Document ba2xgedqg10MLBJJvXmDJjeD3

.... AMERICAN PETROLEUM INSTITUTE BENZENE RESEARCH PROGRAM PRESENTATI0N BY COSMO DIPERNA TO THE HEALTH AND-ENVIRONMENT GENERAL COMMITTEES MARCH 20, 1991 -----------~~-- - --- BP-00011792 BENZENE -Why Important? Component in major products. Causes leukemia at high doses. Federal and State policies lead to stringent controls. BP-00011793 1-991 RESEARCH COSTS ($ THOUSANDS) U of Colorado CIIT Biological Risk Assessment Exposure analysis Meta-analysis Alternative potency estimate Total 365 250 100- so 60 204 1,029 (115 CMA) (110 WSPA) . BP-00011794 INDUSTRY RESEARCH COSTS FOR BENZENE ($ Thousands) Year API WSPA/CMA Additions 1987 560 200 WSPA 1988 570 200 WSPA, 100 CMA 1989- 580 50 WSPA 1990 885 175 WSPA, 160 CMA 1991 698* 115 WSPA, 110 CMA * Does not include $150K pending reprogramming request. BP-00011795 (Legislative I Regulatory-response) BENZENE ENVIRONMENTAL ISSUES Air Toxics Vehicle Emissions Hazardous waste Ground Water Occupational exposure *1 ppb in some-states 10-6 risk fenceline controls (37 ppt) One driving force for gasoline reformulation TCLP of 0.5 ppm 5 ppb cleanup level* Proposed ACGIH TLV of 0.1 ppm BP-00011796 API-BENZENE PRO-GRAM o Legislative /regulatory response o Alternative potency estimate o Fundamental toxicology research o Publish - Publish - Publish BP-00011797 Potential Health Ris-k from Benzene at Ambient Exposure Levels_ -Uncertain Risk, Effects Assumed to Exist ~....... .....:t. ........~.~'b (/) c;;.~., - to:.'(.o'll.e~ .........[ ~(/ ------~::~--------~-11~=iJJ:il=ll1illi~ll ...... . -(37 -ppt) . 1 PP- trillion 1 pp billion Outdoor Air ------~ --------)o~ Residential Indoor Air 1 pp million Occupational Exposure Levels 1 pp thousand BP-00011798 The API Benzene Program Two Stage Biologically-Based Computer Model of Leukemia COx Associates, Denver Oak Ridge Nat'l Lab In real environments, how much benzene Is metabolized In the liver and bone marrow, In humans and laboratory animals? Chemical Industries Institute of Toxicology In real environments, what are the concentrations ot- toxic metabolites In the bone marrow? Physiologically-based Pharmacokinetics tPBPK) of Benzene Metabolite Identification and PBPKinetics in Whole Animals University of Colorado What bOne marrow cell populations are at risk? How big are the populations? How rapidly do they divide? What are the frequencies of transformations? Are there other Important effects on cells? Cell Kinetics and Effects of Toxic Metabolites in Human and Animal Marrow Cells BP-00011799 Alternative potency estimate: New epidemiology data HISTORY OF COHORT UPDATES DOCUMENT LATEST YEAR CONSIDERED NUMBER OF WORKERS 1983 CRUMP AND ALLEN 1985 EPA POTENCY ASSESSMENT 1988 CLEMENT POTENCY ESTIMATE 1975 ~978 1981 1866 1866 1866 1991 UPDATE OF THE COHORTI 1988 12912 l Three additional leukemias found in -addition to the nine earlier cases 2 API will be asking EPA for help in completing the update BP-00011800 Alternative potency estimate API POSITION ON 1985 EPA BENZENE POTENCY ASSESSMENT 1985 EPA Value - 26 x 10=6 at 1 ppb - 1 x 10-6 at 37.ppt - Updated cohort and exposure information not considered - Best available model should be applied to-best available data BP-00011801 Alternative potency estimate: New exposure data IDENTIFY NEW DATA AND REANALYZE EXISTING DATA (ChemRisk) o Newly found data: - production information - interviews with Pliofilm workers details of work practices . shift lengths history of engineering controls o Preliminary conclusions -exposures were higher than previously thought - workers at different plants had different exposures -before the mid-1950's exposures were