Document B5pVnY2Q0jyKvdnwE47anddLw

oooooioi*^ SAL Chapter 4 BENZENE FACT SHEET The following information on benzene is representative of the type of risk communication information you should consider assembling for substances whose emissions you estimate pursuant to Section 313 requirements. The information contained in your benzene material safety data sheet can be used to supplement the hazard data section. Sources o Naturally occurring substance in crude oil and refinery streams o Also naturally occurring in low concentrations in many plants and as a normal metabolite in certain animals o Produced by the combustion of most organic materials and found in exhaust of both gasoline and diesel-powered vehicles Annual Production o US: Approximately 10 billion pounds separated as chemical feedstock (1981)13 o Your facility (?): ____ pounds Uses o Constituent of motor gasoline blend streams o Basic chemical building block used in producing intermediates such as styrene, phenol, and cyclohexane which are further processed to styrene polymers, plastics, and resins; phenolic resins; nylon; epoxy resins; pharmaceuticals; polyesters; and pesticides, o No longer used as a solvent* 14 United States International Trade Commission, Synthetic Organic Chemicals------United States production and sales, 1981. USITC Publication No. 1292, Washington, DC: uTs. Government Printing Office, 1982. 14 SAL 000001022 Hazard Data Benzene is a known human carcinogen which has produced an increased incidence of leukemia in highly exposed industrial workers. Carcinogenic effects also have been demonstrated to occur in experimental animals after lifetime exposure to high vapor levels of benzene or to large doses given daily by the oral route. Sources of Ambient Benzene Emissions and Exposure o Cigarette Smoking (both active and passive) o Diet, e.q., eggs and cooked meats o Auto exhaust o Gasoline o Refineries and petrochemical plants Estimated Benzene Emissions Levels o 5-100 tons per year per major refinery nationwide (based on current reports to state regulatory agencies) Total Benzene Emissions Levels^4 Direct (associated with benzene production) Refineries 3,400 tons Transportation & Storage 7,900 Coke Plants 900 Total 12,200 Indirect (non-benzene production ) Refineries 22,000 tons Gasoline Trans. & Storage 23,100 Coal Coking 2,100 Total 47,200 Gasoline Combustion (Cars, Trucks, Motorcycles) 143,20014 14 D. Gilbert et al.. An Exposure and Risk Assessment for Benzene. Final Draft Report. Prepared by A.D. Little, Inc. for the Environmental Protection Agency Office of Water and Waste Management, Washington, DC. EPA Contract No. 68-01-5949, 1982. 15 SAL 000001023 Ambient Concentration Data o Marketing Terminal Fenceline Upwind 2-3 ppb Downwind 3-5 ppb15 o Ambient Concentrations for Seven US Cities Houston, TX 5.8 ppb St. Louis, MO 1.4 ppb Denver, CO 4.4 ppb Riverside, CA 4.0 ppb Staten Island, NY 4.2 ppb Pittsburgh, PA 5.0 ppb Chicago, IL 2.6 ppb16 17 o Daily Ambient Concentrations (range) San Francisco, CA (urban) 0.8 - 5.2 ppb Stinson Beach, CA (pristine environment) 0.13 - 1.02 ppb San Francisco (mean concentration) Smoker's breath 6.8 ppb Non-smoker's breath 2.5 ppb Stinson Beach (mean concentration) Smoker's breath 4.8 ppb Non-smoker's breath 1.3 ppb1' 15 E.H. Conrad, "Gasoline Vapor Sampling at Marketing Terminal Perimeter," Unpublished paper. May 27# 1982. 16 H.B. Singh, L.J. Salas, and R.E. Stiles, "Distribution of Selected Gaseous Organic Mutagens and Suspect Carcinogens in Ambient Air," Environ. Sci. Technol., 16(12), 872-80, 1982. 17 R.C. Wester, et al., "Benzene Levels in Ambient Air and Breath of Smokers and Nonsmokers in Urban and Pristine Environments," Journal of Toxicology and Environmental Health, 18, 567-73, 1986. 16 SAL 000001024 o Ratio of Indoor to Outdoor Concentrations of Benzene California (medians) New Jersey (medians) Bayonne and Elizabeth, NJ (medians) Estimated Lifetime Benzene Exposure2** Indoor Air Outdoor Air Food Drinking Water Smoking 7.4 grams 0.4 6.0 0.1 10.0 Calculations assume person inside 90% of the time with 'exposure of 10 ppb. Outdoor exposure is 10% of the time with exposure of 5 ppb. Drinking water contamination is 5 ppb. Food exposure is assumed to be 250 micrograms per day. Smoker consumes 1 pack per day. Hartwell, et al., "Comparison of Volatile Organic Levels Between Sites and Seasons for the Total Exposure Assessment Methodology (TEAM) Study," Atmospheric Environment, 21(11), 2413-2424, 1987. Wallace, et al., "The TEAM Study: Personal Exposures to Toxic Substance! in Air, Drinking Water, and Breath of 400 Residents of New Jersey, North Carolina, and North Dakota," Environmental Research, 43, 290-307, 1987. 20 R.C. Russell, Letter to C.J. DiPerna, August 14, 1987. 17 SAL 000001025 preliminary Apportionment of Total Air Benzene Exposures In Six Environments for 54 Population Cohorts DRAFT Prepared by: C. James Sample/ Ph.D. Consultant to API Health and Environmental Affairs Department January 21, 1989 SAL 000001026 Preface The following report summarizes preliminary research sponsored by API on the total Time Weighted Average (TWA) exposure of the population to ambient benzene. The analysis presented Is based on benzene exposure data from EPA's Total Exposure Assessment Methodology (TEAM) findings for California (pre-1987) and New Jersey and on the behavorlal patterns developed by PEI for EPA and provided In the report entitled "National Estimates of Exposure to Ozone Under Alternative National Standards" (December 1966). This Is a preliminary report. API Is continuing to sponsor research In this area. Most importantly, API Intends to expand this work with emperlal data when this data becomes available. SAL 000001027 Preliminary Apportionment of Total Air Benzene Exposures in Six Environments for 54 Population Cohorts API shares EPAvs concern that certain segments of the population may be exposed to relatively high ambient benzene concentrations over extended periods of time. We also fully support EPA's effort to evaluate total human exposure to benzene and other compounds under the Total Exposure Assessment Methodology (TEAM) study program. The TEAM data provides the most extensive information available on such exposures. The analysis presented here incorporates the TEAM study findings from the TEAM study segments in New Jersey (Elizabeth and Bayonne; fall, winter and summer study periods) and California (Los Angles; Seasons 1 and 2 and Contra Costa County) with the 54 population behavorial patterns established by PEI, Associates in the analysis done for EPA entitled "National Estimates of Exposure to Ozone Under Alternative National Standards" (December 198). Given the distributions of benzene concentrations by environment and the EPA/PEI estimated time spent in each of the six environments, stochastic exposure profiles are presented which are consistent with estimates of total benzene exposue reported in the TEAM findings. This analysis suggests that there segments of the population that may be exposed to benzene concentration levels postulated by EPA's Maximum Exposed Individual (MEI). However, this analysis suggests that these exposure levels do not result from, stationery, or even mobile, industrial or vehicle sources. As is well recognized, high exposures result from individual behavorial decisions. It has been well established by the TEAM studies and others that