-> ' w O * v| o* <A 4- u <21 .H*U1 *-- sz B<E OiN 4 coo Oslw CO o CtlX-"' Cl l*> * 00 o CMX- co CO o CM>-> CM CO o JLO CM>-> # > t0 P -CM O CM'w Its 01 .1* h- r-- Its V c p ,* csi i-- co*-- CVi w C O .tn ts~ <0 a. .e o p . p 00 to >-4 00 55 - CO .00 kO 55 * <0 to fr*4- * V) 25 4: . p. <J3 vo vo (A Jit V3 ZS 5s 01 01 i f" 1-- <* C3 ~1 V) o *-4 to vo co <21 Sz* ul a CO VI a. I--!* X z: 00 2 0i* i. CO r-- O XI CM a. o in <r> E B Q- -X cr> Q. E O r--. P cn o ,i I M t--4 H4 t--4 t- co t-- +p ; 0 a. o ooco e E.Xv, 0.01 a. . CO'-O min <to O > +-H c o r* +J <9 fd 5* M~ O P U t3 P CO - 237 - c o 4-> CM u dZ2 O 3 cri t- P 4-* C i 4 } i i > DUP040Q11719 Table 31 - Mean values calcium (Ca - (S mg .E .) per c and. ent) sfuomrmarmyaleo f fa c to ria l and female analysis monkeys o in f Svtaarit iasnt icce aflo r to ta l serum Grouping v. lo X0O3 isb -0x1i 20I3 .01, s <oi 3ua0s)-i X<0C11uL CL coc4 K r ) >n. In 0> O Or~ U5-* at P p p p o at p to P v| XX tn o tn o t>**-* 0O%CrM rttn Cs. rS o O . ,o <0CO P7) r-- O LO CM CO ^ COCM IS. CM p at p ; <r o uvMt <*LO+U---f c oi & p 01 h* f--*0 10 f TO CM . COMlii Pi CO r P P P P O to p 01 *#L6*?* 01 CL X 4O* U)fCM CM 00 CO CO o <4* CM On r-T- pp po pa po .aH_ O B V0 KCbO CO* to 3E vi KO VI v P -XA ' -HI Oil 201: F v> p -- VI r~-- OC v>. CLoD M cSnL oVCOM opQ. co MXCSLu .pe pr>*- uo - p .p it *1~-44 .* ---a1 -4 cun op4.C-rMooJCOL Cal. p P-00 oLO pp 5 H 238 - .co CM faO, ,voo u 0-LT>J DUP040011720 f Table 32 - Mean values ($.) and summary a f fa c to ria l analysis o f variance fo r to ta l serum glutamic oxaloacetic transaminase (5G(3T - K units) fo r male and female monkeys in S ta tis tic a l Grouping G. P tv sr ca N lO CM1 CVI> 5t <3 to 3 o p ins-> in o v| XX OCD op C5 2? VP o CP CP 00 .* * Ip PS-1-* !q<N co rs m cc ** ns> co in > Cp.*f in j *u p ? <4 OP o; w 44ui M C og co cpois in.oi oCM*o--* CtoPsto-* lOor- rc^o. ri--n -M <aus ,s- IS Ip CMcp cp CO CTl E "in co ; cp r-r CM CO CO oQ. LXU tOf- 00 <1u eoO) zut u in !o c? CO to ; CM o flj 0Ql # : Cl mX in ^ lO<4* O CM cn ; ro>--' Plw CM**-' B o o \cx cbvi to 'IZ # OP ,Z -- VP 03<GI<4i/UU:JI S' OOOP E sfrVP z op VP -s 00 <0 *--* 1* 01 &_ 03 . 0V) a.. CO Xz a Z z oi u L r-- 0O -lU gr O M i V3OsoO-. M <NJ O op E P. G. O c- <3 1 -* j--4 sca <-> a. cp .E 2* a rtn a o s --4 i. ca JO+* V-> CMOU O OP op DH Q- cn a. e iO o Cn in CTi Cp 4 > *-4 4- <O+AO3OOVOf ,d-mP oOCPM ui4s-3 s0-> 239 i l j i t j i ij -1 -H i DUP040011721 Table 33 - Mean values (S.E>) and summary o f fa c to ria l analysts o f variance fo r to ta l serum glutarnic pyruvic transaminase (SGPT - RF units.) fo r male and female monkeys In Stai Grouping C, :itu) 44 VI o CWO3 %n S<acu CO to CO cvl ipC--* cOh* O CO r- CM CSI 00 fti^ CO'---' *J"w-.C0w ion yf CL o v> o r-- CM cOor*--w f>- -c O CwO CvO U0 L<U** CM'- <3% -ef . * <0 r-- ca w <M O ' V OH xm w ^60 . r-- CM COs--* r-- O f*- in * CO to r> -- flv* fJv .* O CM CO w C i P nj o *- *-- (O 44 C= fl> e rL L, QJ a. *0CO CJ3 C0 X) M --I \ss CO CO w tr-o <y <3> Z3S 1 Vf-- * to CO z: j s s *-4 I/) - CO CO Hr# s CO CO 2 CtO c CD CM CM W -CM *s--' into CO r-- C0w p X i. a. 7 m u zs XA *. o Q. CO to co 3 35 .35 3 l 1 .*--* SC0 r-- o -Q CM X C> to CO e x d. cn CL o r>* N m . av o ii i-4 *r-- -- M >--t u CQ r>- *O 43 CMO. O toco E^s aot as ro O qn tn qlp 5 k--t c -.o lxt rittl .5* O u 3s- O CO - 240 - eo -O CM Q pO a_ CO L C *-i DUP040011722 Tab-16 34 - Mean values a (S,E.) and summary o f fa c to ria l analysis o f Variance fo r to ta l la c tic acid dehydrogenase (LDH - WROB units) fo r male and female monkeys in S ta tis tic a l Grouping C in o 1--* fs CO fs CO O ^co a* at 1* to rf -ct* CM CM O vl inw ins- kf** CO ** CL v 4J >* % U cp CO VO io at CM *t* r^s in avco fs.s* faO.0r4- *r COr-- .01 nJf- ***** U4 kr * 9 a >-*- vi co cb Z z to m oo M3. CO . C*--D* M .z CO CO in <0u1 01 u 3 v 0 CL X 01 i 01 s. Cu o CP$; o vo co cvi ro MIN IiSn. CO CM p^" 00 r-- CM f*. .CO Jr* <<ud CO CO fstf) *5r<M ><3* CO *psr>n--r^ ijsnsc-o* iasvsc-o* ccmorws ** !% % &; cr ca ; vo vo fs* CO '-- at 00 o ; in CO VO ins- O CO o>s^ rs--> -<Ecy t* 0L1. CL UXi <*- S' C o in X GJ CL o u VI .0<x1u in 5? <n 2 CO z CP 1 oi .fc- 3 o a. V> in CD M X z z CO 01 < tf Q- U CO <rr~ o n CM a. ,o m CO ^ r-r a. .05 O c_ CL +J o c N .in o 05 o *. CO (-! +o J3 CMO. O COCO E*s 0.03 CL 6 coo 03 Cf> at o </> 1 1 t i n i fr--t s o j- H .*-4 -4 CD c o rr- .+ > T3 U to *4- V u* -O Ln o cn - 241 - cr o .4J CM o O 03 a. co C. iw DUP040011723 Table 35 - Mean values (S.E.) andsummaryof fa c to ria l analysis o f variance fo r to ta l alkaline phosphatase (Aik. PO4 - kA units) fo r male and female monkeys in S ta tis tic a l Grouping C. O 0M33 Sx<ucu 4 CO CO CM CM r--! IS **> *3h M3 rr- fs. a* ; ( at *-- *3* r~* " co . r-.S CO r-- . CM "54* CO CO cn co JtPv> end in 01 wv coco LO CO 10 ION . O d> u) at * . r> <n .r^* r- .* * r-- xn VO>-- u> .3 vf CL v .4-> U .as 4H* IU 4-> tz as +j <0 .01 s~ lp CO o. 03 CO O * ISi '+-< CTt o OJ OlO sM-3" CM a tn> ca> E r- i. <0 ax. *3* . C3 W CO V) 3S , 33 CO IP zE .* co (/) 2= z ' i. Ip Vi as * CO si CO co z 2S to CO V5 '2C oa tA f L 0 CM CO IP CO vo CM ttf a O. m1o. X js f>* --;co *i- co .r-- VP !-- at st* cr>^ *3*S-* *--* x** O Q i- 0 U 3 VI O CL X ai i tP- i. . oa ca r*^ <.3 4* O -Q XI CM .a. rsiO- -O CO co O COCO E r-- X* CL- D EX. o l a> Oc. Q. E O.E -M O ro 0 CS fS id Ct LP O . O a> O o> 0 11 1 f , t t *-4 > *-- i-H 1--4 O <0 'a '5 CM u jb O fts a. CO u u o-c x: 4- oJ- ' .CL 01 ; js*o "CJ 44 fit D* <T| -0 03 CW9J i-- tri O T> -r-J3 a s- c. -.0 Cl rr- en j :i o e U >s S,, 01 4:.o r-- *> oun UJ ? c -a.*. o* oU1 3 i w $-- Hi* .--44 CD .*-* in r* 3U3 l-<>ja* -4r4- w *O- 0 cn)S<d N- i Wn3 a> .n ( <33 2H> tCD 3 *-* 0 HH CD . a. .3 h - p i-4 CD 3' 5CD co o ' Ps o CPSO. oa Ps O lOrCO O rs o -N-. CCOOOGi IS O S41 o01 -* CO ISO -w cCoIaO .ISO I MnB .oOns is-O n- o01 r-- CO r ISsO** iCsO dQ N0 S' >s CO O i PS O S'* ncnoo *HoI orr- IN O IS O S> ' s- oCOO CO is4 o o iso <n o > . Is O s-** PCOs Oo Ko cOol 4oo*s ISO iS-* { PCO>'*OTISO S-' ^>s no fsO N> iso CO o is. o > ^-4, fcso*--o Is# o. *4 4^S lOr* COO .# i iso CcOo4oTo-!* no :ts O f>o > CO r-* no IS* O4 cod co o .* NO S-* AnDoO ISO S' /-N -^^-p.,do iso S' nco oo. .4 ISO S' r-s. 5COP!O>* ISO .rS 0n1 Oo is O S'* .-S tno sop. * ISO S' >s* OCOl or--' fs O S' *KP CO >Oor^ 1^ o Sr- n otnrr* , IS o S' 4--S cPo orris d S' n oIS rr: IS O S' otOA CO r>- O S' 3 S> l P *-* s- CD CM r< r **sr s--* CM Pv . UOstrsr^- *?r r~* *r 00 lO . CO IS 01 -. * CQ rr- <Ow CO r.4 * InS Nr---* 1 4--N cp d > rr- 'Pr ^p.w n Aco .4 .4 fs- CO <^rP?> t r--' 9*w 3*-* o *-* cv LM CD o o CL CL .3 iCD O CO or - *cp w CD CO cISo O w CO CM CO* r*r ); m o* o ,01 r-- ts r-- CO'--- rs.o . .* Ol r* fO.^ CM r-- co^ COW CM,CM . CO r-- CO w fsco CQ O COw 'M* CO NecOw IS O 4 .4 COf^ ^fip'W Nr* .4 CO ^P CO ISO .01 rS rr **r ii)v cc to Olr*9*S-r rr- oi O.i w CO-.-W- O 01 4 CM O *Pw o^ .4 LO -r SP W ^P fs O o ins' cp n 4 ,4 . SO pr* it-S r*r** y-s r-s .A -TV. CO co ^P CO is in3 oi p n Jr CM O o .* .4 CO CM .4 rr- to * CM .* * r-- - o *-*< i- CD 0>?*P 44 in p-> COV CO .*--> . COw Kf PN . O <NI Ol-W O CO > tn r-*cow CM 01 44 CM O Olw 01 CM 4 CO r^" CQw* 1 r- *4 .4 in ; 01 w ai <r * m r-- .01 S^ in is * O rr 0>S-* CL 3 -- l P h -i S- H- CD Cv aG. CL 3 U0 *r-* CD m is IS f-- CO *w- 4--v .01 PS 4 r-- SM 01'-- i<cn7p1 r-- O.* w CO CO 00S-' ,^--v 01 01 - .4 00 **co>-- .r-- t-** cCMpC.M^ coco 4 O r01W -- in ICSOCwM Ui e~ .4 4 *-rCOw- .4 4 00 r-- COw m qi 44 5p 1-4 COw .mu? 44 LcOo*rr--^ in is 4 lOr*-- COw fs C0 ,4 UD rrCOW >r^ rs.co * fs CM Ol.w CM 01 1C9T"VON-' ----Tl, inM1 -.4 Vt CM 01W- <s Ps O n r-r COS' inr in- CJ CM CO w cICsoPoCsM-- oo3 .--< CD <> o r01- wCM co co IS CO Vr--- CO 01 U1 01 SO 01 ICSOr^--~r ICsOOw 0co1 -- con m CO Wr-- in iD ID VO tn <n 5P <VI CmOeW--- .i0--1 wr--> CbOi wCM *0 .Xi di s- T--* <9 >v 3a <u a 44 3; c CO CD CO \o CM 01 n in M0 CO fs r0r1- <op r-- - 243 - DUP040011725 Table -37 Mean values` (S,D.) and summary o f single c la s s ific a tio n analysis o f variance fo r terminal body weight (g .), organ weight (g .), and organ/body weight ratios Group I - C ontrol, Group - 9.70 ppm S02 Group - 0.51 mg/m^ PbCIBr, and [%) fu r male monkeys fo r SI I ta tis tic a l Grouping C, comprisedI I I o f the following.: Group IV - 9.93 ppm SO2 + 0.50 mg/rrw PbCIBr. O y* 4-> <0 (Q C CO 04 r*- 0 . 00 00 Am* co U)i4 3: !, OO -w* # *** CO CO r-* O OO 0.0 OO OO CO 0 00 to CO r4- O <3 0 OO .CTl'!* --o o. a* op !y to tn rs,<o OO >W*r mm CO r-- 00 p r* CO in i/i 44 CO 0 <0 5? "Si 00 sz X3 * 1C, tO .44 ' Op1-#" 140 r-- CO 0 OO to -ci te CM <7> in co 0 00 ^k CO ip CO l>v 1-- w *s fs. fN. ^0 00 *>' is CO 0 4 0 CM CM w 0 9 0 V) v> CD to to to 2: 2; V) z .25 z -s . -M CD >-4 $0 VJ <0 2= VI z .Z z ji il <0 <n v> to <D to 0 *-* 2: z Z V> z 9 to LO - to ,* to CD to -2! .Z 525 Z to -z 0 44; ff*, ta .01 > fmm ID LO CO 04 O, CO uv N r-- I^-'O co>^ 400 CM . r-O o> cx r-~ .CO CM .O w yi-**, - . v> LO < V> to <0 Vi ..2: ss 25 Z - z Z -4 . : 44 .CO fO CO r-^ to ro .* 0 co 00 w co <n si- to ,00 CM to CO * f^xn P l! * in 0 vl LO * cn 2: > to Z 4i .. tO to tO 52 .z Z * O *ir-- st CO *T OO in rs- sj- r-- Q- .* 44 eye* co 0 CO 0 CO O rtj i/> to 00 v>i. CO to <0 44 % " 0 0 0 0 <3 O a0 P [ss s 25 z .25 S+ U ro O to to CO CM CO 0 c cu 4 M zre 44 i^S "1 ' ip *3" ii* * LO CO . VO >!* ?-- Sp. in ^* i~r X. in CO 01 .* <44- 's: 'Z LO si to Z to tO :Z ,';0 CO CO On. ; + rs co fin O . '44 to o iO 0 to 0 . ^ LO O 44 SZ 00 cn LO to to to I'F & 00 O O 00 O fiD Si* <si^ ' fw as u 2= 25 z 25 Z 25 c n - c -4 CO 0 40' CM esi cn in cri r- , 0 z.1 .44 Z r*. to CMs,** . to 00 CM>w ; * 00 01 CM*--' 4in ; m CM C to pOm) 55 lO 25 to z tO to zZ to xo 0 *f4 44 na `Si; *o *r* O u > XZ V-- 44 '3 O 'St O OO <3 O CO LO CO OO CM CM r-- O O CD OO tO *-- LO #~ ? . OO V Cft co OO O <3 00 r* rr #-- 0 0.0 * .* 0 >0w* *-- CO - si" r-- > OO >--* <-- in-* ;O, 00 ,4 , V) to CO to to to 2: ir z '25 2: z . ... .* 00 LO LO to to to 2: z z Z 25 z O r-- 44 c 3 *r* <TJ t.eo 44 3f ___ r**'t-*' 10 CO -- 0 rr- V& Kt CM 1-- O cp>> OO fN. ch in -t to to >- o> in -tn*a* .^o co in * f?v CO to--- <4' rx CM r- O ^i.* ; . co in tOw . VO to CO .tO to to z 2> 2= z :Z .. zto LO to to co to i?: 2: Z z z .44 *-- xz <a .p c: - QJ E2 S-- j--> *a 0 aj O CN> Op-- ' cr -5T sT f-- 0 cr O C4 t>- CO ;O/ CM m 04 cm O cn CO Lf> CM r-r v> 0. =3 O '*-rf H-1 --1 ;2> #-- %- -- CD o^yi -0 LO to co to LO to 5S 25 .25 25 z z M :> t--4 > *-- *-< 1-4 V-r* 4 >* VI in ir> in to / > > > > > > --- *T-* i--< c The variances of these groups were heterogeneous. DUP040011726 Lunq. The Variances o f these groups were heterogeneous. 01 V) .M T? u 0 o> e C*I^ C Id 13 +) -r-- vw <0 5 S-. $ 0 S3 r-- CQ . 