controlled by biological monitoring o Current activities - revise estimates of exposures which reflect new information on engineering changes dermal and peak Inhalation exposures -publish in the next few months BP-00011802 Alternative potency estimate: New exposure data EXPOSURE ESTIMATES FOR THE PLIOFILM COHORT 1981 1984 Original Rinsky study Crump and Allen develop individual worker exposure estimates 1985 EPA adopts Crump and Allen exposure estimates 1987 Rinsky develops alternative individual worker exposure estimates that are lower than Crump and Allen 198-8- Kipen publishes API sponsored analysis of worker hematological data which supports Crump and Allen or higher estimates 1990-l API sponsors new analysis of IH/workplace records BP-00011803 Alternative pot-ency estimate: Model seleGtion SELECTION OF APPROPRIATE MODEL FOR BENZENE (ChemRisk) o Integrate and publish key findings of the last 5 years o Reanalyze benzene potency using - the "best" linear and linear quadratic models - new epidemiology data - new exposure data - other cohorts as reality checks o Perform sensitivity test for - disease endpoints - latency o Examine other non-linear models o _publish BP-00011804 Alternative potency estimate: Choice-of epidemiology studies META-ANALYSIS (Environ) o EPA used three studies: Pliofilm, Ott, and, Wong o GeO!"getown t:onference re~ommended using Pliofilm alone and performing reality checks using Ott and Wong o- Meta-analysis project to determine the -best way (if any) of combining epidemiology studies BP-00011805 Fundamental toxicology research ISSUES WHICH CANNOT ltE- RESOLVED WITH CURRENT TOXICOLOGICAL DATA Do chronic exposures to small amounts of benzene present in the environment pose an unreasonable risk to humans? Is there a concentration that does not present an unreasonable risk to humans? BP-00011806 PLANNED PUBLICATIONS: l. NEW PLIOFILM EXPOSURE ESTIMATES 2. NEW PUBLICATION ON THE HEMATOLOGICAL RECORDS OF THE COHORT 3. ANALYTICAL METHODS USED TO MEASURE BENZENE IN OCCUPATIONAL SETTING BEFORE 1960 4. TEST OF FIT FOR RE~TIVE AND ABSOLUTE MODELS S. META-ANALYSIS OF BENZENE EPIDEMIOLOGY STUDIES 6. REVISED LINEAR AND LINEAR _QUADRATIC POTENCY ASSESSMENTS . BP-00011807 BONE -MARROW CELLS COMMITTED CELLS STEM/ 0 CELL 0 0___. ~0 _.. 0 MATURE CELLS 0 RED BLOOD CELLS ~ 0 LYMPHOCYTES/ PLASMA CELLS 0 PLATELETS 0 MACROPHAGES BP-00011808 Fundamenlill toxicology research BENZENE HAZARD STUDIES (R. Irons & D. Ross, U. of Col.) Goal: Determine if benzene exerts toxic effects against the stem cell or at some later stage in blood formation. The latter would provide evidence that benzene is a threshold carcinogen. Research Questions: o How are toxic effects manifested in bone marrow cells? o How does benzene metabolism in bone marrow differ in animals and humans? o Are high doses required to induce the cell changes that lead to leukemia? BP-00011809 Fundamental toxicology research. MODELING BENZENE MECHANISMS OF ACTION Goal: Construct general computer model accounting for the mechanism of benzene toxic effect in humans and animals. Research questions: o What is the shape of the dose response relationship for benzene at ppb level? o Is there a benzene concentration that does 11ot present an unreasonable risk to humans (threshold question)? BP-00011810 Fundamenta-l toxicology research HAZARD STUDIES (CIIT) Goal: -netermine the concentration of toxic metabolites in bone marrow and other organs Research Questions: o What is the relationship between-exposure (in ppm) and internal doses of metabolites in various animal target organs? o How does benzene metabolism compare at high versus low doses? BP-00011811 