benzene is ubiquitous in the human environment. Unquestionably, the benzene found in the environment is derived from many sources, indoors as wel1 as outdoors; automotive, industrial, and natural; from tobacco smoke and food; from solvents and plastics. Indoor air concentrations of benzene are significantly greater than those outdoors. Although the full range of indoor sources have not been satisfactorily identified, tobacco smoke is clearly an important component for the population at large. The magnitude of indoor air concentrations is very important to the determination of total human exposure, because most of the population spends a great preponderance of their time within Indoor environments of various types. Sufficient information is not yet available to partition human exposure to environmental benzene as a function of source. Nonetheless, EPA data suggests that approximately 90 percent of the benzene in outdoor air (defined as ambient in the analysis that follows) is derived from mobile sources with the remaining 10 percent from non--mobi1e sources. Yet this does not mean that human exposure is governed by this relationship -- although the focus of this Rulemaking is on some of the sources contributing to the 10 percent assumed contribution from non--mobile sources. SAL 000001028 The EPA/PEI behavorial patterns developed for the NEM Model pereit the assessment of total exposure time for each of 54 population subgroups representative of urban U.S. cities into various environments. For the analysis reported here, we have estimated the annual time spent in the following environments for each of the 54 EPA/PEI population cohortsi Environment Defined As Ambient Commuting Urban Street Indoors, Home Indoors, Other Indoors, Work Outdoors, away from a roadway In an automobile Near a roadway Indoors at home Indoors, not at home but in the subject's home monitor district (as defined by the EPA/PEI study cited! Indoors, in the subject's work district The EPA/PEI report provides estimates of the time spent in each of these environments by ten minute intervals for weekdays, Saturdays and Sundays for both summer and non'-summer months. Working with these ten minute segments, we developed a profile of the mean time spent in each environment over a one year period (assuming that the summer period constituted a three month time frame!. The estimated time, standardized to a 24 hour TWA, spent in each of the six environments used in this analysis is presented by Table 1. Given the estimated time spent in each of these environments, it is necessary to 'stimate the distribution of benzene concentrations likely to be encountered in each environment in order to estimate the probable TWA exposures encountered by each of the 54 population cohorts. Analysis of the TEAM benzene concentrations found in all New Jersey and California study segments consistently show that the concentrations are log-normally distributed. We, assumed that this is true for all environments considered in this analysis. The TEAM findings also provide the best available estimates of the ambient benzene concentrations (outdoors, day and night! and the indoor home (TEAM overnight personal readings!. In order to make maximum use of the TEAM New Jersey and California findings, a composite data file for all the study segments was developed. For this analysis, the geometric means and the standard deviations of the log values of the total outdoor (ambient! and overnight personal (indoor home! measurements were used to establish the distributions of benzene concentrations for these two environments. These estimates assume relatively great importance because of the time spent in the indoor at home environment. As a result, we are confident that the estimates provided realistically depict the distribution of exposures experienced by the general population, regardless of the assumed exposure distributions for the remaining four environments. In order to estimate the benzene concentration distributions for the remaining four environments, the literature was reviewed and we used our best estimate of the means and standard deviations of the most likely benzene concentrations to be representative of these environments. Table 2 provides a summary of the concentrations used as a result of the TEAM analysis and our literature search. Admittedly, they are judgemental, but 2 SAL 000001029 rbw s rin in Each Crwirerment by E78/7EI Ppwl*tin Cthort (Annvaliaad and 5a**d an * 24 Hour fteriadl CM/W ftep. Cehert Urban Indaar Indaer Indeer llnbient Ctwiutinp Straat Hm Other UenJr Tetel 1 0.295 0.954 22.534 0.524 24 2 0.232 0.999 0.798 21.929 0.79? 24 1 1.999 0.404 0.295 20.639 0.009 24 9.096 0.907 0.012 17.043 2.900 24 t 9.449 0.524 0.205 17.664 2.07? 24 ft 1.20ft 0.55ft 0.29ft Ift.ftOft 4.970 24 7 2.2ft0 0.541 0.107 1ft.149 2.917 24 9.290 0.511 0.107 17.969 2.72ft 24 ft 0.991 O.ftOS 0.945 14.449 1.402 9.175 24 10 11 1.191 0.494 0.993 1.053 0.205 17.232 O.ftftft 14.902 6.011 4.01? 2.950 24 24 12 0.90ft 0.999 0.17ft 20.994 1.957 24 12 24.000 24 14 1$ 0.492 1.154 0.99ft 1.059 0.012 20.991 O.ftftl 14.219 2.202 4.10? 2.999 24 24 1ft 0.671 O.ftftft 0.249 21.151 1.95? 24 I? 1ft 1ft 20 0.03ft 0.405 0.009 O.ftftft 1.053 O.ftftft 0.101 0.92ft 0.170 20.189 14.939 20.994 24.000 2.202 4.44ft 1.957 2.232 24 24 24 24 21 0.919 0.720 0.999 20.91? 1.714 24 22 22 1.009 0.677 1.047 O.ftftft O.ftftl 14.908 0.249 21.163 4.446 1.410 2.232 24 24 24 0.ftS2 0.720 0.915 20.292 1.714 24 25 0.925 0.90ft 0.529 19.869 0.796 1.429 24 2ft 1.017 0.90ft 0.523 19.480 0.73ft 1.429 24 22 0.046 0.940 0.327 15.92ft 0.923 9.993 24 29 2ft 90 0.054 0.119 0.942 1.00ft 1.41ft 0.957 0.41ft O.ftftl 0.32? 15.979 15.904 19.414 0.922 0.905 0.999 9.933 5.29? 5.922 24 24 24 91 92 99 94 0.970 0.974 0.090 0.50ft 1. 160 1.41ft 1.202 1. 149 0.345 0.345 0.957 0.23ft 15.07ft 14.815 14.809 14.050 0.905 0.905 1.960 2.101 6.933 5.933 9.190 6.952 24 24 24 24 95 0.50ft 1.000 0.244 14.545 1.98ft 9.714 24 9ft O.OftO 1.440 0.957 14.566 1.980 9. 190 24 9? 9ft 9ft O.OftO 0.953 l.lftft l.ft?9 1. 170 1.000 0.957 0.9ft9 0.22ft 14.930 14.013 12.247 1.380 1.980 9.405 9. 190 9.190 9.992 24 24 24 40 1.156 1.000 0.22ft 19.911 1.97ft 9*714 24 41 0.755 1.230 0.963 14.437 1.024 9.190 24 42 0.755 1.47ft 0.963 14.194 1.024 9.190 24 42 0.11ft 1.7ft7 1.041 11.570 0.905 4.954 24 44 0.11ft 2.03ft 1.041 19.943 0.905 4.654 24 45 0.11ft 2.172 1.191 15.11? 0.905 4.554 24 4ft 47 0.991 0.797 1.7ft? 2.09ft 1.053 i4.eoft 1.053 14.709 0.905 0.905 4.554 4.654 24 24 4ft 0.913 2.25ft 1.053 14.617 0.905 4.654 24 4ft 4.975 1.17ft 1.29? 14.969 1.919 0.15? 24 0 4.975 1.41ft 1.29? 14.494 1.519 0.95? 24 91 4.975 1.997 1.297 14.210 1.919 0.95? 24 92 99 5.705 5.517 1.149 1.419 1.297 13.974 1.29? 19.79ft 1.919 1.919 0.95? 0.95? 24 24 94 59ft9 1.955 1.2ft? 19.703 1.919 0.95? 