4S O P <4- OiH- _Q O to Tf,t-* X<Df.Ofi. >fr"D: V-' r- O O SaQ OS GZ 0) tf> e cAo3 -V*-) o> o i- i- -4f->- O -CSL', I flj XJ O *** g c u ,m r- <Q .m rsr-- 0 Q, to 0 c nDc> O&. ir~ N^'-rf CD U 4- 3Q_ * .Cp ,aj.c o c mp it -- D) L Q *-! CO-r- O CO O c u>0' *4r/^l 0* Bo> USs*. --*v *J3 I OIX) . E *40 3 0 -h O W N^ *o + > O4- M a + SC -G ' 3 CM .tO D) w O O r- >> L. tO Q-* <3D-^aC IQ it* S-- *--* >-- > CD O ***- e ns 03Ol 30O. Z01 <oi- V^*--i CSD- 0i- 1 CO CO <-* to CM CM O PO PP COCM CSI O PP OO `>^r* * to o> Nfvl 4- 3: O O co *3tno :* * OO o> ro to *- . ' -O 0 'O/ CMcri r*N.o * OP .0 *r-- V) >. flCf V C s 4-1 S: rt <3 0 . 00 H CM *3* * 'a CO 1-4 p w* CO O ' 00 0 a ' CM i4- O tn uo p .a a 00 P . CO ^- ^rp a OP PCM a . ir 3* to tn to * . <5 M *0 in .* 25 25 Z to 2? z CO LO LO tO CD to 55 Z Z ' z **4 in z . .</> VO a to P .*1-4 TZ. 55 22 cn CO * a .a 0 a co a vo in tO co 25 .2: 2t mg- to rs r4* #--- CM O f) st i*O0\irv?' LOiV- a\ csi F%.>.Q?3> CO *3tO V4 sM* 5?* 04 0 Of? 0*1 o wv tV *3* io p CM O ON cCMo!>v. pto vl to to o * *-!l z 2: V) to to to Z .2: Z- 0 cfl. 'i M 25 to so xn CD <9 . *--4 > * .2 V) CO Q. ;Cr--O'.pC-- rr- CO co o fcNo. mo CO to CO o v> to cri an co co go CO op 00 Po .0 Q :* Z ZZ # . . ,m<CtuS 4'3->: P P-. CP M> Ur-?" CM.r-* O CMa frP----a I>v vCyS*I Ccu H<g- 2to5a vb .z. VO Z VO Z LO z in Z O xms- hO- OP OP <INM.rr--PO ihn% l0o O0 CipM Po OP o 4C-> ts VO 25 to z VO z to z to z to Z 4- U0 st- tO *" 43->:: .1o-->C-M^ CCOM>--W h> :C0 COM>C--M a\ pr--.sp^a Pc; to P 2.: VO z' to a z to z p0f-4 00 z S3* *53" or- oO OO > -C fco 'a\ H* Kf P pp 3; 0 -J3 nj a i. r- rd CsQ- * 4-J 3 *c3r-a rC~O*a r* O tn.* *-a <n co p>"-- .r0--0 *O3- :0 O oO 0 06 <JQ O OOs--> pr>.ar*oo.a r~ O O) co a OlO N- r-- S3* 1-- O Op 0O OrPpOO rtOa CM COa CM P oa CO-a p to in - o-- 0o pq in *4 CO r-- op oPi rp-- r~ PP -ha O go co oo Z 2 .sc tn <n to Pr- :i<45 .to z z Z to P z v> m to to to v> z 25 25 z z z CO in CO to to to Z Z Z Z z z A3 O' :C -r- E 0_=c <D ^>4 i-- O O CQ UO too in *=c CM ; 1 ro 2 O CM l O *3* r>. co ; 4-- inis J>x CO - o ;3 : j --- VO VO CO z z 2: tn CL o.3 U- CD. - 24:5 V* VI >> V) > / DUP040011727 Table 39 - Histopathology incidence table for Statistical Grouping C, comprised of the following; Group I * Control, Group XI *- 9.70 ppm ' ' SO2, Group III - 0.51 nig/m3 PbCIBr, ar-d Group IV - 9.93 ppm SO? + 0.50 mg/m3 PbCIBr, LUNG focal Pleural Thickening Peribronchial Brown Pigment Artifactual Eniphysema Alveolar Duct Fibrosis Thickening Bronchiolar Wall Bronchiolar Epithelial Hyperplasia Bronchiolar Epithelial Hypertrophy Pneumonocyte Hyperplasia Peribronchial Lymphoid Hyperplasia Emphysema Focal Necrosis Focal Hemorrhage Parasite Perivascular Edema Pulmonary Edema Bronchiolitis Bronchitis Monkey Pox Vasculitis Granuloma Pneumonitis Abscess Lung Mite Infestation Adenomatosis Bronchiectasis Purulent Pneumonia Epithelial Necrosis Thickened Alveolar Wall Pleuritis Crystal1 in Material (yellow) Mucous Focal Fibrosis Pleural Fibrosis Alveolar Wall Fibrosis Vacuolated Media Endothelial Hyperplasia Stenotic Chronic Pneumonia Eroded Bronchi Emphysematous Bull a GROUPS I 11 III 2/9 2/9 2/9 1/9 5/9 3/9 4/9 5/9 0/9 9/9 0/9 3/9 0/9 2/9 1/9 0/9 0/9 0/9 0/9 , 1/9 2/9 1/9 1/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 1/9 1/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 1/9 1/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 6/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/S 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/6 0/9 0/9 0/9 0/9 1/9 0/9 2/9 0/9 0/9 0/9 2/9 0/i 0/9 0/6 0/9 0/9 0/9 IV 1/9 2/9 0/9 2/9 0/9 0/9 0/9 2/9 2/9 1/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 2/9 0/9 0/9 2/9 0/9 0/9 0/9 0/9 0/90/9 - 246 - DUP040011728 Table 39 - Continued LUNG - Continued Atelectasis Congested Extravasated Blood Collapsed Alveolar Wall LIVER Pericholangitis Bile Duct Proliferation Focal Necrosis Sinusoidal Pigment Foca' Hepatitis Focal L/mphoid Infiltration Nematodiasis Thick Capsule Granuloma Abscess Hepatocyte Vacu.olation Greenish Granular Material in the Hepatocyte? PERIBRONCHIAL LYMPH NODE Phagocyiized Pigment Lymphoid Activity Lymphoid Atrophy Adenitis Granuloma Reticuloendothelial Cell Hyperplasia Lymphadenitis TRACHEA Tracheitis Increase in Goblet Cells Exudate in Lumen ffecrosis of the Epithelium Inclusion Bodies Epithelial Hyperplasia Cilia Atrophy Squamous Metaplasia Focal Hemcrrhage J, 0/9 0/9 0/9 g/9 0/9 1/9 0/9 2/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 g/g 6/9 8/9 0/9 0/9 1/9 1/9 , 0/9 x/9 g/g g/g 0/9 0/9 0/9 0/9 q /9 0/9 GROUPS II III 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 4 3/9 3/9 4 3/9 1/9 0/9 7/9 2/9 0/9 0/9 2/9 1/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 1/9 5/9 7/9 6/9 0/9 0/9 0/9 0/9 0/9 2/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 4/9 0/9 1/9 0/9 1/9 0/9 1/9 0/9 1/9 uri/c*/?> 0/9 0/9 0/9 0/9 0/3 0/9 - 247 - IV 0/9 0/9 0/9 0/9 4/9 3/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 7/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 { DUP040011729 / gutieoa^sp- -1 Table 39 - Continued GROUPS I II III KIDNEY Interstitial Nephritis; Epithelial Vacuolation Tubular Dilatation Loss of the Brush Border Nuclear Vesiculation Tubular Hypertrophy Pyelitis Focal Mineralization Glomerular Degeneration Inclusion Bodies Vasculitis Congestion Focal Fibrosis Perirenal Abscess Protein Inhibition Intima Thickening Endothelial Hyperplasia 0/9 2/9 2/9 1/9 3/9 3/9 3/9 2/9 0/9 0/9 2/9 3/9 0/9 0/9 0/9 0/9 0/9 0/9 C/9 1/9 * 0/9 0/9 019 1/9 0/9 2/9 0/9 0/9 0.9 7/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 D/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 HEART Fecal Myocarditis Endocarditis Epicarditis Myocardial Degeneration Vasculitis Subendocardial Hemorrhage Thickened Endocardium Focal Hyperplasia in the Endothelium Intima Thickening Granular Pigment 3/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 2/9 0/9 1/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 IV 0/9 8/9 1/9 3/9 7/9 1/9 0/9 .0/9 0/9 8/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 - 248 - DUP040011730 HAZLETON LABORATORIES. INC, VI. STATISTICAL GROUPING D - RESULTS OF THE CHRONIC EXPOSURE OF CYNOMOLGUS . MONKEYS TO 65.46 PPM CARBON MONOXIDE (CO), 0.51 MG/M3 LEAD CHLOROBROMIDE (PbCIBr) AND 66.43 PPM 0 COMBINED WITH 0.47 MG/M3 PbCIBr. / Four groups of animals comprise the fourth statistical grouping-0. One group was maintained as the control group exposed to filtered room air, while the other three groups were exposed to carbon monoxide and lead chioro- bromide singly and in binary combination. Group designations used throughout this section are presented in Table 13, t- Table 13 - Group D designations Group Designation (No.) Aq.ent Nominal Concentration I 0) Control 0 II (7) 111 (9) CO PbCIBr 67,50 ppm 0.60 mg/m3 IV (20) CO PbCIBr 67.50 ppm 0,60 mg/m3 Mean Analytical Concentration 0 65,46 ppm 0.51 mg/m3 66.43 ppm 0.47 mg/in3 1, Exposure Concentrations The chamber concentrations as determined analytically are presented in Tables 1, 2, and 3, Appendix D, for Groups II., Ill, and IV, respectively. The mean and standard deviation for the group exposed to CO aione was 65.46 ppm 3.33; for the group exposed to PbCIBr alone 0.51 mg/m 0.27; and for the group exposed to the combination of CO and PbCIBr, the means and 3 standard deviations were 66.43 ppm > 2.28 and 0.47 mg/m 0.21, respectively. - 249 - f DUP040011731 j4i` HAZLETON LABOR* TORIES. INC. v; 2:. Particle Size Determination The mean and geometric deviation of all count particle size determinations fcr PbCIBr converted to mass median diameter (MHO) were 0.550y 1,57 and 1.050u i 1.79 for Groups III and IV, respectively, A composite size vs, distribution log-probability plot from the pooled count data is presented in Figures 66 and 67 for Groups III and IV, respectively. 3, Biological Measurements .3.1, Body Weight Analysis of variance of regression for body weight (Table 4, Appendix 0} indicated no significant differences in slopes among the groups. The regression curves (Figure 68) indicated a trend toward increasing body weight values in all groups and growth rate was similar in all groups except Group II which started slightly heavier and ended slightly lighter due to the deaths of two male members of the group. 3,2, Survival No deaths occurred in Groups I, III or IV durif the 104 weeks of exposure. Two deaths occurred in Group II during Weeks 42 and 78 of the exposure period. Daily observation of the animals revealed no clinical signs, of toxicity or abnormal behavior attributable to the exposure atmospheres. - 250 - DUP040011732 i X ---j* Count Diameter * microns (/*-) Figure 66 - Particle size distributions (count diameter) of PbClBr. - 251 - DUP040Q11733 f 5 i ;i Count Diameter - microns { j x ) Figure 67 - Particle size distributions (count diameter) of PbCIBr for the group exposed to the combination of PbCIBr and r.O. - 252 - DUP040011734 tOBY W lSH T V#.)( * rigurs 53 - First degree polynomial regression curves.for body weight prior to and during exposure to carbon monoxide and lead chlorobromide singly and in binary tosifeitsation. Cacti point represents the mean for the animals testea au the indicated time for the various groups. - 25.3 - DUP040011735 jM0R.ilJ541 f**K?WS* HAZLETON LABORATORIES, INC. 3.3. Pulmonary Function Tests 3.3.1. Mechanical Properties of the Lung and Respiratory System ^ 3.3.1.1. Total Respiratory System Flow Resistance During Inspiration [Rrs(i)] Analysis of variance of regression for Rrs(i) (Table 5, Appendix D) revealed non-parallelism among the groups. The third degree polynomial regression curves (Figure 69) indicated that Rrs(i) values for Group I decreased slightly at the beginning of the exposure whereas values for Groups III and IV similarly increased slightly. Separate t-tests of the pre-exposure adjusted means for the first nine weeks indicated that Group I was significantly lower than Group III and Group IV during this early interval (t - 4,33, d,f, - 16 and t * 4.66, d.f. * 16, respectively), 3.3.1.2. Tota' Respiratory System Flow Resistance During Expiration [Rrs(e)] Analysis of variance of regression for Rrs(.e) (Table 6, Appendix 0) indicate.; oon~'>'rallel sm among the groups. Third degree polynomial regression curves (rigure '9) indicated that Group II started into the experiment with lower Rrs(e) values 1 lan the other groups, and did not exhibit as much of a decrease as the other groups, A t-test of pre-exposure adjusted overall .exposure means comparing Groups I and II indicated that Group II was relatively sig- ificantly higher throughout the exposure period (t = 5.03, d.f, = 14.3). A similar test comparing Groups I and IV Indicated that Group IV was relatively higher also (t = 3.72, d.f, = 16). Group III was not significantly different from Group 1 by this test (t * 1.92, d.f. = 16), - 254 - DUP040011736 / IO * l ItSPIRArOW'SYSItM F lo w KSISTAn C I - IN S P lK A ll& N .tM il-tta .M jO /n l/'rtt] Figure 69 - Third degree polynomial regression curves for Rrs(i) prior to and during exposure to carbon monoxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 255 - DUP040011737 t Figure 70 - Third degree polynomial regression curves for Rrs{e) prior to and during exposure to carbon monoxide and lead chlorobromi.de singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 256 - X DUP040011738 HAZLETON LABORATORIES. INC. 3,3.1.3,. Tidal Volume (V^.) Analysis of variance of regression for Vj (Table 7, Appendix D) revealed no significant differences in slopes among the groups. Vj increased with time in all groups, as shown in Figure 71. 