REGULATORY LESSONS FROM API BENZENE ACTIVITIES o Can not rush the process but need to: Have ongoing research to keep current -with the science Peer review and publish new findings Involve regulatory agencies at the Federal and State levels Have high quality communication at all levels BP-00011812 CONCLUSION If today is the decision day for ACGIH, then the Environ Risk Analysis, with the Crump/Allen exposure estimates, should be used. The-resultant risk level at 1 ppm is the same as Rinsky's risk level at 0.1 ppm. Ongoing work to imp~ove the- Pliofilm exposure estimates should be published within the year. A new risk assessment will be performed using the updated Pliofilm Cohort and will also~ be- published within the year. BP-00011813 WHY IS THE PLIOFILM COHORT THE MOST APPROPRIATE FOR QRA? Leukemia is the disease end-point in question for benzene. There is no question about the number of leukemias in the Pliofilm Cohort. Individual exposure estimates can be made for the members of the Pliofilm Cohort. There was an absence of significant exposures to other chemicals. BP-00011814 WHAT IS THE PLIOFILM COHORT? Pliotilm was a strong, thin flexible covering similar to Saran VVrap. It was manufactured by Goodyear from 1936 to 1976. The manufacturing process and the cohort was first described by Rinsky & Infante in 1981. Three plants at two locations: Akron, Ohio St. Marys, Ohio Cohort size (Crump/Allen, 1984): 18.66 non-salaried-white males. BP-00011815 PRESENTATION OUTLINE The Pliofdm worker cohort provides the best basis for developing a quantitative risk assessment (QRA) on benzene. The Pliofilm exposure estimates are critical to the outcome of the QRA. Crump/Allen (1984) exposure estimates are demonstratively more accurate than those used by Rinsky (1987). More--recent research shows even higher exposure levels than Crump/Allen (1984) based on work patterns, production levels, engineering changes, early monitoring biases and dermal uptake data. Using the Rinsky (1987) risk model and the Crump/Allen (1984) exposure estimates, Environ researchers found that the level- of risk at 1 ppm is equivalent to Rinsky's risk level at 0.1 ppm. BP-00011816 PRESENTATION BY: Cosmo Di Perna (Mobil) Chairman Of API'S Benzene Issues Group Joseph Rodricks, Ph. D. - Environ Corporation Dennis Paustenbach, Ph. D., CIH, DART Chemrisk--A Division Of Mclaren/Hart BP-00011817 .--. \ PRESENTATION OF AMERICAN PETROLEUM INSTITUTE AND WESTERN STATES PETROLEUM ASSOCIATION TO THE AMERICAN CONFERENCE OF GOVERNMENT INDUSTRIAL HYGIENISTS MARCH 26, 1991 BP-00011818 NEW ANALYSIS YET UNPUBLISHED PAUSTENBACH et al. 1991 BP-00011819 DERMAL UPTAKE U-ptake N X SA X ET X RA + BW N =__Number of contacts per day SA = Surface area exposed ET = Duration.of exposure RA =Rate of adsorption BW = Body weight BP-00011820 EVIDENCE THAT BEN-ZENE EXPOSURES TO BENZENE WERE LIKELY HIGHER THAN ESTIMATED BY CRUMP/ALLEN o Air monitoring data for benzene concentrations, used by both Rinsky and Crump/Allen, underestimated exposures. detector tubes read 40% too Tow (Hay, 1969) combustible gas indicators read about 100% too low (Pagnatto, 1961, Cook, 1947) o Extended work weeks were common after 1942. o IH standards were relaxed during 1941-45 (Department -of Labor 1942, Rothman 1942). o Crump/Allen attempts to characterize peak exposures were limited by a-vailable data. o Medical monitoring (blood counts) was used in-place of air-sampling to manage worker exposures. BP-00011821 OTHER EVIDENCE THAT CRUMP/ALLEN IS MORE ACCUR-ATE THAN RINSKY o Rinsky estimates are inconsistent with reported cases of benzene toxicity among pliofilm workers--in the early 1940s (Conn 1942, Wilson 1942) and reports of workers in the 1940s and 1950s being removed-from production jobs because of depressed blood counts. o Industrial hygienists' reports of difficulties in meeting benzene standards before 1950s (Hamilton 1922, Greenburg, 1930, Sappington 1940, Stockinger 1955). BP-00011822 CRUMP/Al:LEN (1984) BENZENE EXPOSURE ESTIMATES VS. WHITE BLOOD COUNTS 11.000 ---~--------~---~------r-l-- -~----,----r--- -~ 10,000 -----------t---------t------t-------t---1----------~-----j------t------1 ! 