24 3 SAL 000001030 they represent our best estimates of these exposures experienced in these environments. Table 2 Estimated Benzene Concentration Distribution Characteristics by Study Environment Log Normal Mean Std- Dev. Ambient Commuting Urb. Street Indoor Home Indoor Other Indoor Work 0.71 ppb 1.40 2.40 1.37 1.50 1.50 1.00 ppb 1.25 1.00 1.07 1.00 1.25 Using these data -- the EPA/PEI annual time distributions spent in each environment as presented in Table 1 and the estimated benzene concentration distribution characteristics as described in Table 2 - an exposure model was developed (based on Monte Carlo sampling with 300 iterations) to estimate the TWA benzene exposure for each of the EPA/PEI 54 population cohorts. This analysis was based on the following. * Benzene concentrations t _*re assumed to be log-normally distributed in each environment. * The log-normal concentrations were sampled stochastical 1y for each environment over 99.5 percent of all possible concentrations (it. the range in the possible concentrations was established at the geometric mean or -- 2.576 times the geometric standard deviations). a Given the EPA/PEI time distributions, each of the 54 population cohorts were randomly assigned to each environ ment for the specified amount of time to estimate the TWA total exposure by summing the exposures estimated for each environment. Tor each of the 54 cohorts, 300 TWA exposure estimates were calculated. (This was done after an analysis showed that the distribution variances stabilized at this number of trials). Tables 3 and 4 summarize the results of these analyses for the 50th and 95th percentiles respectively. These findings rely on the assumption that (1) benzene concentrations are log-normally distributed and that (2) the EPA/PEI population meti^ity cohorts are reasonable estimates of how much time the general population spends in the specified environments. Table 3 provides a summary of the estimated benzene TWA annual exposure levels for each of the 54 study cohorts given the estimated benzene concentration distribution characteristics cited above. The relative exposure contributions from each environment represent the mediar 4 SAL 000001031 2OTCOOOO nvs 9 9$r ***9 9M* 999*9 OAi` 60*4 too*9 situ 994*9 suu 049*9 4*9*9 0***4 94*4 419*4 039 *9 UC'I W'l 09V cat *9 40**0 669*4 99V 9 9T9*9 91 4*4 WO 199*9 099*9 0t**9 149*9 *99*4 999*9 9*9*4 911*9 *91*9 090*9 999*4 909*9 699** 940*9 661*9 909** 9*9*9 9*9*9 049*9 9*9*9 *C4*9 *94*9 449*9 6*9*9 999*9 999*9 CM *9 9*9*9 994*0 991*0 400*0 S*0*0 490*0 999*0 *09*9 099*9 999** *09*9 099*0 *99*9 *19*1 490*9 C99** 499*9 049*9 *90*9 999*0 199*0 199*9 091*0 090*4 194*9 9*9*9 491 *0 99V9 910*0 990*1 990*1 **4*0 690*9 999*1 S9**t *94*0 -****! 990*0 990*1 949*0 9*9*0 999*1 *90*0 999*0 911*0 491*0 900*0 101*9 910*0 601*0 999*0 69**1 949*0 909*0 991*0 669*0 *99*1 *99*9 999*0 99**0 090*0 699*0 09**0 494*0 991*0 990*0 9*0*0 99**0 91. 9 9*9** 699*0 9*9*0 1*9*0 09V0 9*9*0 909*0 966*0 9***0 094*9 9*9*1 099*1 999*1 999*9 469*9 919*1 096*0 999*0 6SV0 991*0 -`490 I 461 *9 999** 109*9 0*9*9 099*1 009*9 901*1 414*0 900*0 09**1 99**9 990*9 416*9 09**6 **9*0 991 *9 096*6 946*9 409*9 909*6 906*9 199*9 *99*1 499*9 969** 09t *4 9t<*0 196*0 999** 994** 6ta*9 *01 9 119*1 990*6 *91 *9 9*9*6 909*6 999** 649*6 096*9 699'* 909** 9*9*6 919*0 99V9 ***** 9*9*9 669*1 691*1 *69*6 909** 949** 499*9 96**9 -*****1 440*0 991*0 949*0 9*0*0 419*0 9*0*0 99**0 996*0 919*1 141*0 *4 VO 449*0 090*0 190*0 910*0 111*0 990*0 999*0 0*0*0 1*0*0 600*0 900*0 EOt *0 611*0 900*0 990*0 949*0 4*0*0 96**0 410*0 990*0 99*0 650*0 490*0 110*0 660*0 400*0 199*0 460*0 100*0 910*0 619*0 990*0 400*0 900*0 910*0 960*0 9*0*0 010*0 099*0 99**0 410*0 091 *0 990*9 001*0 0*0*0 099*9 499*0 480*0 960*0 99C*t 049*0 4IC*f 619*9 4*1*0 990*0 919*0 4*9*0 06**9 061*0 990*0 *60*6 996*0 499*0 409*0 090*0 991*0 469*0 S9C*0 SIO'O 9t9'0 09**0 919*0 990*0 9*9*0 *91 *9 646*1 199*0 009*0 941*0 916*0 010*0 669*0 091*0 6*0*0 601*0 490*0 699*0 4*1 *0 069*0 9***0 410*0 440*0 9*0*0 9*0*0 499*0 49t *0 499*0 690*0 606*0 900*0 990*0 900*0 060*0 010*0 660*0 960*0 996*0 491 *0 490*0 **0*0 100*0 090*0 660*0 990*0 900*0 490*0 909*0 610*0 toa*a 960*0 910*0 610*0 196*0 9*0*0 *40*0 69**0 991*0 949*0 090*0 196*0 900*0 *10*0 019*0 910*0 *41*0 040*0 990*0 411 *1 969*0 900*0 911*0 599*0 906*0 110*0 *t 69 99 19 09 6* 9* 4* 9* 9* ** 6* 9* 1* 0* 46 96 46 96 96 *6 66 96 16 06 49 99 48 98 98 *8 68 98 18 08 41 91 41 91 St *1 61 81 11 01 9 9 4 9 9 6 8 1 9wf*AwM3 *u*?4**9 -**** 194/9*1 mu**-*4 h* ot (WU !** 944) SN0X1994N93N00 3nS04MJ 0319UI4S3 *19*4 rM* 9 estimated ekaosuae concentrations CARO Annual TUA> 95 th 9*rcntiU Aufeiant C--iwufcing 1 0.019 2 0.010 0.017 9 0.005 0.006 4 0.759 0.578 9 0.099 0.202 9 0.100 1.700 7 0.192 0.080 99 0.150 0.019 0.890 2.795 10 0.052 0.015 11 0.199 0.133 13 0.379 0.031 19 1A 0.039 0.019 15 0.023 2.171 19 0.105 0.159 1? 0.258 0.178 10 0.079 0.527 2109 0.975 0*973 21 0.101 0.829 23 0.179 0.990 29 0.177 0.379 2A 0.259 1.008 25 0.035 0.092 29 0.091 0.055 27 0.001 0.217 20 0.013 0.023 29 0.007 0*099 90 0.029 0.095 3312 0.253 0.052 0.022 1.893 99 0.001 0.778 9A 0.095 0.191 35 0.019 0.129 33 0.057 1.059 37 0.057 0.191 30 0.129 0.022 99 0.237 0.090 90 0.988 1.083 91 0.529 0.325 93 0.071 0.798 99 0.002 9.257 AA 0.013 2.852 95 0.008 2.875 99 0.758 0.028 97 0.379 9.299 9409 0.082 1.990 0.891 0.080 50 0.053 0.927 51 9.080 0.058 52 9.255 0.891 59 9.199 0.297 54 1*409 1*792 Naan Raad 0.289 0.703 0.010 0.001 0.019 0.500 0.080 0.059 0.011 0.115 0.909 0.197 0.007 0.288 0.039 0.002 0.020 0*072 0.010 0.994 0.007 0.955 0.071 0.171 0.018 0.077 0.120 0.005 0.930 0.005 0.095 0.088 0.091 0.049 0.029 0.058 0.038 0.080 0.182 0.900 0.051 0.954 0.154 0.820 0.228 0.708 1.794 0.821 0.821 1.980 0.972 0.199 Indaar Horn 25.491 89.954 92.428 22.493 24.983 21.418 18.352 24.448 7.538 21.724 19.798 23.892 99.792 28.047 20.001 28.884 28.451 21.019 29.892 90.255 25.991 22.487 29.790 22.911 27.989 27.421 27.982 24.842 19.994 24.225 15.295 29.295 10.757 1.190 25*525 22.892 18.190 9.990 29.996 24*412 22.874 9.084 15.782 28.924 19.057 18.718 8*574 9.510 19.493 22.885 20.001 12.585 15.588 19.298 Indaar Othar 0.155 0.249 0.080 0.912 0.093 1.913 2.199 0.974 2.084 1.499 2.720 1.704 2.031 0.592 0.447 0.222 0.198 1.704 0.509 0.384 0.97D 0.414 0.890 0.139 0.140 0.787 1.397 0.158 0.101 0.112 0.089 0.529 0.183 0.210 1.149 0.258 0.150 0.107 0*979 0.033 0.170 0.299 1.280 0.753 0.101 0.091 1.315 0.591 0.273 2.499 0.728 0.302 Indaar 5!5--m-- 18.179 0.939 1.995 2.898 0.219 0.907 1.173 2.212 1.945 7.293 0.109 0.019 2.212 14.246 22.931 1.90$ 2.347 0.510 20.986 0.397 1.875 0.114 20.958 5.250 0.084 0.295 7.121 19.559 13.559 0.040 0.559 0.045 0.011 0.019 0.024 fatal 25.573 25.475 32.555 24.749 25.238 25.158 20.842 25.850 28.844 23.993 22.779 25.950 93.702 29.156 24.825 27*40? 25.107 24.833 28.222 30.255 27.141 24.304 21.798 24.952 29.753 29.996 30.539 27.471 23.234 24.958 24.073 27.198 25.830 25.000 27.777 28.814 28.114 24.810 24.878 27.825 24.179 25.171 25.492 91.123 23.399 25.994 24.395 24.942 29.392 94.734 24.477 20.830 20.867 29.038 6 S*L 00i033 exposures found from 300 trials for each of the 54 study cohorts. As shown, the estimated median TWA total exposure to benzene is less than 10 ppb. The contributions from ambient (outdoor, away from the roadway) Is minimal. With the exceptions of cohorts 21. 