3.3.1.4, Respiratory Rate (RR) Analysis of variance of regression for RR (Table 8, Appendix D) indicated slight non-parallelism among the groups. The third degree polynomial regression curves (Figure 72) indicated that Groups Us III, and IV exhibited essentially no change during the exposure period,.while Group I demonstrated slightly decreasing values due to an abrupt increase after "exposure" started, 3.3.1.5. Dynamic Compliance of the Lung [Cdyn(l)] Analysis of variance of regression for Cdyn(l) (Table 9, Appendix D) revealed no significant differences in slopes among the groups. The third degree polynomial regression curves (Figure 73) indicated that all groups increased in Cdyn(l) during the experiment, with Group I showing a sharp increase after "exposure" began. Although the pre-exposure adjusted means of the first year were significantly different between Groups I and III (t = 2.69, d.f. - 16), the fact that Group I showed a large increase at the start of exposure renders any interpretation difficult, 3.3.1.5. Pulmonary Flow Resistance (Rl) Analysis of variance of regression for Rl (Table 10, Appendix D) indicated non-parallelism among the groups. The third degree polynomial regression curves (Figure 74} indicated that Group I did not decrease as much as the other groups during the exposure period. Curing the first nine weeks TIDAL VOLUME (V f mU)- Figure 71 - Third degree polynomial regression curves for Vy prior to and during exposure to carbon monoxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. v N. \ DUP040011740 ii ? / *E5flAATCRY RATE U X ft'O rtH */m fo)` Figure 72 - Third ..degree polynomial regression curves for RR prior to and during exposure to carbon monoxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. S 'Jen ,, OUP04001 DYNAMIC COMPLIANCE o ! IH t LUNG [clr (l| .mt/w, H jO ] Figure 72 - Third degree polynomial regression curves for Cdyn(l) prior to and during exposure to carbon monoxide and lead .chlorojbroraide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 260 - DUP040011742 tm.MON.AAY FLOW RESISTANCE (Ri - . H ^/n t/W c ) Figure 74 - Tlii rd degree polynomial regression curves for R1 prior to end during exposure to carbon monoxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. DUP040011743 HAZLETON LABORATORIES. INC. of exposure, Group IV was significantly higher than Group I (t 4.66, d.f, - 16) as was Group III (t - .66, d.f. * 16). Separate t-tests of the pre-exposure adjusted means of the overall exposure period and of the first 52 weeks exposure between Groups I and II were not significant (t < 1.64. d.f. - 15 and it = 2.05, d.f, = 16, respectively), '3.3.1,7. Work of Breathing During inspiration per ml Tidal Volume [W(i)/ml V.J.] Analysis of variance of regression for W(i)/ml Vj (Table 11, Appendix D) revealed no significant differences in slopis among the groups. The third degree polynomial regression curves (Figure 75) indicated that Groups III and IV were lower than Group I throughout the exposure period. 3.3,1.8. Work of Breathing During Expiration per ml Tidal Volume [W(e)/mi Vj] Analysis of variance of regression for W(e)/ml (Table 12, Appendix D) indicated no significant differences in slopes among the groups. The third degree polynomial regression curves (Figure 76) indicated very little change in W(e)/m! Vj values throughout the exposure. 3,3,2. Diffusing Capacity of the Lung for Carbon Monoxide (DLC0) Analysis of variance of linear regression for OLCO able 13, Appendix D) indicated that there were no significant differences in slopes between the groups. The third degree polynomial regression curves (Figure 77) indicated that all groups increased in DL^q values with time. %V wOS'K O'f MEATM1NO PISl'NO fW > A riO N R m l tiO A l VOhUMI VTJ Fignro 75 - Third degree polynomial regression curves for W(i)/ml Vt prior to and during exposure to carbon monoxide and lead c.hloro.bromi.de singly and in binary .combination. Each point represents the mean for-the animals tested at the indicated time for the various groups. - 26.3 DUP040011745 WtJftfl O f SHEATHING bUSIN'6 EXPIRATION PEUrnl. TiDAl VOttiME fr f.W m l V ; 11 i........... ! a 3.0 --------- -- 1 11 . I''" 1 i i. 1 .. . ....................... - * * 8 ...................... l.s i i .t 2.5 _ * i i i 2.0 ^ --- . .... . . . .............................................................. m* '~a ....................................... 4 r q X5up i -fc*i<sr *a | GROUP H - 45.46 Pp GO; a. a a 4 __ ' |-` ^' -~ 9 ma - i, _ ......................... 9 j OKJUP IH - p.il '' ^ a' f* pbClS,j - ". 2.5 2.0 *,, 1.5 1 i i i t -11 1 i t* J ]&-------- . ... . ., 1 1 .... s* r .................................... a l'-!0 o 8 i> its .4 '' '"i 1 6789( q IV-M.43 ppm to i Q.<7 mg/m^PbClfif j ^ l'il g 1 a a ' xr eo ' n :;<D -=D D >? m 9 Too rJ Tio Figure 76 - Third degree polynomial regression cloves' for W(e)/ml Vt prior to and during exposure to carbon monoxide and lead chlonobromide singly and binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups.. i- - 264 - DUP040011746 wVmtiUrTM. H j. PD) * > aaijpiwiwwiji ; f 'I I1 5 | fi DirfOSING CAPACITY b f J H liU N O KO* CWtSON MONbSHDE t. Figure 77 - Third degree polynomial regression curves for DL^q prior to and during exposure to carbon monoxide and lead chiorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 265 * :1 | -a DUP040011747 3.3.3.1. Number of Breaths from 80% to 1% Nitrogen [N,(l% Ng)] y Analysis of variance of regression for N(l% N,,) (Table 14, Appendix D) indicated.non-paral!elism among the groups. The third deg. polynomial regression j '-i ; curves (Figure 78) indicated.that values for Group I were somewhat higher during ' the pre-exposure control period than values for Group II, III, and IV, During - the entire exposure period, N(l% f^) values for Groups III and IV were at a higher level than Group I values. A t-test of the pre-exposure adjusted overall t exposure means of these two groups indicated that Group III was significantly- i \ : : higher than Group .1 during the exposure period (t - 4.55, d.f, = 16). A ; similar t-test comparing Groups I and ,7 showed a similar relationship (t = 5.24, d.f. = 16). A t-test of the pre-exposure adjusted overall exposure means of Groups I and II showed them to be significantly different (t = 2.21, d.f. = 16), - 3.3.3.2. Respiratory Rate Measured During Pure Oxygen Breathing (HR*) Analysis of variance of regression for RR` (Table 15, Appendix D) indicated no significant differences in slopes among the groups. The third degree polynomial curves (Figure 79) indicated that Groups II, III, and TV were slightly higher than Group I after the 45th week. Separate t-tests of the pre-exposure adjusted overall exposure means comparing Group I to each of the experimental groups, indicated that the first two groups were relatively higher than Group I throughout exposure (t = 2.18, d.f. = 16; t = 2,61, d.f, - 16, and t < 1.64, d,f, " 16, respectively). - - 26b - j i i ! ] \ DUP04001174S V J ' 30 rr------ 1-- l J ....... i a B Bi *? * 1 - -i CKXlf u 6i.<i pv* CO) a' 1 ^_ a a. s ' B - a a -- - t . . . . yf 1 N W ilR O f SWATHS T a T * N ltit6'0E N '[N (T * N j) ] Figure 78 - Third "degree polynomial regression curves for N(V% %) prior to and "luring exposure to carbon monoxide and lead chlorobromi.de singly and in binary combination.. Each point represents the mean for the animals tested at the indicated time for the various groups. - 267 ' :j :J ia ;% l I i DUP040011749 #SKS Figure 79 - third degree polynomial regression curves for RR' . prior to and during exposure to carbon monoxide and lead chlorobromide singly arid in binary combination. Each point represents the mean for the anitnals tested at the indicated time for the various groups. - 268 - DUP040011750 HAZLETON LABORA TORIES. INC. 3.3.3.?, Cumulative Tidal Volume from 80% to 1% Nitrogen [CVj {1% N2)1 Analysis of variance of regression for CVj(l% Ng) (Table Its Appendix 0) indicated non-parallelism among the groups. The third degree polynomial regression curves (Figure 80) indicated that Group III was slightly higher overall than Group .1 throughout exposure, A t-test of the pre-exposure adjusted overall exposure means comparing these two groups indicated that Group III was significantly higher (t 2.24, d.f, = 13,7) throughout the 4- exposure period, 3.3.3.4. Tidal Volume Measured During Oxygen Breathing (V^1) Analysis of variance of regression for V^.1 (Table 17, Appendix 0) revealed non-parallel,ism among the groups. The third degree polynomial regression curves (Figure 81) indicated that Group I had lower V^' values than the other groups during the pre-exposure period and exhibited more of an increase during the exposure period. The lack of increase in Group II, when comoared to Group I (t = 2.51, d.f, - 16), was probably due to the deaths of two males during the exposure period. 3.4. Hematology The group means and analysis of variances of the various hematological variables measured are presented in Tables 18, 19, 20, and 21, Appendix P. No consistent trends were noted in any of these variables which remained within normal limits throughout. Random statistically significant differences were seen, but were not consistently related, to the exposure conditions. - 269 - DUP040011751 f w NJ001U.IN M .01 SIW.OA TVOU ^ ItfU tlW P TIME ^-WEEK'S Figure 80 - Third degree polynomial regression curves for CVj(l% N2) prior to and during exposure to carbon monoxide and lead chiorobromide singly and in binary combination. Each point represents the mean for. the animals tested at the indicated time for the various groups.. =- 270 DUP040011752 V.v'' i hm [ SdfiiOA iv q u -------------i.......... 0 311, . --.-- ------------ m" B i x &' . .. 69.0 '--T--~-------------------------------- . j_m J GRO.W iU.-9.5I-iiig/? PbCISa'j . .' . .' _ . ' rt i. 'i i "* B ---------------------------------~ - ........................... - i 60 50 60 FfME - WfK$ m figure 81 - Third degree polynomial regression curves for Vj1 prior to and during exposure to carbon monoxide and lead chlorobromide singly and in binary combination. Each point represents the mean for the animals tested at the indicated time for the various groups. - 271 - DUP040011753 HAZUTON LABOflATOniSS. INC. 3.5. Clinical Biochemistry The group means, standard errors, and the .resuits of the analysis of variance of the various clinical biochemical variables measured are presented in Tables 22 athrough 35, Appendix D,. Scattered statistically significant differences were noted; however, no trends were seen in any of the variables'. Throughout the study, the-group' mean values' fluctuated within the normal ranges .of these variables. 