1948 ! Ii!! i 9,000 wi B 8,000 c 7,0CG ! 1943 ' l! 19441. I~! ! . .1 ! -!+~-----+-----+ -r - - - -6,000 --:_:__ ------r-----)- -'~liI---1--!!- -- ~l--- 5,000 0 :i . Ii, ! i 26-. 40 60 80 100 120 140 160 180 PPM R= -0.76 p= 0.016 BP-00011823 RINSKY (1987) BENZENE EXPOSURE ESTIMATES VS. WHITE Bl.OOD COUNTS 12,000 ~-- ,----~------r-------~--:-------~--------1---: ! iI I : ;I 11,000 if I i 1 ;!. 10,000 w 9,000 B c 8,000 +---t--! --~,,i ------1--94-H3r----~-----i --:----------+--!-----i-i19441: i. I I: I I I .,., ' i ;*7,000 c----:;~---~---i -----t--~ -~-----+-- 1 6,000 "- -- --l 5,000 J l 11 12 13 14 15 16 17 18 19 20 R= -0.05 p=0.89 PPM BP-00011824 FINDINGS OF KIPEN et al. (1989) o Strong correlation between annual averages of blood counts at St. Marys and Crump/Allen exposure estimates. o No correlation between blood counts and Rinsky exposure estimates. BP-00011825 PLIOFILM WORKER BLOOD DATA* o Biological monitoring data - red blood counts and white blood counts - collected at the St. Marys plant. o Approximately 1,700 samples taken from 459 workers between 1940 and mid 1970s. o Data not-considered by either Crump/Allen or Rinsky. *Kipen et. al. (1989) BP-00011826 WHICH SET OF ESTIMATES ~S MORE ACCURATE? Peripheral blood count measurements of Pliofilm workers support Crump/Allen assumption of increasing worker exposures backward in time. BP-00011827 AVERAGE BENZENE EXPOSURE FOR "QUENCHER" JOB IN THE PLIOFILM COHORT 140 120 100 p 80 p M 60 40 20 0 1940 1945 1950 1955 l960 Year BP-00011828 AVERAGE ANNUA-L BENZENE EXPOSURES FOR THE PLIOFILM COHORT (St. Marys) 140 120 p 100 p 80 M 60 40 20 0 1940 1941 1942- 1943 1944 1945 1946 1947 1948 YEAR mif!l Crump & Allen, 19114 - Rinsky et al., 1907 Source: Kipcn ct al. ( 1909) BP-00011829 HOW DO THE R.INSKY AND CRUMP/ALLEN BENZENE EXPOSURE ESTIMATES DIFFER o In the absence of monitoring data during the 1940s and early 1950s: Crump/Allen assumed increasing exposures backwards in time to 1940. Ri-nsky assumed a constant level of ~xposure over the period. o After the early 1950s, the two analyses show only minor differences in exposure estimates despite differing assumptions in selection and use of available monitoring data. BP-00011830 PLIOFILM EXPOSURE ESTIMATES: o Rinsky et al. (1987) o Crump and Allen (1984) o Paustenbach et at (1991) BP-00011831 CHANGES IN BENZENE TLV OVER TIME 1940 1946 19471948 1957 1963 1977 100 ppm (State of Mass.) 100ppm 50 ppm 35ppm 25ppm 25-ppm - skin lOppm - - - - - - - - - - - - - - - - - - - - - - - - - ------ BP-00011832 SIMPLIFIED SCHEMAT-IC DIAGRAM OF PLIOFILM PROCESS Benzene --- BRubber --Benzene HCI ~ I IReador Benzene --- I ' ISoda ash Neutralizer Filter press B t Storage . tFilter press A -.. Caster (Spreader/ Dryer) . . IQuencher BP-00011833 ESTIMATES OF OCCUPATIONAL EXPOSURE FOR THE PLIOFILM COHORT: IMPLICATlONS FOR SETTING A TLV FOR BENZENE . .- March 26, 1991 Dennis J. Paustenbach, Ph.D., CIH, DABT* ChemRisk--A Division of McLaren/Hart Alameda, California * on behalf of the American Petroleum Institute BP-00011834 A-V-ERAGE BENZENE EXPOSURE FOR "QU-ENCH-ER" JOB IN THE PLIOFILM COHORT 140 120 . 