35, 46 and 50; over 70 percent of the total TWA exposure occures while these Individuals are Indoors. The relative Impact of indoor exposure Is even more pronounced at the 95th percentile as shown by Table 4. Over 80 percent of the exposure to ambient benzene Is experienced In the Indoor environment with the two exceptions of cohorts 52 and 53. The exposure picture suggested by this analysis Indicates that a realistically defined maximum exposed individual (MEI) Is exposed to the maximum benzene concentrations from the Indoor environments, be that home, other or work. Even if we accept a one-for-one reduction in total TWA exposure due to a reduction In point-source contribution, the Impact on the total exposure of the MEI would be Insignificant. API is continuing Its research in this area. While It Is we believed that the results presented above reflect the best analysis reasonable at this time. The future research will deal specifically with empirical data as apposed to the intuitive data used here. 7 SAL 000001034 00t 2 RECEIVED FEB 14 ENV & OHS 2/8/89 ajcc Benzene Issues Group FYI Gina Helhams Preliminary Apportionment of Total Air Benzene Exposures In Six Environments for 54 Population Cohorts DRAFT Prepared by: C. James Sample, Ph.D. Consultant to API, HEAD January 3, 1989 U/?. SAL 000001050 Preliminary Apportionment of Total Air Ben2ene Exposures in Six Environments for 54 Population Cohorts A. Introduction API shares EPA's concern that certain segments of the population may be exposed to relatively high ambient benzene concentrations over extended periods of time. We also fully support EPA's effort to evaluate total human exposure to benzene and other compounds under the Total Exposure Assessment Methodology (TEAM) study program. The TEAM data provides the most extensive Information available on such exposures. The analysis presented here incorporates the TEAM study findings from the TEAM study segments in New Jersey (Elizabeth and Bayonne; fall, winter and summer study periods) and California (Los Angles; Seasons 1 and 2 and Contra Costa County) with the 54 population behavorial patterns established by PEI, Associates in the analysis done for EPA entitled "National Estimates of Exposure to Ozone Under Alternative National Standards" (December 1966). Given the distributions of benzene concentrations by environment and the EPA/PEI estimated time spent in each of the six environments, stochastic exposure profiles are presented which are consistent with estimates of total benzene exposue reported in the TEAM findings. This analysis suggests that relatively high exposures to benzene do not result from stationery, or even mobile. Industrial or vehicle sources. As is well recognized, high exposures result from individual behavorial decisions. It is in the indoor environment where these ^havorlal decisions have the greatest Impact on the level of humane exposure to ambient benzene. It has been well established by the TEAM studies and others that benzene is ubiquitous in the human environment. Unquestionably, the benzene found in the environment Is derived from many sources, indoors as well as outdoors; automotive, industrial, and natural; from tobacco smoke and food; from solvants and plastics. Indoor air concentrations of benzene are significantly greater than those outdoors. Although the full range of indoor sources have not been satisfactorily identified, tobacco smoke is clearly an important component for the population at large. The magnitude of indoor air concentrations Is very important to the determination of total human exposure, because most of the population spends a great preponderance of their time within indoor environments of various types. Sufficient Information Is not yet available to partition human exposure to environmental benzene as a function of source. Nonetheless, EPA data suggests that approximately 90 percent of the benzene in outdoor air (defined as ambient in the analysis that follows) is derived from mobile sources with the remaining 10 percent from non-mobile sources. Yet this does not mean that human exposure is governed by this relationship although the focus of the current EPA NE5HAP benzene rulemaking is on some of the sources contributing to the 10 percent assumed contribution from m-mobile sources. SAL 000001051 250X00000 1VS 08 496*0 trt COA'Ct A88*1 999*1 696*9 08 496*0 itvt OOA'Ct A86*l 910*1 At!*! yz 496*0 8t9*l 040*61 A86*t 601 *1 OOA* 9 yz 496*0 Itl't 018*01 A86*t A69 *1 9A0* 0 yz 496*0 Itl'T yzy-yt A86*I 910*1 SA0*0 yz at*o 019*1 099*01 A8S*1 0A1 *1 SAO*0 yt 099*0 908*0 4t9*0t C80*l 998*6 619*0 yz 099*0 800*0 OO4*0t CSOM 960*6 ACA'O yz 099*0 fiOI'O 800*01 cso*i AOA *1 too*o yz 099*0 80! *0 411*91 1C1*I SA1 *8 811*0 yz 099*0 808*0 C0C*8f 100*1 960*6 011*0 yz 099*0 808*0 0AS*8t 100*1 A0A*1 011*0 yz 080*1 001*01 coco 9A0 *1 S9A*Q yz Olt` yzo*t AS0'01 C9C*0 066*1 SSA'O yz 014*0 940*1 110*61 966*0 000*1 991*1 yz ni'i 900*6 A0S'St 968*0 OOO't 991*1 yz Olt'f 0!C*t 6tO*0t 09C*O 0A1 *1 690*0 yz oiri 09C*T 066*01 A86*0 9A9*t 090*0 yz Olt'l 006*1 888*01 A8C*0 000*1 090*0 yz 014** 008*1 909*01 008*0 000*1 909*0 yz 8so*o 101*6 090*01 068*0 601 *1 900*0 yz Olt'l O0C*t 8OO*0t AS6*0 806*1 090*0 yz CM*! 808*0 Sto*0l 006*0 910*1 049*0 yz CM*! 808*0 940*91 006*0 091 *1 049*0 yz :ti*i CC!*0 0t0*8t A8C*0 Afi!*0 609*0 yz AM*! 808*0 0OC*8f 100*0 910*1 611*0 yz CM*! 8C8*0 6A9*8t 910*0 000*1 090*0 yz CM*1 680*0 OSO'ST ASC'O 000*0 000*0 yz 064*0 O00*8t 688*0 800*0 410*1 yz l't 064*0 890*81 669*0 800*0 989*0 yz 4*t S8S*0S 016*0 06A*0 890*0 yz OtO*t C91 *16 008*0 999*0 AA9*0 yz CCS"! 900*0 OOC*01 100*0 A0O *1 600*1 yz 014*1 A19*06 666*0 OCA *0 619*0 yz 000*08 yz 496*1 009*08 OAl'O 999*0 800*0 yz sce*e 900*0 C69*0t 068*0 680*1 900*0 yz SOS'S 881*08 tot*o 999*0 860*0 yz act 181*16 808*0 999*0 149*0 yz 6!S*S toi'y eiot 190*0 690*1 091*1 yz SOS'S 189*06 610*0 999*0 690*0 yz 000*06 *c ASt* I 009*06 !A1 *0 999*0 800*0 yz o!*e 410*0 609*01 000*0 690*1 090*0 yz tt0*8 8CS*At 008*0 666*0 161*1 yz Mt* 800*1 900*0t 086*0 900*0 169*0 yz 964*6 89C*At AOl *0 118*0 008*6 yz At8*C 801*01 AOt'O 109*0 008*8 yz 040*0 008*81 096*0 899*0 008*1 yz AAO'S 099*At 006*0 069*0 900*6 yz 008*6 C0O*At 610*0 A09*0 960*6 yz 800*0 CC9*08 006*0 000*0 690*1 yz ACA'O 668*18 09A*0 666*0 868*0 yz 068*0 0M*ee 009*0 908*0 09 69 89 19 09 80 90 A0 90 90 00 60 60 10 00 86 06 At 96 SC 06 66 66 16 06 86 06 48 98 98 08 68 68 18 08 0t 01 41 91 91 0t 61 81 If 01 0 0 A 9 9 0 6 8 1 MU `0`J ** *9*0 174/442 ut| 08 M 0*O pw* pai 124/442 *9 H9*3 t W1 9M*O0 population activity cohorts are reasonable estimates of how imjch time the general population spends in the specified environments. The total exposure and exposure from each microenvironment for the 50th and 95th percentiles for each of the 54 NEM population cohorts are presented by Tables 3 and 4 respectively Table 3 provides a summary of the estimated benzene TWA annual exposure levels for each of the 54 study cohorts given the estimated benzene concentration distribution characteristics cited above. The relative exposure contributions from each environment represent the median exposures found from 300 trials for each of the 54 study cohorts. As shown, the estimated median TWA total exposure to benzene is less than 10 ppb. The contributions from ambient (outdoor/ away from the roadway) is minimal. With the exceptions of cohorts 21 (female housewife, nonexerciser, 16 - 4.9 years of age), 35 (male indoor worker, 3rd shift, nonexerciser), 46 (male in/out worker, commute 20 minutes, nonexerciser) and 50 (male, outdoor worker, commute 20 minutes, nonexerciser); over 70 percent of the total TWA exposure occures while these individuals are Indoors. The relative impact of indoor exposure is even more pronounced at the 95th percentile as shown by Table 4. Over 80 percent of the exposure to ambient benzene is experienced in the Indoor environment with the two exceptions of cohorts 52 (male, outdoor worker, commute 20 minutes, exerciser) and 53 (male, outdoor worker, commute 30 minutes, exerciser). The exposure picture suggested by this analysis indicates that a realistically defined maximum exposed individual (MEI) is exposed to the maximum benzene concentrations from the indoor environments, be that home, other or work. Even if we accept a one-for-one reduction in total TWA xposure due to a reduction in point-source contribution, the impact on uhe total exposure of the MSI would be insignificant. As snown by Table 4, a 1 ppb reduction in the ambient benzene level would result in a less than 5 percent reduction In the total esposure experienced on a TWA basis for all of the 54 population cohorts of the NEM model at the 95th percentile, assuming that the 1 ppb reduction in outdoor ambient concentrations also resulted in a 1 ppb reduction in all indoor environments. SAL 000001053 4 MTxrmrto ckfosihie coNceNmnriONS Wl A#ww*l TU*> IS th CH/sn ftftivnt CvMwtiftf I 0.013 a 0.010 0.017 a 0.085 0.005 0.75ft 0.578 s 0.06ft 0.202 0.180 1.700 r 0.142 0.080 0.150 0.630 a 0.013 a.?ft5 so 0.082 0.015 IS 0. Iftft 0.136 S2 0.276 0.031 S3 1ft 0.068 0.01ft 15 0.023 3.171 1ft 0. 