3.6. Arterial Blood Gas and pH The group means and standard errors for the blood gas variables are presented in Table 36, Appendix D, Examination of these data did not reveal any consistent trend with time.. Ho apparent exposure-related changes were seen in any of these variables. 3.7. Terminal Body Weight, Organ Weight, and Organ Weight as a Percentage of Body .Weight The data of the terminal oody weight, organ weight, and organ/body weight ratios are presented in Tables 37 and 38, Appendix 0, for males and females, respectively. Single classification .analysis of variance revealed that the brain weight for the males in Group IV was significantly higher than for Group 1 males. The mean terminal body weight for the females In Group It was higher than the terminal body weight for Group III females. yhp ki dr*try v/oioht to ,ur 4 i ~n ui v*_M___p. uTTTi females than in Group II females and the heart weight for Group II females was, significantly higher than Group I females. - 272 /* DUPO4O011754 HAZLETON LABORA TOBIES, INC. 3.8. Histopathology Summary A detailed listing of the microscopic alterations seen in the lungs, tracheas, livers, kidneys, peribronchial lymph nodes, and hearts from the animals in the control and exposure groups are found in Table 29, Appendix D, Exposure-related microscopic alterations were seen in. the kidneys of the animals.exposed,to 0.6 .mg/m of PbClBr. These microscopic alterations were characterized-by varying degrees of degeneration of th# proximal' convoluted tubules. The epithelial cells of the proximal convoluted tubules were slightly vacuolated in some animals and a slight to moderate degree of nuclear vesieolation was present in some animals. Acid fast intranuclear inclusion bodies were seen in seven of the nine animals exposed to .0,6 mg/m. of .PbClBr alone and in five of the nine animals exposed to the combination of 67.5 ppm CO and 0.6 mg/nf* of PbClBr, Incidental lesions not related to the exposure conditions were seen in the lungs, peribronchial lymph nodes, tracheas, hearts, and livers from the animals in both the control and exposed groups. Animal Mo. 157-L in the group exposed to 67.5 ppm CD died during the 42nd week of exposure. Microscopic examination of the tissues from this animal revealed lesions consistent with a diagnosis of monkey pox. Necrosis and hemorrhage were seen in the lungs and liver from this animal. Numerous inclusion bodies were present in.the epithelial cells of the trachea, / /' - hz - - -;f DUP040011755 ; \/ 3.9. Summary The inhalation exposure of male and female cynomolgus monkeys to 65.46 ppm CO* 0.51 mg/m PbCIBr, and the combination of 66.43 ppm CO plus 0.47 mg/m-3 PbCIBr resulted in a deterioration in the distribution of ventilation in the animals in the two groups containing PbCIBr.. The number of breaths to 1% nitrogen measured during pure oxygen breathing was sijnificantly elevated in the animals in both groups exposed to PbCIBr.' Cumulative tidal volume to 1% nitrogen and respiratory rate measured durinq pure oxygen breathing were significantly elevated in the group exposed to 0.51 mg/m PbCIBr; These Tatter differences were not seen in the group exposed to the combination of 66.43 ppm C6 plus 0.47~mg/m3-PbCIBr."' .............. Statistical analyses comparing the control group to the group exposed to 65.46 ppm CO indicated a significant mean difference in the number of breaths to \% nitrogen, respiratory rate., and tidal volume measured during pure oxygen breathing. However, these differences were attributed to alteration of the sex ratio and hence the animal size distribution due to the deaths (not compound-related) of two male members of the group exposed to 65,46 ppm CO. Microscopic alterations related to the exposure to PbCIBr were.found in the kidneys of the animals of these two lead groups. These histopathological changes were characterized by varying degrees of degeneration of the proximal convoluted tubules. The epithelial cells of these tubules were vacuolated and possessed vesiculated nuclei. Numerous intranuclear acid fast inclusion, bodies were seen in these epithelial cells. - .2 74 - J I f i i DUP040011756 HAZLETON LABORATOR/S, INC. Hematological, clinical biochemical, and arterial blood gas S measurements made pre-exposure and periodically throughout the exposure period on the animals in the control and exposed groups did not reveal any meaningful differences* No trends were noted in any of these variables, and, in general, the exposed animals were comparable to the controls. Statistical j t ' analysis of the body weights measured periodically throughout the exposure period revealed that all animals in both the control and exposed groups increased in weight with time, although the group exposed to 65.46 ppm CO I showed a slower mean growth rate which cari be attributed to the deaths of two of its j male members. No meaningful differences from the controls in terminal body j weights,' organ weights, and organ/body weight ratios were found for the exposed animals. I i | j t 1 I ! !| - 275 - DUP040011757 Appendix D - Data ccnpilations and summary of statistical .analysis for Statist*cal Grouping D, comprised of the following: Group I - Control, Group II - 65.46 ppm CO, Group III 0.51 mg/m3 PbCIBr, and Group IV - 66.43 ppm CO +.0,47.mg/m3 PbCIBr. - 276 - DUP040011758 Table 1 - Monthly means and the grand mean for the' analytical concentrations of carbon monoxide in Group II, Date 4/ 7/68 - ` 4/31/68 5/ 1/68 - 5/21/68 6/ 1/68 - 6/30/68 7/ 1/68 .r 7/31/63 8/ 1/68 - 8/31/68 9/1/68 - 9/30/68 10/ 1/68 - 10/31/68 11/ 1/68 11/30/68 12/ 1/68 - 12/31/68. 1/ 1/69 - 1/31/69 2/ 1/69 - 2/28/69 3/ 1/69 - 3/31/69 4/ 1/69 - 4/39/69, 5/ 1/69 - 5/31/69 6/ 1/69 - 6/30/69 7/ 1/69 - 7/31/69 8/ 1/69 r 8/31/69 9/ 1/69 - 9/30/69 10/ 1/69 - 10/31/69 11/ 1/69 - 11/30/69 1.2/ 1/69 - 12/31/69 1/ 1/70 - 1/31/70 2/ 1/70 - 2/28/70 3/ 1/70 3/31/70 4/ 1/70 - 4/ 9/70 r 24 31 30 31 31 30 31 30 31 31 28 31 3.0 31 30 3i 31 . 30 31 30 31 n'm ! 31 9 X ppm 52.7229 64.9416 66.0280 * 65.6890 65.2639. 63.8380 ' .63.9106 65.2.470 66.2948 65.3729 66.9978 65.9987 67.5077 68.1716 68.4580 66.8609 ,67.4068 65.5323 . 65.62:03 67.11^7 64.792:3 65.1948 66.7646 65.8845 64.8081 S.D. 18.6179 3.5378 3.2531 3.3289 . . 2.3260 5.0975 3.2811 2.8750 4.1978 1.8454 2.1481 2.4073 2,3761 2.2823 1.9130 1.2850 1.3534 1.9411 1,4197 1.8847 3.4599 2.1385 2,7352 1,7923 5.7551 N = 25 X = 65.46 . $.13. = 3.33 - - 277 - DUP040011759 Table 2 - Monthly means and the grand mean for the analytical. concentrations of lead chlorobromide in Group III. . Date 5/11/68 - 5/31/68 6/ 1/63 - 6/30/68 7/ 1/68 - 7/31/68 8/ 1/68 - 8/31/68 . 9/ 1/68 . 9/30/68 10/ 1/S8 - 10/31/68 11/ 1/68 - 11/30/68 12/ 1/68 - 12/31/68 1/ 1/69 - 1/31/69 2/ 1/69 - 2/28/69 3/ 1/69 - 3/31/69 4/ 1/69 - 4/30/69 5/ 1/69 ^ 5/31/69 6/ 1/69 - 6/30/69 7/ 1/69 - 7/31/69 8/ 1/69 - 8/31/69 9/ 1/69 - -9/30/69 10/ 1/69 - 10/31/69 11/ 1/69 11/30/69 12/ 1/69 - 12/31/65 1/ 1/70 - 1/31/70 2/ 1/70 - 2/28/70 3/ 1/70 - 3/31/70 4/ 1/70 - */30/70 5/ 1/70 - 5/ 5/70 R . ... 20 30 31 31 . 30 . 31 30 31 31 28 31 30 31 30 31 31 - 30 31 30 31 31 28 31 30 5 5mg/rtf* 0.8570 " 0.4743 0.4565 0.60.22 .8,5773 0,5074 ` 0.4286 0.4638 0.4752 . 0.6154 0... 5.6 77 0.5147 0.7770 0,5503 0,5597 0.5010 0,4737 ' 0.535:2 0,4930 0.3871 0.4052 0,5100 0.5561 0.3070 0.1(80 S.D. - -- - 1.0552 0.6379 0,3048 0.1088 ; / .-0,1526 0.1497 0.1944 0,1819 0.133.9 0,7173 0.1515 0.2131 0.1710 0.1740 . 0,2216 . 0.1545 0,2049 0.2722 , 0.0363 0.1065 0,2503 0.3669 0,2525 . 0,5732 0,0295 N - 25 X = 0.51 S.D. * 0.27 - 278 - DUP040011760 / Table 3 - Monthly means and the grand mean for the analytical concentrations of carbon monoxide and lead chfloro* bromide for Group IV. CO PbCIBr Date n X S.D. X S.D. ppm mg/m3 6/ 1/68 * 6/30/68 30 66.0710 2,5214 0.5133 0.2917 7/ 1/68 - 7/31/68 8/ 1/68 - 8/31/68 31 31 66,4219 65.9890 2.2956 3,0532 0.4619 0.2142 0.5868 0.1232 9/ 1/68 - 9/30/68 10/ 1/68 - 10/31/68 30 31 66,5103 64,8868 3.7002 3.8590 0,6360 0.2123 0.4477 0.1979 11/ 1/68 - 11/30/68 30 64.2883 3,2099 0.3627 0.1645 12/ 1/68 - 12/31/68 31 65,0668 2.3887 0.5590 0.2247 V 1/69 - 1/31/69 31 66,0261 1.8732 0.3787 0,1947 2/ 1/69 * 2/28/66 28 65.7504 1,7250 0.3350 0,2189 3/ 1/69 - 3/31/69 31 67,8374 2,1281 0.4094 0.T793 4/ 1/69 - 4/30/69 30 67,2590 2.0255 0.6210 0.3262 5/ 1/69 - 5/31/69 31 66.5474 2,1141 G. 4.374 . 0,1435 6/ 1/69 - 6/30/69 30 66.3283 1.3444 . 0.4703 0,1416 7/ 1/69 - 7/31/69 31 66.2529 1.4520 0.5313 ,0.1443 8/ 1/69 - 8/31/69 31 .67.2262 2.1208 0.5042 0.1467 9/ 1/69 - 9/30/69 30' 67.5253 x 2.2677 0,5493 0.1569 10/ 1/69 - 10/31/69. 31 66.4932 2.0110 . 0.5365 .0,2504 TV 1/69 - 11/30/69 30 66.8467 1.4641 0.5010 0.2181 12/ 1/69 - 12/31/69 31 65,9.313 2.8099 0,5203 0.1853 V 1/70 - 1/31/60 2/ 1/70 - 2/28 70 31 23 67.0703 67.7143 2.1003 1,9892 .. 0.5419 0.2456 0.5368' 0.1744 3/ 1/70 - 3/31/70 4/ 1/70 - 4/30/70 31 30 66.5290 66.1123 1.5245 1,8950 . 0.5568 0.3247 0,3607 0,2049 5/ 1/70 - 5/13/70 13 67.6277 2.7596 . 0.4669 0,2514 N =24 X = 66,43 S.D. = 2.28 - 279 - N = 24 X = 0,47 S.D. = 0.21 I /' * DUP040011761 I $ ?> C 3jO? fX 4* O 5 *1-0 o *x5 "Ocr <tf aS sn ' CtE.Lrx?3. O CJ a j0oU ' . cco s c: ov *r-- .CL : 3-r~ oUm* to o .* I <U0 m 44 <>?< V* O4*r-* Q3t4o- t$o io- o* 4- H +f0J CCLL T3 SsO? j cGmA* r-- SO , CS ;3= * o CL 3 4- p O 5- * Sfl CO CSQ- r.e--: c<n4S4- #3L *3^ f*- 3 e r- H IS 4-? *3* m o l - *4nr4--s J<u33 O 4- +4 CO .* o uj 40s- C0Z*1 & CL sl>O-5*O3r> O- H '3HErO- tC*- */> *4- sp. 1 sf- tU jd rti to o vl a IS 2S tO-T* in *s% UI t<oXUcci pi 2<c Ui X : SO to 0s0o *--- to u. o LU O <S* QC *O :< o tIofl CO to <tor> to a LO 4M CO O *t3 sr] a! per <e( =>i U2 O Pi 13 C o. =8 c o ><r1>> o Uuu4 SOOY cn co fV cr. tcort 00 CO 04 co CO cn 00 CO r~ r-- .<* * o ,0 .0 o CiMOiO- C*OOr*oO C-MO**3O- CiM0s:it0 in to \& Ui <n H COi i-- 3z: Ui oM Uu, Ui o O iss O s<t3uJn:n CD XX *t eo M)<a r^vO? XX ts- CO oS o OS"*- XX co <M sr> o --CO XX at esi ro r-- CO 4-r M +1 4:1 0OLf4 .. 4SOO)- to *Osf OOO scin* -OO +1 H +1 cMo? pO r-- '*P rv. 04 ri CU 280 * cn OoDC : to - h1i *. * 1 DUP040011762 s~ ra 44 xSt cr oo* *r2e Qae.. > r":U> fOtZo ^tAfO>f . 444TC<tstau3Oacicj3noto/4O4u-KO>J--si la'#--O4Mf,"30OucrC3s00.l0*14-4-4LoC...*rOCO_-O0*SO&gqcvs4-O.=j***n'.- >>o2- ae X i- .co .4K^> c 0 id ! <0 i- 5 r- O CJr* I l/l i**"* 5(w1 A0j* >M f--ItJ JaC; 3o, 44 4-> .0 o s44 '4- CD A* o 1. 0 o *o m VI 0CO) fO fQaO) *JfU U*1 t>-fyCLCrQ-f OO e; u -a n> a. .Mi >-- O OO <0 r y rr* C, O' 4C4O O-r-l . H f-- 3 r-- 44 O Lfl ftf w CO44 o o 4- *3 O O -s !>* 4T"4 *?-* 1 A- CO S *4 3rK *" CX S lO O VaH.+O> cts 4 40 - ___I < z: s#* i OO r* >c X .to r^. r-- <4- o> 10 .4 O r" 1. O XX to AO CO CO CO tn 04 r- tO |L4O o t~4 hr to C -- 0 `-C UJ t. n3 o Occ i ZD c o JO 10 tu O so S- UiJ. rs tO tn at 0 CM AO - O O O .0 o 0 r>. co at co r^. co- to ss XA .