100 p 80 p 60 M 40 .... - 20 0 1940 1945 1950 1955 1960 Year 1965 1970 1975 BP-00011835 PAUSTENBACH et al. 1991 Quantitatively accounts for: o . Dermal uptake o Peak exposures o Monitoring biases o Engineering changes o Production levels BP-00011836 CONCLUSIONS o Rinsky (1987) exposure estimates are highly unlikely: exposures in the 1930s and 19:4-0s were higher than in the mid 1950s. o Crump/Allen (1984) exposure estimates represent a more accurate characterization and are consistent with worker blood data. o New exposure estimates will incorporate information not available to either Rinsky or Crump/Allen. o Revised estimates will be sufficiently different from either prior analysis and should be considered when setting a new TLV. BP-00011837 PRESENTATION TO DR. WILLIAM FARLAND MARCH 19, 1991 BP-00011838 PURPOSE OF API WSPA VISIT TO EPA July 13, 1990 o REVIEW RATIONALE FOR REOPENING POTENCY ASSESSMENT o SUMMARIZE API PAST POTENCY ASSESSMENT EFFORTS o DISGUSS API'S CURRENT EFFORTS TO IMPROVE POTENCY ESTIMATE o REVIEW API'S LONG TBRM RESEARCH EFFORTS 2 BP-00011839 API -WSPA- EFFORTS TO IMPROVE BENZENE POTENCY ASSESSMENT July 13, 1990 o CONTRACT CHEMRISK (DR. DENNIS PAUSTENBACH) TO INTEGRATE AND PUBLISH KEY FINDINGS OF THE LAST FIVE YEAR'S RESEARCH EFFORTS o USE PLIOFILM COHORT AS THE BASIS FOR POTENCY ASSESSMENT AND OTHER STUDIES AS REALITY CHECKS o EXAMINE THE LINEAR-QUADRATIC AND MKV MODELS o SEEK CONSENSUS ON: - LATENCY P~RIOD - SELECTION OF ENDPOINTS - DOSE METRIC - -RELATIVE VS. ABSOLUTE o OBTAIN PEER REVIEW OF RESI::JLTS 3 BP-00011840 PURPOSE OF TODAY'S VISIT o STATUS OF API WSPA PROGRAM ON BENZENE POTENCY ASSESSMENT o EPA INTEREST IN REOPENING BENZENE POTENCY o STATUS OF API LONG 'fERM RESEARCH PROGRAM 4 BP-00011841 BENZENE POTENCY ASSESSMENT .ISSUES o DATA ISSUES - CHOICE OF EPIDEMIOLOGY STUDIES - SIGNIFICANCE OF DISEASE ENDPOINTS o PUOFILM COHORT ISSUES - UPDATE OF COHORT - EXPOSURE ESTIMATES - INTERPRETATION OF BLOOD COUNTS o MODELING ISSUE&- - LATENCY RELATIVE VERSUS ABSOLUTE RISK - INDIVIDUAL TRANSITION RATE o REVISED POTENCY ESTIMATES - LINEAR MODEL NON-LI-NEAR MODELS 5 BP-00011842 DJiTA ISSUES: CHOICE OF EPIDEMIOLOGY STUDIES o EPA USED THREE STUDIES o GEORGETOWN RECOMMENDED USING PLIOFILM AND PERFORMING REALITY CHECKS USING OTT AND WONG o META-ANALYSIS PROJECT TO DETERMINE POSSIBLE ADVANTAGES OF COMBINING EPIDEMIOLOGY STUDIES 6 BP-00011843 DATA ISSUES: SIGNIFICANCE OF DISEASE ENDPOINTS o DETERMINE THE EFFECT OF ENDPOINT SELECTION OF POTENCY ESTIMATE o ESTIMATE BENZENE POTENCY USING: - AML ONLY - TOTAL LEUKEMIAS - TOTAL LEUKEMIAS PLUS MULTIPLE MYELOMAS -OTHERS 7 BP-00011844 PLIOFJLM C1llJRT ISSUES: UPDATE OF COHORT- HISTORY OF COHORT UPDATES DOCUMENT LATEST YEAR CONSIDERED NUMBER OF WORKERS 1983 CRUMP AND ALLEN 1985 EPA POTENCY ASSESSMENT 1988 CLEMENT POTENCY ESTIMATE 1975 1978 1981 1,866 1,866 1,866 1991 UPDATE OF THE COHORT 1988 1,291 8 BP-00011845 PUOFJLM COHORT ISSUES: UPDATE OF COHORT RESULTS OF THE UPDATE 1982-83 1984 1985 1986-88 NO ADDITIONAL LEUKEMIA 1 MYELOCYTIC LEUKEMIA 1 MYELOCYTIC LEUKEMIA 1 LYMPHATIC LEUKEMIA NO ADDITIONAL -LEUKEMIA NO ADDITIONAL CASES OF MULTIPLE MYELOMA 9 BP-00011846 J>UOFJLM COHORT ISSUES: ElfJ>OSURE ESTIMATES API - WSPA EFFORTS ON PLIOFILM EXPOSURE ~TIMATES o NEWLY FOUND DATA: - PRODUCfiON INFORMATION - INTERVIEWS WITH PUOFILM WORKERS SIGNIEICANT ENGINEERING CONTROLS WERE INTRODUCED IN THE LATE 1940S IN BOTH PLANTS REUANCE ON BIOLOGICAL MONITORING NOT AIR SAMPLING FOR BENZENE CONTROL SIX AND SEVEN DAY SHIFTS COMMON PEA-K AND DERMAL EXPOSURf:S WERE SIGNIFICANT 10 BP-00011847 PUOFILM COHORT ISSUES: EXPOSURE ESTIMATES INTERPRETATION OF NEW DATA (PRELIMINARY