105 0.15ft 1? 0.258 0.175 18 0.0?ft 0.52? 1ft 0.375 0.37* 20 21 0.101 0.529 22 0.17ft 0.460 23 0.177 0.379 2ft 0.26ft 1.008 25 0.035 0.092 26 0.031 0.055 2? 0.001 0.21? 28 0.016 0.023 2ft 0.007 0.03ft 30 0.02ft 0.035 31 0.256 0.022 32 0.082 1.533 33 0.001 0.778 3ft 0.035 0.191 35 0.014 0.129 36 0.057 1.059 37 0.057 0.191 38 0.129 0.022 3ft 0.23? 0.060 ftO 0.49* 1.083 ftl 0.829 0.328 ft2 0.071 0.738 ft3 0.002 3.25? ftft 0.013 2.853 ftS 0.008 2.675 ftft 0.788 0.026 ft? 0.37ft 3.23ft ftft 0.082 0.991 ftft 1.660 0.090 to 0.053 0.32? 51 3.080 0.556 52 3.285 O.Oftl 53 3. Iftft 0.23? 54 l.ft86 1.792 ImS 0.283 0.703 0.010 0.001 0.018 0.800 0.080 0.059 0.011 0.115 0.60ft 0.1ft? 0.007 0.286 0.039 0.002 0.020 0.072 0.010 0.99ft 0.007 0.355 0.071 0.171 0.018 0.07? 0.120 0.005 0.430 0.005 0.095 0.096 O.Oftl 0.0ft9 0.029 0.056 0.039 0.060 0.162 0.300 0.081 0.95ft 0.15ft 0.520 0.228 0.709 1.79ft 0.521 0.821 l.ftftO 0.972 0. Iftft InSmt 25.ftft1 34.414 32.426 23.493 24.963 21.416 16.352 24.449 7.536 21.724 19.786 23.692 99.792 26.047 20.001 26.664 28.451 22.019 29.692 30.255 25.991 22.487 29.790 22.911 27.969 27.421 27.952 24.642 19.394 24.225 18.245 23.285 10.75? 1.190 25.525 22.992 16.190 3.380 23.996 24.412 22.674 9.06ft 15.782 26.92ft 19.05? 16.716 6.07ft 9.510 19.491 22.695 20.001 12.565 15.566 19.2*6 Oth+r 0.155 0.243 0.060 0.912 0.063 1.913 2.199 0.37ft 2.06ft 1.498 2.720 1.70ft 2.031 0.692 e.ftft? 0.232 0.196 1.70ft 0.909 0.96ft 0.976 C.ftfft 0.660 0.136 0.140 0.76? 1.99? 0.186 0.101 0.112 0.069 0.523 0.163 0.210 1.146 0.256 0.150 0.107 0.973 0*093 0.170 0.296 1.360 0.759 0.101 0.091 1.215 0.591 0.279 2.499 0*726 0*302 UmHi 16.17ft 0.336 l.ftftS 2.698 0.319 0.80? 1.173 3.212 1.945 7.203 0.109 9.019 3.212 14.346 22.991 1.905 3.9ft? 9.510 20.886 0.38? 1.675 0.11ft 20*856 6*260 0.08ft 0.235 7.131 13.558 19.818 0.040 0*539 0.045 0*011 0.018 0.02ft r*ti 35.973 95.478 92*588 24.743 25.296 25.156 20.942 23.660 29.84ft 29.393 22.778 35*860 33.762 26.166 24.625 27.40? 36.10? 24.533 28.222 30*255 27*141 24*604 31*796 24.952 39.759 29.999 30.539 27.471 29.234 24*559 24*073 27*199 35.960 25.000 27.77? 28.614 26.114 24.910 34.678 27*625 34.179 25.171 25*492 31*123 23.999 25.994 34*985 24*942 33.292 24*734 34.477 20.630 20.567 23.036 SAL 000001054 WESTERN STATES PETROLEUM ASSOCIATIOl 505 N. BRAND BLVD. - SUITE 1400 GLENDALE, CA 91203 (818) 545-4105 DATE: TO FROM 1/19/89 BIG, Prop. 65 Steering Group Elsa Evershade The following listed publications or materials have been received by WSPA. As indicated below, the report is available from WSPA or from other sources as indicated. If the document is available from WSPA, please fill out the form below and mark which document (s) you are interested in receiving and return to the above address. ATTENTION: BARBARA CHICHESTER NAME: ADDRESS COMPANY Publication or item Review of the History and State of the Art Regulatory ; . *' Risk Assessments of Benzene" Publisher/Source Address (Cost, if anvl Cox and Ricci SAt- 000001055 Chevron Chevron Environmental Health Center, Inc. A Subsidiary of Chevron Corporation 15299 San ftblo Avenue, Richmond, California Mail Adtfras RO Boi 4Q54, Richmond. CA 94804 0054 January 18, 1989 Product Evaluation and Community Health fl. 0. Cavalli Managar G. H. Bureau Pairoriiamealj J. i. Ford ftjteifcs M. 1. Lakin fttroleum J. L Toney Kaard Information R. M. Wilkenfeld Commvnny Haalth Cox and Ricci Draft Report 1/19/89 To: BIG/Prop. 65 FYI From: Elsa Evershade coe>o CiO Jin Bonin Dick Cavalli Cosmo Diperna Diane Defidellbus Elsa Evershade Scott Folvarkov - Shell, Houston - Chevron Evn. Health - Mobil, Princeton - Mobil, Los Angeles - VSPA, Los Angeles - Unocal, Los Angeles Michael Kahl - K&hl Associates Mark Nordhelm - Chevron Corporation Jerry Ross - Chevron Corporation Dick Russell - Exxon, Houston Randy Roth - Arco, Los Angeles Gordon Turl - Texaco, Los Angeles Enclosed, for your review, is a copy of the draft final report from Drs. Cox and Ricci entitled "Review of the History and State-of-the-Art Regulatory Risk Assessments of Benzene." As you can see from the bulk of the report, it is somewhat longer than we initially anticipated. This apparently resulted from an increased number of issues being addressed than that originally specified in their proposal. Any initial comments that you could provide at the January 26 VSPA meeting would be appreciated. In order to finalize this document in a timely manner, however, X would like to receive formal comments by no later than Friday, February 3. Thank you for your cooperation. Sincerely, Robert H. Vilkenfeld, Ph.D. Senior Toxicologist RMV:pdl-c/01B9-091 Attachment cc: R. Strieter - API, Washington, D.C. Files (2) - v/attachment SAL 000001056 Report Document 89-W-l QObDtfZ Cox and Ricci, 1989 REVIEW OF THE HISTORY AND STATE-OF-THE-ART OF REGULATORY RISK ASSESSMENTS OF BENZENE Draft Final Report for Review by Louis Anthony Cox, Jr., Ph.D. January 12, 1988 Prepared for Discussion with the Western Oil and Gas Association by Cox and Ricci WOGA Reference: Proposition 65 Special Account SI 144-03 SAL 00000X057 Executive Summary V This report sumnarizes and critically evaluates the state-of-theart of regulatory risk assessments of human health risks frcsn exposure to benzene. Its primary purposes are to describe the technical, scientific, and empirical bases for current benzene risk assessments and to offer an independent assessment of the duplications of this available science base, taken together with the remaining scientific uncertainties, for conclusions about the probable human health effects of exposures to concentrations of benzene that are likely to occur in practice. As part of these tasks, we also revi/ and comment on the recent history of benzene risk assessnents in this country. We emphasize the conclusions and policy positions toward benzene taken by various regulatory agencies, particularly the Occupational Safety and Health Administration (OSHA) and the Environmental Protection Agency (EPA), that are responsible for designing standards to protect occupational and public health. Throughout the report, we concentrate primarily on the risks of leukemia, which is the human health effect most strongly associated with high levels of exposure to benzene in occupational populations. Our principle conclusion is that the human health risks from exposure to benzene are extremely sensitive to