>. J,I Voo<oCU3P vt Oos J *-* AO o .0 o 1A/O51] " o <s tv I/- UJ 03 CC cisco .at co co co o t i. 1 1 ti il o O O 0 0 00 OO r*~ r-- r-!" r4* 2T O M XX XX X X Xx 8 O O 0.0 0.0 OO r~ j-** 0 CO oec* AO CO UJ .0t-J. CO tp r^.to CM ^ n r>. 41 UJ +f +1 4t fi AD,AO MO AO AO to tn Ui 1f 1 .1 ( 4 .1 j ^s: OO O O O O 00 o V) 'rr-- r-r* ^*1^ +t X x X X X X X X o Cl- OJO 0 AO CNJ LO COfV f>. CO MO sj- co CM O UJ <n at CM r-- to r^. r* ,r-- UJ 1 J a: H +! +i *H CD Uf p3 O. QC 3" ** l4 1i 11 ti 00 r-- r- 0.0 i-r r~ OO r-* * 00 .* *--* to -CO: LU C ' CD UJ QL XX CM *-4 r-- U3 CM CO +1 XX to <4*0 sii^Kj- 4:1 XX XX CM 1-- 10 CM to 0 CO CM m co* M3 *1 +1 +i CO CO 0 :0 CO VM co O. <D O O O OO O OOOO 1* 11 41 CM CO ssf so m OO00 xco O 0 0 - 281 - %n G_ r> M .-- < 5* 0 -4 --e >-< 01 --4 CD 2* *^* j -h * r 1 s'. : i - DUP040011763 <0 <d E *o o. Du C0 vo +> ' > .** in s l . in . ex. i XxU*-* to CSJ is. CO LO r-- tp . o P P: o .x 01 --* u* C O.CO 'r* ,3 r-- OO 3 tj3 XJ Cfl CL in o to . til vl >O- i coa% os is. CO CO CO XU Ur- E C O^ RJ S- OJ P4J V)C v-* o r> M U ft di U I :o 3s h -i -f o>-* '0.0 <f- =5 O ' O' E fc E QJtu a M Q. > * CO l/l OJ*4* C" >>*r- VO S- 3: vo oo M r-- l !>. 0> l--t*- M CL' (j!Lu/). <-- -4cC4-Ur-; OUC3CL as o 4^ -a OX C *** CJi as V) <f* r- . O i- L ; @ ;A U .QtnCMJ::.o.ro** >, a. re :an. eE fftf o>\ c cn i--m- i uas resxi-- ir- o in MOO as roi 4-> U -f. </S *n- w 4*J H- </} . o-r- a >t 4O-i O=j LR3 < !/-3>; CL3 i? j- CJO.VO* Oo VO 0 -Q .res to U- P4- .1 z o *$ CO to La 0 CD LU pi i. i as o o = r" .r-- LU .2: X X co _j s r-- CSJ oo ui LL co a o "SF r-- LU U 2: <a: w CO r-- o: 1 1 < OO >> Lu x x o *o to Of 'Cf to r-> IS --I CO rto : >- r-- rr_J * z: in 4- CO r^-o r--- f4- - sr D f-- CE S w in O CC i-- `pj1 <C r-- > as res *-- *r- lx. V-- til a UJ O i~r>eS L c I O ro C J- o o i- to Z LU IS. :|S. -in Is oo oto H* oo o o. Ip Zd Ixl M o M LL. lu LU 00 CO 00 CO co co CO CO O 1J 1 1 1 t i( vO p p o p o o. oo f-- r-- r* r--? r- --* >-!" r-- 2 O u-- X X XX X X X X to o o 0.0 o o o o to Ixl <j> eg O IS* p co *-- o 6 CD eg to co in i #r- VO VD ilu pe +i +i 41 +1 <c VO to VO VO VO VO in to UJ \1 11 ii it oo oo oo oo O' z: to P-- *** r-- r--" r** r*-- 'r*" r-- to>- _j +i X x X X X x X X o !<i- r*s eg ?cj* .O rf in to Cl h- co p> r-- CO co m O.op z uj LU LU .M rr-.IS. 1 *}* CO IN VO r^-.p PL o H +1 4i 41 o UJ .o Ui ao ISP'SP <s- a: o ti 11 11 ii w P o o o O O oo ie r~ r^- r-- r~- r^- r^" P-- jP-!* XX pn p O Cvl XX VO o co IS. XX CM O ON XX op tn ^ eg CO \ - r-- CO t 41 vo eg i 41 in crj i 41 03 eg CO O eg co eg eg o o oo ooOo p-p o o 4*1 - 41 4.1 . og P f*. - co oooP ooo O to Cl ID 1--4 O. *--* I--< >44 . 3> 44 OL 4 O. - 282 - DUP040011764 { P.-cr. UO* Ci3>OOx *0 "Cl WV) C<& S- - a. i. aOUS:JCrUnDQ-CO oCr*X 's2s? 3!' rto*Jok*>OL--O +4rf--OJJ! iO--ft 1 ** ~~--~41t 44; CX itf 3 4-> o V) I- s- <ot- <3 "4nO-3> ; ooICEXL r2<E--Q>U tiU^noq3* "dO' m*-* -Mr" C3L O </> CSOO- cVa* r><tiAa-i C oi~ 52 -COau CO 0 r.0*5r UOI iisOEEI D *~r >"* rs 44 <3* v> CX *-* 3 0 44 O <ts + 44 CD OO(A *4-- > O Ot E ^Vdr- CCXl O COL- `HS tf Sr-1- T O LOiir^ 3 c/j v- ip .J rs OJ rr-- JD rtf t--> -1 1 11 h11 I ZOM to to LU CLOUDS OS <O' vLZ_-UJ< OLu OLz<UC <SO>S OLU ; *C--O >LO -Z<< ion vl 1 | CL LU *C1--3O* 1 C+UIO--1! c+u1o*^* XX t2o o* itno .ot-o>** ,r*-- -rr c+u,or +3.or-**- XX ttoo fCtNos st* ,1oc"c--uox is. so4- CO *Rf T3 OZT. --< 1-- EL? PO 1j a; .*-- <f~ p--* 44 as ftj LOU ' -> C Oto <D LU <t3 <J> a. os 1 ot- OID to CO .21 LiLU._ K f>> Mr>O* o> IS . CtoO 4? o o o &\CU fS r** CO cu ro . 2Hto1 .LOfc--U-4* LU LU oLc_U> oas .i0-40 .tUCaoOs) .cLcU -J '2o1--sS4 o-U Cl . LU LU OS CD OLU 1DtOQ---SZ4 . % - 283 - X CO ; . o * o> cu 2^! to ' 44C- O'*. . cu CO 03 CO CO LO LO to to to LO tr> in .1 1 11 11 i o o O O P.p o o r-- IT- f-r* r-- .j*-- X X XX XX XX to ^J* T** CO c-- Cvl +1 ox o P sir>*K CJtO r~ CU :CO.CU t +1 -H O r~ ox in ^ico +1 CO CO 93- .ro *s? rr> oo co LU I1 tJ 1i ii OO o o .0.0 op oo fT-.fT-- r--f f-- pU -H X X X X X X X X to cu sf cu # cu r:3* ..r> 'sf r>o Cpi-- * LO *3* CO O co co -- to +1 H -H +i -- ir~ CU r** P- r-- 11 1 1. 1 1 11 Q O p o o.o -* **-* ,rr-- r-- p-* r4- op l~" f-U l/>to X X X X X X X X LU cu CO VO LO J*CU tors- OfiS LO CO - LO ox p.rs LO r- . m . -4 o:LU CU ,P^" r*-r" -r-^rr- f--cu +1 -H +1 fl cu O in CO <Ti rs rs cu * cu +i -H *H 4-J cu r^ O CT i< <T r-- co CO fi- cu cu CO co co to OcIDu .-- t~~* *--t D> *--4 OS h-H AD ,y` y DUP040011765 fo llo w in g : Group 1 - Control, Group - 6546 ppm 0, Group - 0.51 mg/rr.3 pbCIBr, and Group IV - Table 8 - Summary o f s ta tis tic a l analyses of respI I iratory rate data fo r SItaI I tis tic a l Grouping D, comprised o f tie 6643 ppm CO + 0.47 mg/m3 PbCIBr. Qto vi <a >r Cl cr^o. tcno cUUooccJJ OJ <DUCcJ +o X ou. C2O1 o 3 CGM\ oUJ CO cc +o +o X o to CO CO m to o CM CM CO M CO s IS r->* CO z; o trt. co: 'ir 0r" .> oUJ OcO</c>; rtj OoCI- o U oU i- co CM to o.* O CM *> CO CM o CM X CT> r>^ jr**. Oi CO UJ CM r- CO CM CJ--i *--* u. Ll . OUJ to IO to to tO to to to p 1 ( .1 1 1 . co o> cs to f-T- CVI *- -* CM !>. UJ a: +1 +1 +1 +( <c UJ <o CO CO CO to co *zr.cn I1 11 1t 11 oz to. oo oo oo oo .r-- '<-? r-r- .r-- ff* ir** +1>- _J XX XX XX XX o J--a.. to o o r- <30 coxo oo t>* s: COO* O cn O CM *cr ; BC UJ LUUJ --f cyi ; D CM <3? CM Oa: f 1 I 1 o +1 rW +1 H aUJ. aQ: oUoJ. ss CM I o -- oo oo o o O O tU.r-- r-s- j--* r-- r-- to to X x XX XX X x GUJ to co r-- CM i>*o ;E CD UJ CC r- CM to CO tp co fSi .CM 9 '* CO r-- r- r--* CM r-r ..CNJ *~" +1 +1 -H +1 284 - to to CO to CM .r--* ca * ; CM. l-r* r<* -H +1 +1 CO JO sr ,t*S o co to o a* !-> o icj* <o CO CO oa. M M u* > o M --* M. cc: *-* cc; i *. ; - r Mr4 ]l }i 1i 1 r :3 5 DUP040011766 oro cs s-t o r-- 0 U w :*- r l--* *fc^ . aS Cl . ** S u^Eto o **- o n3 O 4J flj E *0 CL CL OJ C tO a *r r- . to o to JO M I `l- M O *^ U CO <3J CLr-4O 3O C as uO JoO_ - I--|"C5co CL * E E r- \ Q O 03 o uS u c.43 r'>. r* 0-*afr EO . Cra 8 o T>3, - 4- O O =3 . ' . E W X- CL (UCS CL trt r><--3 ,*0.3 C C VO J *r- tO S f-- O I m -- Ui-> 4i(Lv, O >-h <A CL r~ <1> 35 -P X O IQ P L +J CD V VP- ox? tL- f- 0X3/3 <y >> 0 Ui8 Lmn- U gss-r c3 C0<0J {/} <jii s CTs Of X? AS to o v'l CL I z o --4 to CO ui c CD UI o' cm <c Ui z to s r-- f>, to to CO to ^ * 00 X "f* +o o > u. X X O to O CO to to 1--4 to ** CO ' >- rTM CO a: r> * " X3 CO .cc c CS u as A. o 00 C r~ 4* rtf > CD Q U O - 285 co sd-- to do sr CM -<3" oOop j = CM CO ooFIN r-- ; ;GCO ; i ..tt f t ! f ! r / ; 2 :S: tu tX.Oo) fd5* PO .FcTMn4* o u> '1o-4* 0to3 P to to to to to so r** so o }1 i1 ii t4 C_) o p o o op O P ir* r~* *?-- r- r"*" o .V--I Xx X X X X X x to o o O P o o 0.0 00 co p vp St CO tN o r> UI P? r*- SO to p to p CD UI CtL 41 +1 -H -H <C ^ CO to CO CO CO P CO LU {| (t .1 1. 1 t oo op OP 0 O 0 CO r~ r-- -i-" r-- .p* +1 X X X X X X X X O to co CvJ CO .CM sJ" .00 r4 CL P o r>. co co * * co ^ UI I cC o CD (H ui i +i to -- +i r1* r~ -H CIOr-- +1 0 UI 0o Q o CM CM CM CM CM CM CM CM Vo1 1- QP I1 ii o o Q-O tr- r~* p-r^ r> r-- Xx fro to .00 to Kj- XX CM p rl.xa Xx H; tn CM so so to XX CO CM.CO_ sj" tO +1 *1 +1 +1 VO ST P <C -H !-- Q to oo LO to oo tl 41 to 03 oo o p vp to in p hv co P to CL 0 *rH --* *3* > 0 t--t +--< 01 w CD DUP040011767 I I ITable 10 - Summary o f s ta tis o f t-fce fa Mowing: t i cgarol upanIaly-steosn o tf f o pulmonary T , Group I Iflo-w resis 65,46 tance data fo ppm CO, Group r S ta tis tic a l Grouping D, - 0.51 mg/m3 PbCIBr, compr and Group IV - 66.43 ppm CO + 0 .4 7 mg/m^ PbCIBr. u o *1- S4R4j -0 <M a. CL 2/' ro-- 'tsOr 2> so * *rp.so * 4*i MM .-- .&* K' 3GL.rC--O at Os~ O.a cikto a. .r**co~ Q1* -0^5 4J & .XU. f0* ,0ONm- so * OF-- I - o + Oft cf:-OaOo s- o SL ^ *oc2 a Cl . cn xrc*:L, .c05*^n4* #a S to4-> 'r- SO (U o U-- I -Q |L*~ o> 4- <*- i-* O a) a. -X *C 3 U *P o o s- o3: .4- CO 40-^3 T0J <l> 3 (ato/)i 1iJ/--) S*- J oo c u .o to a. r-Cl Rf u cn^ *f s: C7I to4J .r. g ;I r- ~f -- *P GLO <0 4J0O V) f +~ re; O U"*-* S>~>+j/l - P **"!' Cl. S * > 3 S 3 O 3 -t- U CO C/J O JO <0 LO o Vi Q. - 2j. O M CO to Ui cc O LU CC CC -SC UJ C\j U) 04 05 Oo u. CO to o LU o as <c .*--i r-* CO + +cc 'O C3<c 2S* Li. O 03 CM CO >- <c z <c I-* 4-- <3-p CO 2O2 c o cc < rp ;u. o .< >o| "> 0, O so o to to o *i3n* O U- l l to SO VO to sc so SO M3 LU ti 1 ii O O O O oo o o O 0 'r-- r*~ *--* r~- r-* r-L XX Xx XX XX o M .0 O o o 0,0 O0 to avm to LO o> sr r-.p1 Uito CSi "sj* r-- 0 i>-to csi M' cc i t i CUSi +i +1 +f +1 OC LU *4' i** co *d- Kf<t f. i t 1 i . ii O z to Oo P" O 0 F-1* 1-- .!OJ1* Or*-- oo *-- r-- >;. +} s XX XX XX Xx CL r>. in Os co LO o Ui o o 0 o si* -^3* to 3* LU LU M 0 r>* 0 0 CQ 0 r> QC to <3 .1-4 Uf u. M +t +1 +\ O ui O o CM CM CM CM -CM CM CM CM <x o i i i i i i i i >-4 o o O O O o op ac r--* .*?-- f~T" 'l~" r-- r-- ! -- r-- fr-- XX XX X X Xx AtoO O ; *n O CO CO0 ui O o so o to 0 CO o oc to Csl CM f-- 4^. NtO 0 0 LU i >t a: +1 rH +1 +1 0o 0SO 0SO 0r~" oaoo < -1* +i +1 +1 *05.8t Fcr-*. fO 00 287 to K; : ZD OttXo DUP040011769 HWp iAfv* MP^yg^jw* n..-J| U a JO 4i-d* O o , CL va e. 23-CO r* ^vf O> un so 4pH* .. )Q I *0 *" M .44 M r** C^-iQ H 3 r- , OO UOf OU J3 a. G- *CO Cr- S O O 'N.. r- &- D> +J+* E <d c: S* ON *r" O *d- CL X I 13 oCD> >- -V 2 0.0 r- 23 O s- o 23 S- JH ixT3CD a *CTi--Oi-iO- M05* X2 N;' * 4-5 M- <> itf 3:v> Q) HO'"' ( r I J3 iH- O <*- <4- h -> O dj o. -x J= o. 5- 4- O O SL S <*- O <,fc- O XJ 01t3y Cia </> >0.03. r-- E r-- id o o C<a u -O a. ,f-OM id E u Cft^ r- C CT3 -n V) CL' r* ,23i r-r 44 0 Id Swi 4M->l <a o r- I 4- Id 0 Oh r-- >- N.-4*':*--* U vi S P 3id -f- c l iJSg CO </J O 1 CM _Q <d t0n vj -M CO 0 CtoO LU 02 0 LU CC QL <C LU 222. LU o cc Lu o oo >- --J <c 22 < oo r~* XX CM CO N. ,CSI CO CM 4*. O X tt/o* to o to <71 to LO .N. d* -p CO o J--. <5 'S Ml c o >lu O ns JL. o co SL to LU to ro r> <T O to CO LO 00 CM Pv. <71 CO CM CO CM Xo LO C7 a|2 ci CM > 4 . CM CM :Z LU O o 'o O M o Lu Lu LU LO 10 11 tog/ to to to to ir li ii O O oo .0 O- * oo i-- r4-* 0.0 r~ ,H" X X 2< X X X X X :0 O 0.0 0.0 o o MO QM* COCO CO r*- Cs| to LU 02 0i0 CM *-- .CM >-- CM CM CSi g? LU +1 +1 4* -ft 02 LU *d* ii ll JI ii O to 0.0 o o O O o o 2: r<* r~r" j p^* -r-" r-- <rr rr-- .i---" > -H XX XX XX KX O to a. H* /2TI tb O N. IN. St CM CSI zr ^ IS* O N. o r>^ fN co LU LU 02 10.00 CMi CO coco i-- CO 0 +1 -H +1 -H Ui 0 Ui Q o CM CM CO CM CM CM CO CM 02 o r < ( ( * 1 . ( 1 O0 oo oo oo zv r- r-- r I-** fH- o #--t X X X X X x X X V5 to to o O to fN O to Ui 02 to to COLO r- LO CO CO . f 0 CM r-- in p-- CM r-- CM p-- Ui 1 t1 02 +1 +1 M 288 to d* to *& s--* r"-- r* o OOo -H +1 -H in CO CM co to jPN N- - V 3--~ to O- 0 >-- M o M t~4 -- 02 M C3 .- l .: DUP040011770 SM * *8 * is U_ AS CX P id to -o*r O -< fee G O cn < V 0) uo <0 O Cl S- 0> ex i c o G xRa3 o 1. UJ CO CO CM fV CP V> CO CO CO CO CO CO "5 CM an rv Is O ox to SO CO O Ui --4 o NN N S II It 0.0 oo p-- - r" M* fv tv 0.0 0.0 Mf r-" r-- XX XX XX X X asto to oo o OO to to <?*" LO IV . ' i- ?