CONCLUSIONS) o EXPOSURES ARE UKELY TO BE HIGHER THAN CRUMP-ALLEN FOR MOST WORKERS FOR MOST YEARS - BIASES IN ANALYTICAL METHODOLOGY - PEAK EXPOSURES NOT CONSIDERED FOR MANY JOB CLASSIFICATIONS - DERMAL NOT CONSIDERED_ o ST. MARYS DIFFERED FROM AKRON IN THE 1940'S ST. MARYS LARGELY SHU' DOWN DURING 1942-1945 DUE TO SHORTAGE IN RUBBER SUPPLIES - ST. MARYS INSTALLED BENZENE CONTROLS IN 1946 WHICH WERE NOT IN PLACE IN AKRON PLANT - MORE FREQUENT BLOOD MONITORING o BEFORE THE MID 1950'S GOODYEAR RELIED ENTIRELY ON BIOLOGICAL MONITORING FOR-BENZENE EXPOSURE 0NTROL 11 BP-00011848 I'LIOFILM COHORT ISSUES: EXPOSURE ESTIMATES 12000 ESTIMATED ANNUAL PRODUCTION {Lbs. Per Day) 10000 L B 8000 s I 6000 D 4000 y 2000 0 .--- 1934 1936 1938 2APLASTIC ANEMIA DEAUIS AT AKRON 1940 1942 YEAR 1944 AJ<R:N D-ST.MARVS 1946 1948 195 12 BP-00011849 PUOFILM COHORT ISSUES: EXPOSURE ESTIMATES CURRENT ACfiVITIES o REVISE ESTIMATES OF AREA CONCENTRATIONS IN THE 1940'S TO REFLECf NEW INFORMATION ON ENGINEERING CHANGES AT ST MARYS o PERFORM TIME AND MOTION STUDIES TO CHARACfERIZE DERMAL AND PEAK INHALATION EXPOSURES o DEVEWP "TOTAL' TWA ESTIMATES OF SHIFT EXPOSURES o PUBLISH OVER THE NEXT FEW MONTHS 13 BP-00011850 PUOFILM COHORT ISSUES: -JAI.TERPRETATJON OF BLOOD COUNTS o NEW ANALYSIS OF WORKER DATA CONFIRMS PRELIMINARY CONCLUSION OF KIPEN ET.AL 1989, THAT TEMPORAL BLOOD COUNT TRENDS WERE NOT AN AKflfACf OF THE DATA SET o ADDITIONAL DATA SUGGEST THAT WORKERS IN HIGHLY EXPOSED JOB CLASSIFICATIONS CAN BE DIFFERENTIATED FROM WORKERS WITH MODERATE AND LOW EXPOSURES o AKfiCLE WILL BE SUBMITTED TO PEER REVIEW JOURNAL WITHIN NEXT TWO MONTHS 14 BP-00011851 MODEUNG JSSVES: LATENCY LATENCY: o BASE LATENCY ON RADIATION OR PLIOF-ILM COHORf ITSELF o GEORGETOWN RECOMMENDED THE PLIOFILM COHORT o PERFORM SENSITIVITY ANALYSIS 15 BP-00011852 MODELING ISSUES: RELATIVE VERSUS -ABSOLUTE RISK CHOICE OF RISK MODEL o 1985 EPA POTENCY ESTIMATE USED BOTH o FOLLOW-UP OF PLIOFILM COHORT OFFERS AN OPPORTUNITY TO TEST APPROPRIATENESS OF MODELS 16 BP-00011853 MODELING ISSUES: RELA TJVE VERSUS ABSO~UTE RISK PRELIMINARY ANALYSIS OF COHORT DATA THROUGH 1981 SUGGESTS THAT RELATIVE RISK MODEL OF PLIOFILM COHORT DOES NOT FIT OBSERVED DATA TIME PERIOD 1940- 1953 1954- 196T 1968- 1981 NUMBER OF CASES PREDICTED BY RELATIVE RISK MODEL 3.0 5.7 6.9 NUMBER OF CASES OBSERVED 7 API - WSPA PLAN TO UPDATE THIS WITH NEW COHORT DATA AND PUBLISH T-HIS YEAR 17 BP-00011854 MODELING ISSUES: INDIVJDVAL TRANSITION RATE INDIVIDUAb TRANSITION RATE (TREAT WORKERS AS INDIVIDUALS RATHER THAN COMBINING INTO SIX DOSE GROUPS) o STATISTICALLY MORE EFFICIENT o RECOMMENDED BY GEORGETOWN 18 BP-00011855 REVISED POTENCY ESTIMATE : LINEAR MODEL o BASE ON PLIOFILM COHORT ALONE: OTT AND WONG TO BE USED AS A CHECK o NEW EXPOSURE AND COHORT DATA o INDIVIDUAL TRANSITION RATE o DIFFERENT LATENCY ASSUMPTIONS o DIFFERENT ENDPOINT ASSUMPTIONS o ABSOLUTE RISK AND RELATIVE RISK o SENSITIVITY ANALYSIS ON - ENDPOINTS -LATENCY - RELATIVE AND ABSOLUTE RISK- 19 BP-00011856 I REVISED- POTENCY ESTIMATE: NON-LINEAR MODEL o BENZENE: A CANDIDATE FOR NON-LINEAR MODELING - BEST FIT OF THE DATA o EXPLORE LINEAR QUADRATIC AS ONE NON-LINEAR MODEL - GEORGETOWN RECOMMENDATION - LEUKEMIA INDUCED BY RADIATION FGLLOWS A NONLINEAR MODEL 20 BP-00011857 -!!LANNED PUBLICATIONS: 1. NEW PLIOFILM EXPOSURE ESTIMATES 2.. NEW PUBLICATION ON THE HEMATOLOGICAL RECORDS OF THE COHORT 3. PAPER ON ANALYTICAL METHODS 4. TESf OF FIT FOR RELATIVE AND ABSOLUTE MODELS 5. META-ANALYSIS 6. REVISED LINEAR AND LINEAR QUADRATIC POTENCY ASSESSMENTS 21 BP-00011858 API'S LONG TERM RESEARCH PROGRAM ON BENZENE TOXICOLOGY 22 BP-00011859 STATUS OF RESEARCH IRONS