both the time pattern (or "regimen") of exposure and to details of individual biochemistry that vary substantially across individuals and systematically across sexes, age grojps, and -- for animal studies -- across species and strains. These sensitivities are based on the biology of benzene- -1- SAL 000001058 induced leukemogenesis, which differs significantly fran the biology of other cancers, such as carcinomas, that are usually modeled in quantitative risk assessments. in particular, benzene exposure has dynamic effects on cell populations in the blood-forming system that are quite different fran the usual effects of chemical carcinogens on target cell-pcpulaticns. These effects make the mathematical models usually used for dose-response modeling inappropriate for benzeneinduced leukemogenesis. A. General _Qmclusions; Current Risk Estimates are Poorly Supported We end up being quite critical of past regulatory risk assessments of benzene health effects. A major finding, at nrirfg with our inititial iirpressions based on regulatory rulemaking documents in the Federal Register, is that past risk assessments do not provide sound arguments or justifications for drawing inferences about the effects of exposures to benzene at concentrations between 0 and 10 parts per million (ppm), which is new the range of greatest concern for regulatory policy. Virtually nothing is really known about human health effects at these concentration levels. Regulatory risk assessments have extrapolated risks down to these levels and have expressed considerable confidence in the results. Our examination of the empirical evidence and methodologies used has convinced us that this confidence is misplaced: the extrapolations are based on unsound assumptions, modeling methods, and data analysis techniques, and their results have little credibility based either on the modeling methods used to derive them or on cotparisons with empirical observations. -2- SAL 000001059 One reason for this state of affairs is that, without exception, the risk assessments cn which current regulatory positions are based have made an assumption that risks of leukemia depend an exposure history only through cumulative (or weighted cumulative) exposures, measured in ppm-years or in lifetime average ppm. This assumption has enabled investigators to extrapolate frcm estimated exposure-response relations observed at concentrations of dozens or hundreds of ppm in occupational settings and in animal experiments to exposure-response relations and corresponding risk estimates at low concentrations (belcw 10 ppm.) Hbwever, the fundamental assumption that risk depends only on ppm-years of exposure is almost certainly wrong. The biology of benzene metabolization and leukemia induction, although not yet completely understood, is understood in sufficient detail to strongly suggest that leukemia risk depends dynamically and nanlinearly on the detailed benzene exposure history (the time-series of concentrations experienced) rather than only on the cumulative exposure. This expectation based cn biological theory has been strongly confirmed in animal experiments that show that smaller total cumulative doses of benzene can create larger leukemia risks than larger cumulative doses that are administered more gradually. It ~rirm~ likely that in human populations, too, short-duraticn, high-concentration doses contribute disproportionately to leukemia risk. The fact that this relationship has implicitly been assumed away in current regulatory risk assessments, by the use of ppm-years as the relevant measure of exposure, biases their risk estimates and provides a biologically unsound basis for their extrapolations of risk projections to lew concentration levels. -3- SAL 000001060 In addition to this major concern, we have identified many errors and biases in the risk analysis methodologies used to derive current regulatory estimates of benzene risks. Most of the biases that we have been able to analyze tend to lead to artifactually inflated risk estimates. It is therefore likely that their net effect is to system atically overstate the risks from usual patterns of benzene exposure. Thus, current regulatory policy and positions may be based on exaggerated estimates of the true risks front benzene exposure. In arriving at these conclusions, we have reviewed risk models and modeling approaches, the basic biology of benzene leukemogenesis (as far as it is known), the state-the-art in statistical approaches to data analysis supporting benzene risk assessments, the animal and epidemiological databases used to derive risk estimates, and the arguments for and against the currently accepted risk estimates in regulatory proceedings. Our conclusions in each of these areas are summarized below. Although one of our initial goals was to identify current regulatory positions that are well-supported by current science and sound risk analysis methodology and to distinguish them frcsn positions that are now obsolete or poorly supported by current science, we have only partially succeeded in this task. It seems to us in retrospect that none of the current regulatory positions is adequately supported; moreover, we believe that fundamentally different risk modeling approaches that pay greater attention to the biology of benzene toxicology and leukemogenesis (which interact) will be necessary to achieve defensible conclusions about benzene risks at low concentration levels. -4- SAL 000001061 /4 BENZENE CONCENTRATION IN AIR FOR 1 X 10~ RISK RISK ESTIMATE CALIFORNIA (ANIMAL STUDIES) 1985 CAG (HUMAN STUDIES) 1985 CAG UPDATE (CLEMENT) NON-LINEAR MODEL WITH LINEAR COMPONENT (CLEMENT) NON-LINEAR MODEL (CLEMENT) PPB BENZENE 0.006 0.09 0.3 1 80 SAL 000001062 MAXIMUM EXPOSED INDIVIDUAL (HEI) I HEI USED TO CALCULATE RISKS TO RESIDENTS NEAR FACILITIES SUBJECT TO CONTROLS. EPA'S SECTION 112 ESTIMATE: EXPOSURE AT 22 PPB FOR 29 HOURS/DAY FOR 70 YEARS PROBABILITY: < 2 IN ONE HUNDRED MILLION API'S PROPOSAL: 1/ EXPOSURE AT 2.3 PPM FOR 22 HOURS/DAY FOR 35 YEARS PROBABILITY <1 IN 8000 (99.99%) SAL 000001063 ANALYSIS OF OHIO PLIOFILM SOLID TUMOR DATA ALL SOLID TUMORS CANCER OF DIGESTIVE SYSTEM CANCER OF RESPIRATORY SYSTEM CANCER OF PROSTATE NO DOSE/RESPONSE RELATIONSHIP TOTAL COHORT N - 1172 OBS SMB 95% .Cl 56 93 78-121 16 89 51-195 18 76 95-121 9 109 29-278 SA t 00000X064 Interoffice Communication TO: Environmental Council/Safety & Occupational Health Council/ P.L. Youngblood FROM: V. D. Broddle DATE: October 28p 1988 SUBJECT: PROPOSED BENZENE AIR EMISSION STANDARD The Environmental Protection Agency is required by Section 112 of the Clean Air Act to establish national emission standards for hazardous air pollutants (NESHAPS). The NESHAP is developed so the pollutant concentration in ambient air is sufficiently low to provide an ample margin of safety in protecting public health. The pollutants regulated are those having no Ambient Air Quality Standard (AAQS) and are capable of causing increased mortality or serious (reversible or irreversible) illness. Benzene fits this definition since repeated exposure to high concentrations can cause blood abnormalities, including certain types of leukemia. Previous NESHAPS, including the existing one for benzene, have been set by EPA using a one-step approach where both health risks and non-health issues (cost, improved technology, alternative chemicals, etc.) were evaluated