*- ,i*"* to Nfs *d- to 11 a: +1 +1 fl +1 _u r? T *P*3: LO U> LO LO I1 11 60 oo oo j--* ,-u. oo r---> fr** OO r-- rs-- z >.--i +1 XX Xx XX X X o CL to oo 5#- On VO to is.yj H 'M- O CM IV CM r** O.lv Z M* UJ Ui S O LU ..--i *-* CM IV 1 H CO CT> +1 i--1" r"-* *1 r-- CO +1 Ui U. a Ll LU oro L-> CO CO CO CO CO CO co 1t 11 11 11 o o oo o o oo >-- r~ r^*r" r~- r" ttoo X X X X X X X X LU f-- CM IV CO 'd' *3- Q <3 o on Ip r*? COCO vp vp .* UJ CO CM CO *d" co <d* CO CO CC t i +1 +1 +1 *1 j 2 i : ; S 289 - CM CM CO ter to ooo 9 oop 41 . +t CM on IV VO to p odd <51 CO o *1 IV On to M M > o --4 a *- * X -- % - * .A .. 1 ; DUP040011771 tti -Ce-jfO aa.Eil gt O r-ES S po 33 V) -Hi tO .Q- &. <0 '* *o -o u = .a -oPOJtoX ^:J* +*' * 6r=;iWO> O.H*4 JL. 44 CO O-r-* 3O .44J= SO-OJt-i <19 a? *,. % OS- EJD P 44= r> &- o^ "v- ? C"sOi* <s8 cWto (0 -r- AO 3C r-- O i -fl3 *-* y^*> 4r4- <OH -* V) a. r-- t..ifr0-t1*0*3-1Cf9t? . a* *.V s- /a S- cq E Qkr--* tS3o -00E-O403. <y 43 to O v> v| aj > a to o z .*o--1 to l/l tJ CX <5 LU or. CM CM ex b +o < LU lCOM oco CO to LU O ><--i co in CSC- 4*. -f` oo Q to to to N *3* CM CO ftf" to >-. c fSS. <c cn IN03 s: o c: G CtL r* 44 <tj U. > o -u O jUJ CD ad. ex i &_ o =3 G S- OO to CO co uo?o si* to to oooo CM CO CCMO Ui to- AO *F co to LO oo* u> *-4. <L> to to tn tn tn in in m 1o fo. i1 1O-- O ii oo ,r4 <4- io er- ifo-* XX XX XX XX to oo r- CM OO to CM OO OO to to Ui X CD CM LO 1 a> co CO f 51- ..ft1 -H 4-1 +1 +t Ui ex UI CO co CM {*> COCO oo CO o z CO rC--D Or-- oo :f-F* oo r*- r- Oo i-- r4- >u +1 X X X X X X X X o LU LU CC. to h* Z CO co to r> to to O *-r o co coco f-- o CO CO Ui f-- 1 to to OLU +1 +j +1 +i O U- a wa: a: H- U! oCJ sr o CM r-- n r-- i-- i-- 11 oo r* r-- 1t iO--- rO-- 1 1. o--- Po-" it rO-- ,Or- CO X X X X X X X X utoi be in to 00 CM ianvion r-- CO in ^ oo CM CO o LU CO 00 sir CM CM CM r- CM ex 4*1 41 +1 -H CM '*51* CoO CoO CcOn CO CM cO CM +1 41 +i 4| in co OCO c>IN- 0%. to CM -M* JOSf sr ps. oo 290 - >r-4 MM >- -- 3 -"J .H *3 *3 -=i .2 : 3 H >a - DUP040011772 IS -u. i- m su oU-CoU o rn U Cf> rr: 4-* f* M> 8 in . s~*-< o *- 4-w io a. 4^ s 0 . o \u O o --COo g s n. at a. i. -Q VO c c*r Cl LA 03VO S', o h-t CRH Cp* cx u3 3O X U wo S___.' fc. CQ 3 Of* r- ILO OP A >c& o <o s "O f ^ r 03 4*^'H4 E (h ars O 3^ V3 o <D CO u% + *--* O ta C730 cc . flj *r" g ^ CX *-- o a. *0 r-- Of--CO **- O P <f- 4U-r>)..j:<eJr| ivOO <0 4- t 4-> to qt- > o h* <4- jD^j a. .3 > ws O 5- 'r- &. i 5- O Es E-H 3 in oa cs js *a . to to O vl VJ o 00 * aoMs </; <0 UJ C O Ul os CM CM 4- -fr a: O O -aC Ui r-- c\j - CO VT> O Ul o z:: *HC C -.< ! +oo o u. X X o CO I ^ v j 50 s03 L; p 4/3 >- 03 c -<C o> H- m r>. GO * xi r-r--- Ga- J-- #cs , s<U->I Qi ClL c o vr 2S o *4t >p f3 > o O . &ou > Ul 1o^ 4CO0 rs yt CM CM CO CO CO CO X t>o 0o0.* 40 ur<?.* 4*=0f CO 0o0 Ul tnio into 40 to 40 40 8 i i i i. 1 1 1 1 o o oo oo o o r-!* * r~ #r" r-- r"rr XX Xx Xx X X 4/3 W CO*-- VO P> to to CM CO COCO 40 CM CO 15^ O vo Ui cc o ^*co 00 40 f- CO com 11t UCi H -H H 2so = Ul 0)0 com CO OO m co 1f ii ii i i v> QO oo OO oo r^ r-- r* a- -H X X X X X x X x 2O 4/v H= CM O 03 0^ mo 00 03 -5T H .* . C-.Q* O 40.40 Ui; Ui u Ht to1 uo toco VO 40 cc o o +1 H -H -H Ui o u. Ul o oHs XJ-- 8 H* -- 11 r- f-- .4 1 .1 .1 t7 0.0 .p-- r- oo *r- r-- OO r-- r-- oo i--;r-- 4to0 Q UJ o LU: t XX O On CM ^ CM CM H XX K UO CM CO 1 4: XX 1^.0 p -CM 1 H XX ;M IO CM CO CM 1 +t .. *0* - CQ 03 ' rs. o 40 CM co CM CM -K +1 -H *H 03 CO O O o CO .03 40 m '<# co 5T to CL S3 M 1--4 i--4 >* O or to ;: ;-:-u .*'3 Si -9? --.J 3S %r **?S52 'J 'v DUP040011775 Table 18 - Mean values {S .E .) and summary o f fa c to ria l analysis o f variance for.. hematocrit (Hot. - percent) fo r male and female monkeys in S ta tis tic a l Grouping D. B uiI Si si f o> t3 iO O CL X .01 I fU u Q. K * CM<h toe? <ro .-* o *rw CO o v! X tO O . <3T>m 'i- r** CO M _ . NW r- ^03wO nlOvff* n<jv| *^ 1u<3a 4> c r-- O' CO r4 ; CO CO coo tON-' W0 ,* !tO CO*!--' cstm .* <n o <0w co w i^ fNv **" CO 03 to o co>-- r-r^ .OOw *"03 AO . cow 3- Wr* co>--* Wj NO C0>^ COIN. 0O Ms> {M ra <21 tm 1- r-- P c .02 .L P a.. UXJ o 1co/5 r* .u rt3 t It * a to CD S3 =c to to KO VJ <9 tao-* </> VI CD to -X ->4 V) H-i CO Q> 1 OJ fcx O *4~ c a CD w. So' ** fc. CD 02 O O CD E CL Cl to <t in <o i a. to E n 05 E fW o 1 M .M *--< M c5a+ r,oCo?u O^o _E*sE* a. tit CL E co t> - *o o MS c o +*Ja *Cr-i fw <UUi O' -cau Oo 4h^u<-j>y s3-l' C ! - 294 * DUP040011776 Table 19 - Kean values {$>.} and summary o f fa c to ria l analysis o f variance fo rt hemoglobin (Hgb. grams percent) fo r male and female monkeys in S ta tis tic a l Grouping D. 4041J&W- CtoO i/i 5Jo&XBi, CIO r*rQ .r- O O O *-- O IV O 01.0 *f\CO .03 * -. * 9 O.o '-o OO r-- O. O Vf ;N VI U to tA icpo m o M V) co ai ^ i/> co to M CO 2T CIO 41 3J0VI to co CL aXa1)i La. c** pL. c Po vs 1 g *-- o o r0^s3~- OQ JPaQ. ro ECL E a. o> CO* * LO E *-- to> U) P 1f a-- .*-* iCO u + ja . ;O .ooo e SSs CL Cft CL S or* *3** *& coo CO 1 w c 0 <a c'r fc. m c o r-- p o. is o rtj ; P . p 1. 0 4J> - 295 I ?I? * =5 ii J DUP040011777 Table 20 -Mean values (S.E.) and summary o f fa c to ria l analysis o f variance fo r to ta l erythrocyte count (RBC - TOb/emm) fo r male and female monkeys in S ta tis tic a l Group!n.g D, O co si* on* .^ `co rr- <9rr CO .00^ ' a > . in o vi we> wo u)o wo .2L *3r > P vi v> is as tn o iri im i- k i- <o co in fOt so Q RCO >-- <o o 10 ; 10 ; * * -J - > WO WO 10 O 10O VI to <cuu 3c CO I 01 ZV-3i 0 CL fX<1ut U CL O CM t>*CM ^ WO r~. *3J5f.fi- - , WO CTto MCO .* 10 <0 *f<3\ t0 C3 4fxi-tt-S` "SfCO Jtf- cno JWr-- CD t-- CO .CM Of-- 10 O loci KJ-O 10 a G .ft MH ft UHC4L *3* co sf CJ> -r-- CO 00 03 r o r-4* rr* CO.*-' in o in O in o o Co vi SS Q. & oO V? <n 4z: tn v> fat? z v> V) v> 2: .22: CO I V> V) Xai Cxi l IX O X f<J c o o -1 3X O tX5 X s. 63 *C--Q r-- C_> o + jQ j Q a. o a. o o CO uxco s S CL CL *o*>* E>s CL O) a. s to e ^ nrs *ca* >-- tn to * vo o VO o VO .1 -* 1 w --4 --1 >*--4 Ml Co CQ 2Pi tr - 296 - Go pi- i i i DUP040011778 Table 21 -Mean values (S.E.) and summary fcf fa c to ria l analysis o f variance fo r to ta l leukocyte count (WBC - per cmrn) fo r male and female monkeys in S ta tis tic a l Grouping b O CO v> 30:a1 J CO 1 . OO CuMi tLoo .v' CQ?s-> oo oo oo OO CM .CO CM VO COv- CO CM CO rv r* .r- r-- CO uooi oiC--O- OO trsoi. rr-s9- oo cU3v"pM* Oo oO*cChO ocOn oteoj CQ>s r- O* S-* CM r~ u> o Vj sx VI 44u0r41i i4u-* .c4* 4'l4l i0n)f 5- o ,oot S.00 ; to oo *^r to r-- CM 01.03 OO r*N. "s--' .CD >--* >-* co 6o b; S r- CO pv w XaCU TT** <s~u Cl x Lxi ,^S oo st* *tf CM .00 K>-< oo r* ,VO r-s. co r* r~- 0-0 CO O <x> .00 >> Oo *3* .CM O CO c o 5- -CaL a -V O CD .C0 CO CO .3$ 22 ;3> v> </> to rO Jl * a: to to CD CO A3m<06<C3u: . .CO 2= 50 CD z`: tAo-e cIo csn- a *-- to o I o oco a CL 0> CL . vjO O U3 | +-- i-j* t-H > *--* *--* :H4 *-- - 297 - y \ i > iI I i i { I i ! 4 ,| i -.i4 J *< DUP04Q011779 Table 22 - Mean values (S.E.) and summary o f fa c to ria l analysis o f variance fo r blood glucose (GTu. - mg percent) fo r male and female monkeys in S ta tis tic a l Grouping D4 tGoO VO J0>1 <D & cio 0) s~ vSo3> o. X :*< 04 r-- co csi fs*o cjOaprsw 10 ch NV rC>Otow '*(** to o v) a. co co fs. u> OVW i> to to r^.w *ftn co co <?>>--> r-* lo K. CO ipw S3 u 0* lL* lii p c CT *?ir tQW i^'O to CO vow O JCM . o csi CO w cq d) IO>$. aw ar- uo co Oi co tow to ip r-^Csl VOw^ *fs* Oo itsl CO tow 00 co CO*f p>w \ <9 i- *3 p <s I r* o*^9*- CvOoCwM a\ CTl oc 1/J <ir0*. a.CeL Sp to* CO C3 <i M to 3 M V) :wi VO <rj fc-- otui to 3: CD t--< to 3 <3 L-4 to CO co 3<uu O O M 01 <Iu t. a. ro s. . p G o o ' 1--4 o o E CL CL VO * to VO I IH 1-- iCO *!-"* o JO Cl co H 05 B r .so * o 1 M 1--4 -ca ,r-f o + J3 CL. o oco e CL. T> CL S oirs VO o to ?>' M co p19 <9 cp % OIff O ;T Uo PO<9 0 0t-J 3P CO - 298 - I i /i ii DUP040011780 :*jr Table 23 - Mean values + (S.E.) and summary o f fa c to ria l analysis o f variance fo r blood urea nitrogen (BUN - mg percent) fo r male and female monkeys in S ta tis tic a l Grouping D. o <Mr- cvan COr- vo <j% .* 9 * * o CO *-* VO r-- -0S *ro VJ CMw P^S-X* & (O N t W VO VO W vo aat vo <M OCO CM CM CM i !>%<M <CM^ CM>-> SJn > '3' rQ**x O *-* w to as vo o10o w5K oo to S0<c1u, I cio 01 S- <0/> CX X0> 011 L o vo jr-*':0 in 00 <n o< c6 c> co i r0t1l CM O *J* co in ^ cp a\r~r .p r~* in p rt o CO o vo co to in co VO r-- VO o t* ,<D CQ CM c <Su *-- &. 01 4Xa4. 4- O c o M JrS*- a_ 0o :00211 , to to i--4 to NT H *o-- to to vo *S co i 0u1 .3 0Sax1. s1i 1 2 a. o c +> c: . o ys ' .a3^ M o tss. 3 5 ' CL CL VO in VD S JL CO o .0 o- co s oi a *--* in * o i 1M --r( M -- csa- r- O 4- -Q a. oCl P0 a; U- aes CO IN. d* **' '* M3 O 43 2a* -* >cfO c cS p ep rOC J<OX oo -0SMr1-- 01 299 " m DUP040011781 Table 24 - Mean Values (S .E .) and summary o f fa c to ria l analysis o f Variance fo r to ta l serum b iliru b in (mg percent) fo r male and female monkeys In S ta tis tic a l Grouping D. Table 25 - Mean values 4 (S.E.) and summary o f fa c to ria l analysis o f variance fo r to ta l serum protein (grams percent) fo r male and female monkeys in S ta tis tic a l Grouping D< warn o 09 VO vo in CJ 30at/t. CO 0 CL XHi a1i L. CL --'s. * N Ol e--W 40 o OVr-- n . ^o r*s o 4**+ . *> .Otto *3*<O Csl.r* 09 '* > o o o^ to o v| 1 Q. s*- O CM CO .0*0 tft 0 Or- fS.O * ' * PS. o IN o *s.p N O 4oa0*1*i * -- UJ O Cp.<T> to CM NyOi Cyl r- JS. r- N CM N rCO <D NO N>.0 fNp CO CO to 0 ^ c\ 03 o N i--? C7 p N.r^ fprf> fN O NvO N. O fN.p o tn CO r~ IN. p oo u> .00 rISO ; VW * iOrfN.O r*-'o CftOJ r>0 cr j-M y & 4*-5> aCt & r* 50a1- x LU H- :o c o srt*j. CL a Sf? CO o .al 0 0vp9 A_O >C-D* 'NCD# z: to <o^ VO to to SO ?h SO CO to CO I u0~13 VI to CD CO XcaOxi as: .*-4 0 .2? < ai s. la. r*~ Q L +- cr . o o Ol 1 zT r-- o s~CD L CQ c-i . -a O o. CJ> E CL a. <> r tn to 4 E N o> rLO .* p t r-- K-l #4--*-4 u cp . * o _Q o a. oco .E E'n . Cl 2> CL S CON. . to o va i .& :*-4 c o *r~ 4-> S. ol CuQ :> O a3 O * C 301 - ?i 11 y DUP040011783 Table 26 - Mean values (S.E.) and summary o f fa c to ria l analysis o f variance, fo r serum albumin (grains percent) fo r male and female monkeys in S ta tis tic a l Grouping. D, Table 31 - Mean values (S.E.) and summary.of fa c to ria l analysis o f variance fo r serum calcium (Ca - mg percent) fo r male and female monkeys in S ta tis tic a l Grouping p. O*3r CO CM r-- r*> ,rr-KO J* fO C0r-* p*-- Q Of PO P pO PO SO Y Z09 xr o *a- ou o ; ; cri to oo to r-~ o> r-- xn o cnq p o o> p o COCO COO PsCS. .r- P r-n- CO CM r w -* ** oo p.o o>o op ,dGJi. scoo i--MVi*--f) CM r-- Pr--CIM-- oi O op p p co p ? cy i- iVOsI tMv* C; [\J SsOo rc--n r>. co Oso rt--o $ p o p o p o op oj O.1J $CL, s- p f-- o COJ XI ,CL CO JE CL Q o. \SoT g> S r-- oO sson SO * o VI 3Q. CD SL P r-- O j:s 5- O- O SJCO 's fc= * >. CLP Cl E co rs so o SO. I in. S ta tis tic a l monkeys female and mate fo r K units) fSGOT - transaminase Table 32 - Kean values (S ,E .) and summary o f fa c to ria l analysis o f variance fo r serum. [p O CSl Cvj ,<o ip co o PU> N so ; \ st- ^ tn o n urj'-- vj jo so .