PUBLICATIONS ON EFFECTS OF BENZENE METABOLITES ON HEMOPOIETIC SYSTEM PLANNED FOR MID 1991 cox COX "PUBLICATIONS" DEVELOPMENT OF PC BASED PBPK MODELS FOR BENZENE THE NEXT STAGE IN MODELING CIIT WORK PROGRESSING 23 BP-00011860 EPA/API INTERACTIONS: o LINDA BIRNBAUM ATTENDANCE AT OCTOBER MEETING WITH CIIT o TONY COX TO MAKE A PRESENTATION TO EPA -sTAFF IN RTP (LINDA BIRNBAUM) IN LATE APRIL o NEED TO DO BETTER: - CONTACT FOR BENZENE INFORMATION - ROUTINE ATTENDANCE OF EPA STAFF AT IN-TOWN MEETINGS OF BENZENE TOXICOLOGY WORKGROUP 24 BP-00011861 - CASE 1 2 3 4 5 6 7 8 9 10 11 12 13 t4 LEUKEMIAS AND MULTIPLE MYEWMAS IN THE RINSKY COHORT ID 000228 000123 000043 ClOia44 000282 000240 001013 001106 000248 000140 000460 001079 001181 001109 AGE AT DEATH 36 29 60 65 62 57 57 28 67 69 52 62 68 82 YEAR OF DEATH 1958" 19.50" 1958" 19tl<t 19618 1961" 1957" 19548 197Cf 198if 1963 1968b 1981c 1974b CAUSE Monocytic leukemia Chronic myelogenous leukemia Acute myelocytic -leukemia Acute n1yclogcnous leukemia DiGugliclmos acute myelocytic leukemia Acute granulocytic leukemia Acute monocytic leukemia Myelogenous leukemia Acute myeloblastic leukemia Multiple myeloma -Multiple myeloma Plasma cell sarcoma Multiple myeloma !="_to ""' 1'1 1 .;:- RINSKY ARTICLE 204 204 204 204 204 204 204 204 204 203 203 203 203 brn>:._w\011956a.tbl'04\09\91:01:bms:KEW -1- NEWICD (on w.-n:ut~ sheet) 204.2 204.1 204.3 204.3 204.3 204.3 204.2 204.1 205.0 203 203 203203 205.0 EN VI RON BP-00011862 CI\SE 15' 16. n t8 19' "ICD6-7 blCDS <1c09 'New (not in article) LEUKEMIAS AND MULTII'LE MYELOMAS IN THE RINSKY (_'QHORT (mntinucd) 10 001290 000465 000602 000190 001126 AGE ATOEATII 67 67 67 71 81 YEAR OF DEATH 1984< 1985' 1985" 1981f 1981' F001NOTF.S CAUSE Ci1r~<">"1"1<,~ ll.cJ:.J. """"Ll1 ".~ ltc-"f-t .J ~~u. tJ1>r ~ '"" w"r .5: RINSKY ARTICLE NEWICD (on current sbcct} 205.1 205.0 204.0 208.9 208.9 bms\w\OI-195Ga.tbi:04\09\91:01:bms:KEW -2- E N V I It 0 N BP-00011863 UPDATE OF LEUKEMIA RISK POTENTIALLY ASSOCIATED WITH OCCUPATIONAL EXPOSURE TO BENZENE Joseph V. Rodricks, Ph.D. ENVIRON Corporation EN\'IIlON - - - - - - - - - - - - - - - - - - - - - - -- BP-00011864 -BASIS OF ACGIH-TLV-TWA RECOMMENDATION OF 0.1 PPM Rinsky et al. (1987) analysis that suggests that "the odds of benzene-induced leukemic death at 0.1 ppm approach very nearly the odds of leukemic death for a worker who is not exposed to benzene." ~)..'ill- Ull..uh2.01.41Jll,. 1-: N \' 1110 N BP-00011865 RINSKY et at. 1987 RISK ANALSIS PRINCIPAL RINSKY ET AL. ASSUMPTIONS: (i) Plioform cohort data are the best- available for quantit-ative analysis. (ii) Conditional-logistic regression best describes relation between OR and exposure. (iii) Rinsky et al. exposure matrix represents benzene exposures of Pliofilm cohort. (iv) Appropriate matching criteria (cases vs. controls) are date of birth and date of entering Pliotilm work. ENVIRON analysis (Brett et al. 1989) reexamined these four assumptions. 1-:NVII!ON BP-00011866 PREFERRED DATA SET FOR BENZENE RISKASSESSMENT Rinsky et al. cohort of Pliofilm workers. Benzene- as predominant exposure well established. Individual exposure estimates can be established for this cohort based on industrial hygiene data. ENVIItON BP-00011867 PREFERRED RISK MODEL FOR BENZENE RISK ASSESSMENT Matched Case-Control Conditional Logistic Regression (Rinsky et al. 1987) Makes maximal use of data available on individual ex-posure levels-; Avoids loss of information and resultant imprecision in analyses that dichotomize (e.g., linear and one-hit models) or categorize -(Crump and Allen absolute and relative risk models) cumulative benzene exposure. ,..,..Vli-II'J'lanlol_.ftl-fl1211U