simultaneously. The health risks for cancer have been derived from ultra-conservative mathematical models that yield an upper-bound cancer risk (95% confidence limit). In 1987, the U.S. Court of Appeals/District of Columbia Circuit concluded after reviewing the lawsuit of NRDC v. EPA, which involved the vinyl chloride NESHAP, that each NESHAP should be based on two steps, as follows. Step 1: EPA sets an acceptable pollutant exposure concentration based on health data and health risks alone. Step 2: The final acceptable ambient air concentration is then set after including an ample margin of safety and after considering both the uncertainty of the health data and the economics, technology, etc. involved with controlling pollutant emissions. Note that the second step must allow an ample margin of safety in minimizing health hazards and can not result in a higher ambient air concentration than was set by Step 1 where only health risks were considered. The proposed benzene NESHAP proposal appeared in the Federal Register on July 28, 1988 (pp. 28496-28502). A copy of this proposal can be supplied upon request. Five types of sources are addressed: - Ethylbenzene/Styrene Process Vents - Benzene Storage Vessels - Coke By-Product Plants - Equipment Leaks The only standard that potentially affects Conoco is the one for equipment leaks. the same source which the current NESHAP controls. The present proposal contains the same exemption for plants whose SAL 000001065 Environmental Council/Safety & Occupational Health Council October 28, 1988 Page 2 industrial streams are below 10% benzene and most Conoco operations would qualify under this exemption. An exception would be limited operations at the Lake Charles Refinery. The EPA proposal lists the following four (4) options for setting acceptable health risks (see Attachment): -4 Approach A - Lifetime cancer risk would be set at 10 (1 cancer in 10,000 exposed people) or less. The risk analysis would simultaneously consider the uncertainties of the health information, applicability (biasness, inherent assumptions, etc.) of cancer risk mathematical models and quality of the health information. For equipment leaks, the 1984 NESHAP provides an ample margin of safety. Approach B - The cancer risk is set at one cancer in the nation per year per source category (ethylbenzene-styrene process vents; benzene storage vessels; equipment leaks; and coke by-product recovery plants). For equipment leaks, the 1984 NESHAP provides an ample margin of safety. Approach C - Set the lifetime cancer risk at 10 -4 but do not consider the relative uncertainties of the data base until Step 2 (ample margin decision) is reviewed. For equipment leaks, eighty percent (80%) of affected plants would be forced to close. Approach D - Same as Approach C but the acceptable cancer risk is 10 or lower. For equipment leaks, all affected plants would be forced to close. Conoco did not submit comments on the proposal because our operations will be generally exempt. However, since this EPA action is important from a precedent setting standpoint, we assisted with comments prepared by API or Du Pont. A few highlights of these comments follows: API o API favors Approach A but the quantitative risk analysis should be used to derive a MOST PLAUSIBLE cancer risk, but not the usual EPA ultraconservative MAXIMUM UPPER-BOUND cancer risk. API's contractor, Clement Associates, Inc., has used new information on benzene health effects to propose a new mathematical model which predicts benzene's cancer risk to be 0.1-10% of the present EPA risk values. Clement's values seem more reasonable since OSHA or EPA values predict a 1% excess incidence of leukemia when benzene exposure Is the OSHA standard of 1 ppm for 40 years (8 hrs/day, 5 days/week). This excess would nearly double the total observed incidence of leukemia in the U.S. However, it is comforting to know that refinery fenceline benzene concentrations are 0.001-0.005 ppm. SAL 000001066 Environmental Council/Safety & Occupational Health Council October 28, 1988 Page 3 o API also stated that the petroleum industry adequately controls benzene emissions so that human health is protected and industry's voluntary emission controls continue to be improved. API thought EPA should consider that benzene exposure occurs from both industrial sources and non-Industrial sources (food, decaying organic matter, cigarettes, etc.), as follows: Average American Intake of Benzene Food (fruits, vegetables, milk products, meats, beverages, nuts, etc.) Air (urban air averaging 16 ppb) Water (public water averages < 0.5 mcg/1) Cigarettes (2 packs a day) 250 mcg/day 600 mcg/day 1 mcg/day 990 mcg/day Total: 1841 mcg/day DU PONT o Du Pont also favored Approach A (10 -4 cancer risk with database uncertainties factored in on a case-by*case basis). Mechanisms of carcinogenicity or detoxification should be incorporated so that the risk is not overly conservative. Without these changes, EPA's approach to risk assessment is too conservative and inflexible. o EPA's exposure evaluation Is too conservative (24 hrs/day for 70 years) and workplace or fenceline air concentrations do not reflect the lower exposure concentrations that occur with the general population. This completes my comments on the benzene NESHAP proposal. The benzene NESHAP itself will not affect Conoco greatly, but its implications are significant to industry. The final rule is expected next summer. This benzene NESHAP proposal contains two options (Approaches C & D) that could cause a loss of 3,000-35,000 jobs in the affected industries. Future NESHAPS will likely affect Conoco operations if EPA opts for stricter regulations resembling Approaches C or D of this proposed benzene NESHAP. W. D. Broddle /cjs Attachment SAL 000001067 4 9-m -ow* 1003 w rrm TABLE 1-1- SIMtARY OF ESTIMATED BCOHOMSC IMPACTS OF AMPLE MARC IN OF SAFETY DECISIONS UNDER TUI ALTERNATIVE POLICY APPROACHES Approach A; C>n*bif-C>n Annual encrtl ooit, Altlloq S/y* Cloeura/Mo. of faclUtlaa ^Jobe loot Approach t. <1 coa/vg Annuel control coot* nillion $/yr ^Cloour/No. of iMlUtlai - Job* loot Approach Ct <1 10 * Annual oontrol aoot, 111ion 6/p* W Cloowra/No. of feell&tlop -^Jabo loot Approach D: -6 <1 a 10 Annual control mat* ntllloo $/pr -'?Clooura/No. of fecllltlea >^Job loot Ethylbansam/Styrem rre* y*flti Mo additional coot. 0/1) Mom Sana aa above. Sana aa ebovo- Unknown 6-6/1)*.4 Unknown Santana Stores* yfwn 0.1 0/126 Mom San* aa abovo. Sana a* abovo. Unknown Unknown/126 Unknown EauLfoat Leak* Coko Bv-frorfuct Ploflto da additional aoat. o/m Mom 16 0/** Mom Sana aa abovo. Sana ao abeva Unknown* but at iaaot U. 16 aoatrola mm appUad. 