<C*-DO* - CO C/>| a<#u [co coco ; ]^ coin n o NO>HM'NCfM*w IcTo >dw0* fCoM* NCM ; _ cp co o n r>*W- `O O vO j-- fN co ; to CM-'W CM**-- to - 0**s-- u (U UJ .c E +J (0 OJ coco to CM CMG LdO-NCO-* Cf*M> "t->>J tc--o Owj CO to P co CO CM Csir* CO CM CtoM w4- CCMOWCO OfOwCM. OO rC-M .0<s) .S *p sQ. X <*- O C vO* r* id CL <3 t3 to [to CS CO V) (p <3 H co Oi 0J </3 * -as C3 MCO <3g00u/1>-v>c-b,< 01 QIJ t- CD CHO-4 cuq 5 0c3. .4- r-oQ* ? X33. 3 . +O4*. oE CJ v. oo CEL. 2X. ooE ot=>. 0 C^ oco CCLLCBT CO ttoo to o to 1 -c o r-- -M3 i- 3A>J' 0t3- co r-- V O o -Q O -u<L0* i o > uO CL o QJ -4. 3. s.Ooj .308 - DUP040011790 oxaloacetic II. f iglmuit ian i nm inc - 60S - d o c m o ~o i o ;o Q o^ C3 0Hi .3 i d o> V V> 3'73 ta t o ^3 3_ COQ O *TJ cr + o CP *s o cn 3 U3 '^Ss. 3 CO o cr ri to t Ch <n -rpj>* 7J "S .o O o n 0 1 *. tA . :0 O rt ^4 O "Of -1 a i b cn iSi v>M *C--D CD CHD fcto C *1 ID <ki s *o -->co .^.ro .^v -j <to --* ro o> <r > ts> iv pi cu to p tnto Ml CO -t* Ja to o 3 c i fD *t3 O I, .00 dHCDi VHCDH) co 4> H 2 fl> </> 7T HH o V* OI V> v> l/i CD OojM .*- cN D v o 3C3DJa 3CD ^--r*\->p -- VJ &P) ---ro to o d<n cnco l.Oi O M -5 .r^vrovo ^to>i\o> T-^ ro >r^o>rd\> --4ct> p PJ O fS3 tp >,4 S4 rt 53 % 3 roco >*i -**rio\i --ro fD '* S* '*j CO -- CO 4* O rt V) tJ )A CO -IV j 0 O CO o o ` p% d co d co in fD fD ?r UJ ; d; pcr -. - CO f Oca 5c ~s -h ra oc0 C (+3 XJ p H25 -Bh -. ji<t to n H ptj > - < v> *4 . C H< o </ r**Tj -s .pw 3 bl fit P3 .a3^Ia CL 3W PC co . e M p <^*s"J d4< CD 7Hf*j H0i * Hi 3*n0 ofofut* c -7 os-3 -* dr -- io *h tft 3 '-* pw 0O Hi a 7c5x P-< H;Di C-tto 3 -3 01 O --fD n> Hi g -O 7 3 KVI SCcD nID v> c 3 OO ct P St v> rt ti O P DUP040011791 Table - Naan values (S.E.) and summary o f fa c to ria l analysis o f variance fo r la c tic acvd dehydrogenase (LDH - WROB units) for male and female monkeys in S ta tis tic a l Grouping D. 60 tA JmS0C |.SB 1 &\CO <7 019^ _ to .in Vs- O.r-* 00 CO co to tp>-- in Q vj Q. .to i>> m CO r r-- rr* lO to cn AO CO 0<M iov n.r- cvo f-- o CM CO o o to ca in CV..CO Op - <S1 Cn . <7l LO tow tO r-- Co.- to CO N>^ c9to* *cc!-o-- ovco ocooco v> 4-* ti :Q) 44Ui +4 c: 61 44 0<19 ,L- 4F<->9* -*0Lr1". 5 V) CD CD 25 <n <n *# .:SX<U5^ to as to to at . -a: 3is CD to <.D-4 to z: V) CO O V 01 Vi 1 ' U7 CO "S* o eh to,to in o <C 0 fo. m in w- O <fr 00 -r-- ; tn OV>-- CO VO iOV- Q. XO 01f O 01 Q- P 01 J- 3 V) O </) CO <0 CL 5? X z: CO Of 1 01 L. o. f"" oL44 .c o u 1*A 3a. o *-4 s~ CD 05 o CL CO 07 Q. . CX Or a. o. oco E '* >. a. oi CL <99o- rL in 071*% -9- :in to .4 no o 1 1i Lr* *--i .--* > 1--4 c *oMr !5 Mr~ L > 4O y to co CO o CL oo un> 0L1- 4*1 .c i : : ; 1 t DUP040011792 Table 35 - Heart values {$,} and summary o f fa c to ria l analysis o f variance fo r alkaline phosphatase \ATk. PO4 - KA units) fo r male and female monkeys, in S ta tis tic a l Group!ng D. o<# sCoO <U` QJ S CI l in CO CO lo o CVI CO to f-- !*>. 10 xt **?-* c*?-**" cr>ro .* >- fN Ct* *5^ to in VO CO oi to CO CM to T-* cn CO CO to >-* 10 to w Ch CM u<J1 to co -! f. .cn eo t > co,co coco oto o^r lO>--1 CO>-- s3*w fj G ;OeJ r1 0L3- CL X Q*? to to to ,s .ss . 4 0CO to to <0 2: 2? 2: to CO to J-- C3 gVi ; 'co o > to d fs rtJ 0 f'*- f"-. co to 00 CO CM CL e01x <3X LO r-- in -w LO >-- *Or- .= u0I1 .or 3s. * 20 to CL jgj to S2S to 2S Cl 011 im CL O .c -L> < O L-> 1 O O E a. CL. to . 10 t V CO 0f-- JO a. CO . s* o> fci r-- m .0 t o trH -* M -* oc. 1--4 > CO 0f-l + -Q 0 0. on E h; Cr> a. S co K 0m Mi M? 1d* -- 0 u01 ccc. o-P CL o O . +-aLaiu0>d1> t5o3o- 311 - DUP040011793 errs* - 0.51 mg/m3 PbCIBr, and Group IV - -66.43 ppm CO + 0.47 mg/m3 PbClBr. in S ta tis tic a l Grouping D> comprised of the follow ing: Group I - Control, Group - Table 36-Mean values + (S-E.) I IfoI r blood gas and pH variables measured in male and female monkeysI I C.nOu3D.J> M. lcOp Or- rC*O^o0 irno#>0---*?>* 1P37 ey0~-** .cCOoOo SCOO<OO>*v IS. Q Is*s0> 1>-<0 Jv,s0-- .N'SQ-o ISO 1 SCOO 0O^S S0O >0O"*?* 0CO tOp Is* .0- Isl 0 f> O eO3oU?.**----* 1- ciao.r0~ CISO* OCD lC^Of-Or fcNo- .0-- th*orO* sCop 00 cRof r<--3 C0Or0-- 0*4" O0 is'W0* ISO' ..fsj.COL**' INO Ko*!--' Cs. O 0 Cn O IS 0 Da3. CO3OrDt-l **---- CCOO0r^ r>. 0 *** CT1 rr^ CO 0 Rcof- 0-- : co 0 rs-vSO--' r>*s.^0f cPoD O0 fs O icno4>o--"**' CCOO O0 -i>* 0. r>. 0 fcso- >^1. 0 CCOO rC--D rs O' T>> O ctoo 00 NO JC3OSc3L! M 0CO0 00 IS. O rC>O* 0O fs*o 1 1co^00 CcoD p0-- . ccop 00 cCoO 00 co 0 cPp> r0-> ttOorp-- IN. O K.O ls*.C3 p>* >0-> P>0s-- fs. O <"QCO3D-. 3H-*< co _0 i5--4*s0--' 1" fN M3 ri- so O rR--f"QW P>r-- co-^* CM CcoO >-->- r*% 0 to 1 *PCM IT* ,0> ,P^* Rjr so #** RRP Of^ CO #--* . 3Qp. *-* SowQC_M_J CD 0.5aS03-. >--** O co -rR--f -WO 0 *C**M*> (O0i*Nr--> CO CM CROT*r----- CO>c"s** .C.COOs4---- 0 1-- ,fOw <0 RT Mr- ; i '^ CCOO>r---r-' *--* ps KCO>0--^ ,p>. 0 :C0 O slvo <c7oi ^r---- CO ;IrSo,>-- co r-* IsOns-- 51* 0 t>.0 CO 0 CfOO /--v O* r~* #t n?*s,r-- CO 0 RRTj-'SO--' Cp U? 0*r>---* - Rf CO CRhf-sf----' .r~ 'oi <CfOt O-w rr~ AO OR4*s ^ C3L CD GU^S-v noi w0 CCf>MO.->rO----*- *V O Rtl*r>r---- cp co CCTOl r>---^ CO CM O^r*w-^* *1* 0 5Of>r---- r--SO 50 CM *1* C5M}*sr----> -*3> 0SC-M* co xn OCOi w--r- CC53OD-L s">H Oi 0 ; j in i--cn 00 CM COro .LCOOv"--s-' RCjP"'--r-s-* aCO*>r---- cUO7?i*-^ <t3o0 rr- SO O ICsp. sr----' :| CO 0 SC CO rs. 0 -cRnP.>---- .CCOOrW-- CcMp w'r-- OaC.\ C$Q3OD_*wh--H4 5T fsr0>0 s--*--' aiN fo"y- >C-M> .d* 0 CCOpsr----' in co O rr- .. tOr-- C=0f >#---* sl'i-- GeOor--^ in p's 0 ITi SCO0>r---- .o1**.*sCM^ Rt- CM r>* 0 Cco?v.r- COiC3-DL>*-r* 0 OCMisr---^ CM CO OCOVt-- CcMn>O^ CO CO r>* 0CTV>.r*--**' jCOMl r-r*' fS.C--Ss* ScpO s*^ sc* i0COs---r 1^*0 cCrO^r-J> CC.OOrrW--^? -Oi 0 rOJ*i-<-M- i 3C^OL*--< KO O <O-- Cl^M a? .to ^03 p-- ,C"CLOs.,O 0v* to 01 ;cf-o*0w 10 Oi . CO CM <C3O%*~*--* %C0n>rW--- in so .MC3Or-fr^- so SO ' l T/ 0 r-- r-- .C0O3 *CsM-- RT CM *Oni W; k* r"* .O>SraJ--C4 '-3<<iSLdy C1O rr SO 1c--o -SCSOJ CO 0M3 fC?O> r0-- R0J* - 312 - DUP040011794 65.46 ppm COi Group -- - o VS id *<c4<ts31d- * 5 COQCOQM O0` '<OUo*3OSf?-. .>$Visiddr15 OiJ`4-pSh*a=1*->-.~tc3.O-o--c.<"ifO_-,|iztS~d>>-i Q f/i I<fu- 2 O O. OCHO VS >*-C *s* >v"0 4J crc 1-- O a .6 ;c *>* o *-- fij c in J 03 .C CIOJ.O O S- vi r- O -r- 1 o VI "0cOr1* 4iia>-M ! M tOO O O. K3 to 00*.. ! f O " 4-> rd S. JL. 01 > 1-- -J . +J 5! LO .US CO CM r- O r- fO CO CO CO r-- w id *30 Q_*-* O C H Hr* r <S O h i*- O *-- ** cu Vl^ '23 .VI *C3 O Id OS t- w OStS O ` P *r*, : " S-. o r 0.0 co o o O ^ O >rr> 4- iud S. d 01 3: . 4-> 3= *f tn 07 O CO 0 ' S->* to to * -. to Rj* r--* %--p o^ p o C o C E J3 ^ co 0.0. vr ex; C p-* ,CO h - id o o e o OS U dP ^ i- <r-- ' Os e S- VI tO id *>. - O r-- 4-J ra sa c 3 * co .00 in . 0* 00 co 0 *- ; gy^4> 1 "d* <tt 3 O) 4-> - O USW^tO *"* 4-1 !*s tO 3 4* *0 --> 5- CL eZ o 3o id om* .Q o .*P" ! t~ '-mv s o 6 m 3: :>s Q. o <a ; >*-* r-*- W d c o co woo S-dP j Q 4*> - 41 C tO r- <V d .^d VS If u in c id i 3 r1* 1 --* H ':' > lO L L m h :> 0 ,0 . +*.*** na. ; C 33 id . *-> ci o 01 o ^ S* Si. Z tj-WtiP O O p* +J id . "O u *f-- O > _c 1-- * 4> 3: O *d* i--O OO *. O0 L-- ^-77S co tn co . * op s-- O r* 4- 3 10 j-" 1- <d S- ca !>>. r-- us p .. r--O i li. cors. , . co rs. trOoo-*OcOoo* rto--O* dCopM >--V c0o> 0co .*0<w*p r`>> co> ?% r-*: pmum'ayMr c> COf-- r*~ O i-- r% * ^0 IS 1-- -w to CM CO 0 0p i--S to 9 ;ClO-9 f--- y*-% ICS.P in 0 OO P**!S .> CO CM Wv -*- CM r- O OO OP w* sr ?r . OO v^> r-- tO r>. cM .* *p" O os m r> to w CO 01 JL) <d H* *-> r-- JC rd o: 3 r- 03 es S- f-i. T3 O as OO CM r--* a> ^ ?* **- r>.r>. to 0 O Os *d--w -rot--o POoO or-P0loO O o Op 0tN'o-tC0oO. CLOOcOo o.4 so*** vsa z to 25 coos 0. .00in*' CO to co r-. . p*St`inO O. OPSS*. >c0'sr--'-*S^ '. -izn:* .C2O co rs* CO CM F . . r-i* O co 10 ' sf to CO CM w to H .-p 0 00 d* .* . uses* v--* CM is. to P OO CMOS co os CSi w os <n :0 O OO OP <*s. CO p CO CM r*~- * O w ro'm ' <N p iL w p 11 P S3 0p pp , . LO sf rr*W* d' as in 0 pp ***> Ps #* oo Kd* CM W ***** 0 d* QO OO PO US O V] p. V) XU XJ E .2: 0 in 2 00 m in* 2C tn 2: 00 - tn ;? p-- CO . Op ccno m i-L . . O0 5S os us tO 'M* . -- O r- in dr co r-- a co m > r>. <n CM <n 0 to tow in a H3Z a in 2: O CM l; in or> ; p sr ; ^--* .0 -- CO CM dP i-rL dp r*- P 2: to ZCO 4 VS Z V?A 2:' to.4 2: Zinaa i2n=it -. VS .2.5 . VS z .t2n5 . tn 25 v>M 25 tn* - tn 2: z: ',2: tn in to 2: .2: .tn vs vs 2: z 25 . tn tn vs 2z # i. <n ..<n vs .z: 25 tn vs vs 2 25 25 > a* to in in a? 25 z . tn vs vs 25 z * vs tn tn 25 2: 25 , ,a tn P vs .M .z: <n z 44 tn tn tn "ZZ 2 25 4 in to zz in a v) zz .4 vs tn z 25 vs tn' Zz tn4 tn% zz in; .4 in zz a tn in zz .4 to Vi Z ' 25 4 VS tn zz tn tn z *25 44 in P 2: Z 4 vs to > zz vs tn zz . vs v> zz ,4 tn V? 2i z w ~4 > -- :> * >--1 1-4 *--< r --4 --1 vs > >d 3 >-- 5> VS v> VI vs CO VI >>> > O i_ t--1 h-- *--t 313o l-H --4 M .--1 - K1 M The variance o f th is group was heterogeneous. J - .1 Ai - 'i " ) DUP040011795 xn !* U O Ol G J5ir- G *a <0 +4 V p* 9 S * D D aD > +J r- ir qD JS o o crm-.~a O - IX a> <y. 3s.x:co r- 44 V* >> Si. >*T3 <E cn -- o o e <s ja ESm"0 ^ lO C 0)10 w ? E CD-.- o -O E D 1- 0.6. I 44 B (BU Ow 54 C V4 *" -*r- id *4-- * **-* + Q Q, V|mm 3 w ch o to cr> c D .*-->-**- O u o. 44 3 ~ E E O OJ-r- CS *c- <3a: *-- D rEs> W CL . CO CO *4-- (Q <> O {* 3*44 <3- \ Em D) >> o to D J- 4->l flj * io eg^-*44 1 E </l S3 Ol ,H O </>>-- E -r* -O + XT -M 4- a Ex: 3 0 <9 Q(A OO '-> 01 3CD E 3E 4^ Q. a c - ql > Q *"*" -co *3 g o n *--' O E a +> 4-t *r D vo r- id O IO Vl EO Q3 c: a# i 3 E 1 r- E > IQ S- JL 4 M > <y io 44 SjL- Q. X G<0 -3 Ep*v o 3 o 4 IO E IQ C a E "T3 ' . < 44 X! o i/i ! > 44 OJ <0 E irXT r ii 44 X ..o p--. 44 to DE QJ 5t--* --1 +4 5 ,r~~ 44 44 10 EE fO OJ ur * : 44 % a 44 10 E cG 3 _J 4-> 'r--. 44 id XJ E r-- O E 2* 4= 1-- .* 0: 44 G id r-- <a E CD +4' 3=i 44. f--" T" C_ *p~ r- QJ E3 E fl > J--XJ O m ICO CO' rwf ao ' 01 . oo > ?- Ko .m rs. .csi OO tr> io CM o O O' OO co tn rs. - oo >-< *n eg eg o oo .*,. oo .s4 co tn eg o oo .* OO cn co to Oo !W MM eg eo . C*?- irw . i. oo co ^ ^o >> o v-oS^ . eg 5f- .00 * I--*-*'---1' o eg 54- O oo AM' r-- VO ?**' f--? o tn in o 1 * .* oo AtM' I>pO CO i-r j(^s in-*5f f o * o Aow MM r-- in ACT *-- |!W- !W* vo r> p--" r-- * CVJ o ***& co AO 4^*' co O CM O * 'A eg O -M' IO N IV-.W sr r-- r-^ r CM O o c> eh 03 JO***" MM pr- CO e!g. i^-* eg o MM g* o is m rr" CO O. ao fN* CO . cr o in eg . ro o * oo E-' :eg in ego in fO o ?> oo eg r<. o eg mM PM CO co o oo MM r- cn O r- ii-rrs O 00 T^. O : oo vE-* VO . i-- eg <MV ! *0* ,r- O 0-0 > Oo 'Am' n cr o * oo vO o oo O' is#- coc eg dcg>M- ^*!S to m <-- o QO OO <n o in eg .oo to to O. oo M*"** C*> CO - o eg (MS4 MMr~ p-- O OO OO O pTM co^ . oo mm eg co IS O oo a3 ,oi CM co cg>-' in in OO oo MM sf eg OO /-A| .