ENVIIlON - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - --------- BP-00011868 COMPARISON OF R-!NSKY ET AL. AND CRUMP/ALLEN EXPOSURE ESTIMATES Tne exposure estimates of Crump/AH~n are generally higher than those of Rinsky for the majority of job titles and time periods covered. Crump/Allen exposure estimates appear more plausible because they are consistent with changes in the TLVs and with industrial hygiene practice over that time period. ENVIIION \ BP-00011869 DATES OF FIRST BENZENE EXPOSURE FOR 9 LEUKEMIA CASES (Rinsky et al., 1987) Case 1 2 3 4 5 6 7 8 9 Year of First Exposure 1941 1948 1944 1944 1939 1941 1942 1951 1942 Year of Death 1958 1950 1958 1960 1961 1961 1957 1954 1979 ...p'411.J9n ..wUJmz" ENVIRON BP-00011870 150 -"0 125 u A. ..llC Ill 100 0 -"0 75 i!: .A 0 50 0 ;0 25 a: 0 Acute Myelogenous Leukemia In the Pliofilm Cohort (1940- 1981) Number ol Cases ObservedJNumber ol Cases Expected 010.44 010.23 110.21 010.14 2.5 12 50 . 140 Estimated Average Cumulative Dose (ppm-years) 600 Z/0.02 1500 BP-00011871 A:LTERNATIVE CASE-CON~ROL MATCHING CRITERIA FOR CONDITIONAL LOGISTIC REGRESSION ANALYSES Rinsky et al. controls matched on: . Date of birth Date of entering Pliofilm ENVIRON controls matched on: Date of birth Date of entering Pliofilm Plant location I:NVIIlON BP-00011872 ENVIRON ANALYSIS MODEL EXPOSURE MATRIX MATCHING CRITERIA Date of Birth <~Rinsky Exposures ~ Date Enter Pliofilm Date of Birth Date Enter Pliofilm Case-Control Plant Location Conditional Logistic Regression Mod~el <(Date of Birth . Date Enter Pliofilm Crump & Allen Exposures Date of Birth Date Enter Pliofilm Plant- Location I:NVII<ON BP-00011873 RESULTS OF ENYIRON ANALYSIS RISKS ASSOCIATED WI11I 40 YEARS OF BENZENE EXPOSURE IN WORKPLACE Exposure Assumptions Rinsky et al. (1987) Rinsky et al. (1987) Crump and Allen (1984) Crump and Allen (1984) Control Set Matching Criteria 1 Date of Birth Date of entering Pliofilm 2 Date of Birth Date of entering Pliofilm Plant (Same-as 1 above) (Same as 2 above) Odds- Ratio 0.1 ppm 1.05 1 PPID 1.66 1.04 1.53 1.01 1.07 1.01 1.07 10 ppm 154.47 69.41 1.97 1.97 ENVIUON BP-00011874 CONFIDENCE LIMITS (95%) OF ODDS RATIOS FOR CRUMP/ALLEN AND RINSKY EXPOSURE ESTIMATES CRUMP/ALLEN ESTIMATE AT 1.0 PPM l+-11----+ RINS.KY ET.AL. ESTIMATE AT 0.1 PPM II III IIII IIII III III 1. 0 1.25 1.50 1.75 Odds Ratio BP-00011875 RESULTS OF THE UPDATE In 1990 NIOSH completed an update of the Pliofilm cohort. This update extended the follow-up of the -cohort from December 1981 through December 1988. API received a computer file of the information on the follow-up on March 20. This file is currently being analyzed. A preliminary scan of the file indicates that some additional cases of leukemia occurred during the 7 additional y:ears of follow-up. . , . ,. , _ 1 1 ' 1 7 U J I I 1 1 1 \ J I ' " I ICNVIIION BP-00011876 CONCLUSIONS Case-control conditional logistic regression model represents an improvement over prior models for benzene risk analysis because of maximal use of indiv-idual warker exposure data. Exposure estimation has most significant effect on risk estimates; matching on plant had relatively minor effect on risk. Odds ratios associated with a working lifetime of benzene exposure at I pQm, 8 ho_ur TWA under Crump/Allen exposure estimates are not significantly different from those associated with a working lifetime of exposure at 0. I ppm, 8 hour IWA under Rinsky et al. exposure assumptions. Because risk estimations are so sensitive to assumptions about exposu-re, there is a need to define more precisely the actual historical-benzene exposures of this cohort. ENVIIION BP-00011877