^J* co Ch r-- r-- O Id r-- * <T <0 UlS-C Ol CO VO r-- O ^*CO ... CO to u j -m- vo eg *6- CO * eg o ---cn co co vo m m-- MM ?3* eg co eg 93* 93" CO 50 ,U3'V* VO VO r>A o O CSI CO-w tfj O f-N ?! d' 03 CO-M- MM o eg VO Cf* r>- co eg-*-- tn o 1M CO .r-* iO P)>M </j o. 3 *-4 O *-r >-4 E p-r* O - 314 - LUNG Focal Pleural thickening Peribronchial Grown Pigment . Artifactual Emphysema .Alveolar Duct Fibrosis Thickening Bronchiolar Wall Bronchiolar Epithelial Hyperplasia Bronchiolar Epithelial Hypertrophy Pneumpnocyte Hyperplasia Peribronchial Lymphoid Hyperplasia Emphysema Focal Necrosis Focal Hemorrhage Parasite Perivascular Edema Pulmonary Edema Bronchiolitis Bronchitis Monkey Pox Vasculitis Granuloma Pneumonitis Abscess Lung Mite Infestation Adenomatosis Bronchiectasis Purulent Pneumonia Epithelial Necrosis Thickened Alveolar Wall Pleuritis Crystallin Material (yellow) Mucous Focal Fibrosis Pteyral Fibrosis Alveolar Wall fibrosis Vacuolated Media Endothelial Hyperplasia Stenotic Chronic Pneumonia Eroded Bronchi Erapnysematous Bulla GROUPS i II III 2/9 4/J. 2/9 1/9 1/9 3/9 4/9 1/9 0/9 9/9 0/9 2/9 0/9 0/9 * 1/9 0/9 1/3 1/9 0/9 0/9 2/9 1/9 0/9 2/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 1/9 0/5 0/9 0/9 .0/9 0/9 0/9 . 0/9 0/9 1/9 0/9 1/9 0/9 0/9 0/9 0/9 1/9 0/9 1/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 .0/9 1/9 0/9 0/9 0/9. 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 2/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/5 2/9 Q/9 0/9 0/9 0/9 .0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 019 0/9 0/9 0/9 315 - IV 2/9 2/9 1/9 4/9 0/9 0/3 0/9 0/9 1/9 0/9 0/9 0/9 0/9 .0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 1/9 1/9 .3/9 0/9 0/9 0/9 0/9 0/9 0/9 i i ? : i 3 I 4* 5-; j i i 1' I i a\ DUP04001f79? Table 39 - Continued LUNG - Continued Atelectasis Congested Extravasated Blood Collapsed Alveolar Wall LIVER Pericholangitis Bile Duct Proliferation Focal Necrosis Sinusoidal Pigment Focal Hepatitis Focal Lymphoid Infiltration Nematodiasis Thick Capsule Granuloma Abscess Hepatocyte Vacuolation Greenish Granular Material in the Hepatoeytes PERIBRONCHIAL LYMPH NODE Phagocytized Pigment Lymphoid Activity Lymphoid Atrophy Adenitis Granul orna Reticuloendothelial Cell Hyperplasia lymphadenitis TRACHEA Trachei ti s Increase in Goblet Cells Exudate in Lumen Necrosis of the Epithelium Inclusion Bodies EpitheAlial Hyperplasia vtiift nvt ujjn,/ Squamous Metaplasia Focal Henorrhage I 0/9 0/9 0/9 0/9 0/9 1/9 0/9 2/9 0/9 1/9 0/9 0/9 0/9 0/9 6/9 0/9 6/9 8/9 0/9 0/9 1/9 1/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 GROUPS II ill ____IV 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 6/9 3/9 i 3/9 2/9 3/9 1/9 0/9 2/9 2/9 0/9 0/9 1/9 1/9 0/9 0/9 0/9 6/9 0/9 0/9 0/9 0/9 2/9 1/9 0/9 1/9 1/9 1/9 1/9 0/9 0/9 1/9 0/9 0/9 0/9 6/9 3/9 0/9 7/9 6/9 8/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 1/9 .0/9 0/9 1/9 0/3 0/S 1/9 0/9 0/9 a/Q 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 316 - j1 1 '1 i '| - .< : % i -i 1 iS 4 .i I -4 2 4 K` i % -3 S J 4 iai i `I .'M jy **5 1 -s :a DUP040011798 CP *- nip wawp.xuwi'u.iiw4 e*W|Wwngf /.'s ' '->1 I I Table 39 - Continued KIDNEY ;Inters ti ti al Nephri ti s Epithelial Vacuolation Tubular Dilatation Loss of the Brush Border Nuclear Yes!eolation Tubular Hypertrophy Pyelitis Focal Mineralization Glomerular Degeneration Inclusion Bodies Vasculitis Congestion Focal Fibrosis Perirenal" Abscess Protein Inhibition Intima Thickening Endothelial Hyperplasia HEART Focal Myocarditis Endocarditis Epicarditis Myocardiat Degeneration Vasculitis Subendocardial Hemorrhage Thickened Endocardium Focal Hyperplasia in the Endothelium Intima Thickenlng Granular Pigment I 0/9 1/9 3/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 3/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 GROUPS It HI 4/9 2/9 1/9 3/9 0/9 0/9 0/9 3/9 0/9 0/9 1/9 > 0/9 0/9 0/9 0/9 1/9 1/9 0/9 0/9 7/9 0/9 0/9 0/9 0/9 1/9 Q/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 1/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 IV 1/9 4/9 0/9 2/9 3/9 1/9 0/9 0/9 0/9 5/9 0/9 0/9 1/9 0/9 4/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 0/9 3 :1 J | -% i - i:5 i 11 : ; xj - .. - i i 1 3 * i M aS 1 Jj 1 - 317 - DUP040011799 WJMI'.WgtgWg suMwaJ-Xiw1 HAVerON LA80RAi6Kii$. IN6. VII, RESULTS OF THE SPECIAL HEMATOLOGICAL, SERUM BIOCHEMICAL, AND URINARY TESTS IN CYNOMGLGUS MONKEYS EXPOSED TO LEAD CHLOROBROMIDE ALONE AND IN BINARY COMBINATION WITH NOg, SO^ and CO, This section describes only the results of special tests performed in monkeys from the control group and those exposed to PbOlBr alone and in binary combination with NO^, SO,,, and CO. Group numbers used throughout this section are presented in Table 14, Table 14 - Group numbers for control group and PbCIBr exposed groups Group Designation (No.) Agent Nominal Mean Analytical Concentration Concentration I (1) II (9) Control PbCIBr 0 0.60 mg/m3 0 0,51 mg/m3 III (10) NO? PbCIBr 0.50 ppm 0,60 mg/ml 0.48 ppm . 0.54 mg/m3 IV (18) so? PbCIBr 10.00 ppm 0.60 mg/m3 9.93 ppm 0,50 mg/m3 V (20) CO PbCIBr 67.50 ppm ^ 0.60 mg/ffl3 66.43 ppm 0,47 mg/.m3 Osmotic Fragility of Erythrocytes Results Results of the erythrocyte osmotic fragility studies performed during the last 24 weeks of the exposure period are presented in Table 15. Single classification analysis of variance revealed that relative to controls, all groups of monkeys exposed to PbCIBr-contamihated atmospheres showed significantly decreased mean erythrocyte osmotic fragility> i.e.> lower mean concentrations of NaCl at both 50 and 80 percent levels of hemolysis. The mean of the group exposed to PbCIBr alone did not differ Statistically from those of groups exposed to PbCIBr in combination with NQ2, S02, and CO. - 318 - HAZLETON LABORATORIES. INC. Table 15 - Salt concentration (% + $..) resulting in SQ% to 80% hemolysis of red bipod cells from monkeys exposed to PbClBr alone ana in binary combination and sunwary of single .classification analysis of variance. Group I Control II 0.51 mg/m3 PbClBr III 0.48 ppm NO? 0.54 nig/m3 .RbCISr IV 9,93 ppm SO? 0,50 mg/m3 PbClBr V 66.43 ppm CO 0.47 mg/nr* PbClBr % Hemolysis 50* .80* 0.354 (0.007) 0416 (0.607) 0.284 (0,022) 0.212 (0,021) 0.269 (0,034) 0,194 (0.030) 0.293 (0,021) 0.210 (0.030) 0.220 (0,028) 0,153 (0.025) Groups I versus II I versus III I versus IV I versus V II versus III II versus IV 11 versus V Significant differences (p < .05) Sig. Sig. Sig, Sig. Sig. Sig. Sig, Sig. N.S, N.S, N.S. N.S. N.S. N.S. * The variances of these groups were heterogeneous- 2. Blood Lead Results A plot of the mean values and faired turves for blood lead determinations-measured during the pre-exposure control period and the 104 weeks of exposure are presented in Figure 82 for Groups I through V, As shown in this figure, the mean blood lead levels in all PbClBrexposed groups increased td a higher level than the control group in the first few weeks of exposure and remained elevated throughout the study. The control group remained at essentially the same level throughout the exposure period. More variation was observed in the exposure groups than in the control group. Inspection of the curves indicated that the combination groups were not appreciably different from the group exposed to PbCIBr alone. 3. Delta-Amino1 evu1 i ni c Acid Results Plots of the mean values and faired curves for measurement of delta-aminolevulinic acid (5-ALA) in the urine are presented in Figure 83 for Groups I through V. This figure shows that mean 5-ALA levels increased early in the exposure period in all PbCIBr exposed groups, and fluctuated at a higher level than control levels throughout the remainder of the study. Group Vs 6-ALA level tppeared to rise somewhat more slowly than those of Groups II;, III, and IV, ' H - 320 - DUP040011802 BLOOD LEAD Sug o f le o d / lOOnvL o f blood TIME - V/EEKS figure bZ - Mean blood lead levels in monkeys exposed to PbCIBr singly and in binary combination. URINARY DELTA AMINOLEVULINIC ACID ( / - ALA -m g/100 m l. o f urine) ----r-----------I GROUP V - 66.43 ppm CO + 0.47 mg/nfiPECIBr 1 I 1 1 ---------- i I - 1 J - ' - - - 1 - J--- -- -10 0 30 20 30 <10 SO 60 23 30 90 ICO. HO ' ' TIME - WEEKS ' Figure S3 - Mean urinary 5-ALA levels in monkeys exposed to P.bClBr singly and in binary combination. - 322 - DUP040011804 HAZLETON LABORATOR/Ei. INC. 4, Urinary Coproporphyria Results Plots of the mean values and faired curves for urinary coproporphyrin determinations measured during the pre^exppsure control period and the 104-week exposure period are presented in Figure 84. this figure indicates that the mean urinary coprdporphyrin levels increased early in the exposure period in Groups II through y and remained at a higher level than Group I throughout the exposure period* Values for Group V (PbCIBr + CO) appeared to increase more slowly than values for Groups II. Ill, and IV. y URINARY COPROPORPHYRINS -^ g /m i/2 4 h r. to ta l urine Figure 84 * Mean urinary coproporphyrin levels in monkeys exposed to PfaCIBr singly and in binary combination. - 324 - DUP04Q011806 HAZLETON LABORA TOBIES. INC. VIII. Surmary and Dis-cussion of PbClBr Effects The inhalation exposure of male and female cynomolgus monkeys to 0.51 mg/m PbClBr for 104 weeks had an adverse effect on the distribution of ventilation which was ftpt. appreciably different from the effect of the binary combination of 0.54 mg/m3 PbClBr and 0.48 ppm NO.,, 0.50 mg/m3 PbClBr 3 '. and 9.93 ppm S02, or 0.47 mg/m PbClBr and 56,43 ppm CO, Thus there was no evidence of synergism among these combinations. '# Similarly, exposure to these levels of PbClBr concentrations, alone or in the binary combinations, resulted in significant kidney effects characterized by degeneration of the proximal convoluted tubules. All groups exposed to PbClBr showed decreased osmotic fragility of erythrocytes, increased blood lead, and delta-aminolevulinic acid levels, shortly after the beginning of exposure, and increased urinary coporoporphyrin levels which tended to fluctuate in rhythm with the <5-ALA levels. 1 -Vj ' l' .1 'j a ..J ' DUP040011807 HAZLETON LABORATORIES, INC. IX. REFERENCES 1, Threshold Limit Values of Airborne Contaminants and Physical Agents with Intended Changes. The American Confer? - * of Governmental Industrial Hygienists, 1971, 2, Saltzman, Bernard ., Colorimetric Micfodetennination of Nitrogen Dioxide in the Atmosphere, Analytical Chemistry 26, 1949-1955, 1954. 3, Rest, Philip and-Gaeke, G, G.; Fixation of Sulfur Dioxide as Disulfitomercurate (II) and Subsequent Col primetrie Estimation , Analytical Chemistry 23(12), 1816-1819, 1956. 4, Sandell, E. 8,, Colorimetric Metal Analysis, Vol. 3, Section IV, pages 139-74, Section XXIII, pages 555-563, Interscience Publishers, Inc., Hew York, 1959, 5, Hatch, Theodore and Choate, Sarah P,, Statistical Description of the Size Properties of Non-Uniform Particulate Substancesj 0. Franklin r Inst. 2D7, 369-387, 1929, 6, Mead, 0., Control of Respiratory Frequency, J. Appl. Physiol. 15, 325-336,1960. 7, Murphy, S, D. and Ulrich, C. ., Multianimal Test System for Measuring Effects of Irritant Gases and Vapors on Respiratory Function of Guinea Pigs, Am, Ind. Hyg. Assoc. 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