100/m -f/.OOfl* Unknown m/m -os.ooo* UNrnawn* but at lat S6> A cloourte and I with cadusad production/** *61 lop* of aako productloo capaolty- Unknem but ot loact 26 U oootrplc ware PpU*d */** 7.000* *Tho coat of cloaura la not included and cannot ba aatioatad at (hie tlaa. Cloaura ootlnato la ftoj bated on eeononis faaclblUtp. iitiMit raprosantc only joba that would ba dlraatly effected by laur o< plante. Mp aU*etp can bp node for Job loatoa in paaPeUttd induatplpa. Thlo ttuaati l* only a rouph approainctlon af job loaaeeCEatlnaca derived fro* maaber of faollUlaa with natealooa aacaedlnp 2 M*/yr. Rente rallocte variation In anount.of additional roductlan required. ^Thaep foclllttae aro alto affectod by atandard for aqulpnent laaka- Thuo, eatuel ounhor of cloeurpc will ba dofpmlnod bp tb* p^ilpnant laak ptondP**- /Federal Register VoL S3, N o.! / Thursdsy, |aly 19M / Proposed Relee CO 'O o r-4 o o o o o McCuntock, Kirwan, Benshoof. Rochefort & Weston c.NV & OHb ATTORNEYS AND COUNSELORS AT LAW 444 SOUTH FLOWER STREET. FIFTH FLOOR LOS ANGELES. CALIFORNIA 90071 JAN 13 1989 ?C!VC A LAM PARTNERSHIP INCLUDING PROFESSIONAL corporations TELEPHONE <213) 623 2322 TELECOPIER (213) 623 062-4 December 23, 1988 Jerry W. Ross Senior Counsel Environmental Law Department Chevron Corporation Post Office Box 7141 San Francisco, California 94120-7141 Re: Petition For Review Re Benzene Range of Risk Dear Jerry: Enclosed for your review is a draft Petition for Review of the DHS range of risk for benzene. As I mentioned in our meeting, Health and Safety Code Section 39662 provides that determinations made pursuant to the listing section are reviewable. Arguably, the only "determinations" the ARB makes during the listing process are whether to list the substance as a toxic air contaminant and, if so, whether there is a threshold level. The attorney for the ARB has expressed the opinion in the past that the ARB makes no determination with regard to the range of risk and that, therefore, the risk numbers are not reviewable. For this reason, there is quite a bit of detail describing how the risk numbers are an integral part of the entire listing process and how they are subsequently used both by the ARB and SCAQMD to justify regulatory decisions without providing an opportunity for rebuttal or reconsideration. I am trying to build a case that the ARB should liberally construe section 39662 to provide an opportunity for review, since as a practical matter this may be the only vehicle available. SAL 000001069 PETITION FOR REVIEW PURSUANT TO HEALTH AND SAFETY CODE SECTION 39662 REGARDING UNIT RISK NUMBERS FOR BENZENE This petition is filed on behalf of the Western States Petroleum Association ("WSPA" or "Association") which represents many of the producers and refiners of petroleum products in the Western United States. The Association is seeking review of a determination made by the Department of Health Services ("DHS") and the Air Resources Board ("ARB") pursuant to Section 39662(e) of the California Health and Safety Code. Specifically, WSPA requests review of the risk estimates (range of risk) developed by DHS and ratified by ARB as part of the identification of benzene as a toxic air contaminant ("TAC") in January of 1985. This petition does not ask that benzene be removed from the list of toxic air contaminants, only that the range of risk calculated by DHS at 22-170 excess cancer cases per million population per part per billion benzene be revised in light of newly developed data showing that the DHS risk estimate significantly overstates the risk from exposure to benzene. The new data show: 1. The lower end of the risk range, which is based on EPA's evaluation of human epidemiological data (Rinsky), should be revised downward. 2. Reanalysis of the Rinsky data based on refined worker exposure histories and job codings, as well as three additional years of "Worker follow-up, SAL 000001070 1. The Identification Of Toxic Air Contaminants The ARB has been given the authority to identify and regulate toxic air contaminants pursuant to Chapter 3.5 of Division 26 of the Health and Safety Code.1 The identification process with which we are concerned begins with a request to the DHS to "evaluate the health effects and prepare recommendations" regarding a substance selected by the ARB. The DHS is required to "assess the availability and quality of data on health effects, including potency, mode of action, and other relevant biological factors, of the substance." (Section 39660(c).) The DHS* written evaluation presented to the ARB must: "Contain an estimate of the levels of exposure which may cause or contribute to adverse health effects and, in the case where there is no threshold of significant adverse health effects, the range of risk to humans resulting from current or anticipated exposure." (Section 39660(c).) The DHS* evaluation of the scientific data, calculation of the range of risk, and recommendation regarding whether to list the substance as a toxic air contaminant and, if so, the appropriate threshold are developed without formal input from the public. While drafts are not circulated for review and comment and no workshops or public hearings are held on the DHS' initial 1 All references are to the California Health and Safety Code unless otherwise noted. 3 SAL 000001071 includes the recommendation as to whether the substance should be listed as a toxic air contaminant. (Section 39662(a).) It is based upon this record that the ARB makes its determinations with regard to listing a substance as a toxic air contaminant. At the listing hearing, the ARB is directed to determine whether the substance under consideration is a toxic air contaminant. Further, the ARB is directed to do the following: "If a substance is determined to be a toxic air contaminant, the regulation shall specify a threshold exposure level, if any, below which no significant adverse health effects are anticipated. In evaluating the nature of the adverse health effects and the range of risk to humans from exposure to a substance, the State Board shall utilize scientific criteria which are protective of public health, consistent with current scientific data.11 (Section 39662(c) and (d) .) 2. The Range Of Risk Numbers Are Used Throughout The Air Toxic Regulatory Process And Bv Other Agencies Following the identification of a substance as a toxic air contaminant, the Health and Safety Code sets forth the procedures for regulating emissions of such substance. The first part of the process involves the preparation of a report "on the need and appropriate degree of regulation for each substance which 5 SAL 000001072 petition.] Other regulatory agencies also use the risk estimates adopted by the ARB. The South Coast Air Quality Management District ("AQMD") uses the upper end of the range of risk as the basis for decisions on whether to grant or deny permits to construct or operate. The South Coast AQMD has proposed rules to govern the permitting of new or modified sources that emit toxic air contaminants. (Proposed Rules 223 and 1401.) Attached to proposed Rule 223 is a list of toxic air contaminants along with their unit risk factors. (Table 1.) Footnote 1 to Table 1 states that: "Unit risk factors presented here are those developed by the California Department of Health Services (DOHS) and published in a staff report pursuant to Health and Safety code. Section 39661, for those substances identified as a toxic air contaminant by the Air Resources Board (ARB) and listed in Title 17, California Administrative Code, Section 93000." While proposed Rules 223 and 1401 have not been formally adopted by the South Coast AQMD, the District has nevertheless been subjecting permit applications to this process informally, relying on authority it claims under the California Environmental Quality Act to avoid significant adverse environmental effects. 7 SAL 000001073 As part of the air toxics program and other regulatory activities concerning toxics which called for the preparation of risk assessments, the DHS issued a general cancer policy. The policy, which is entitled "Guidelines for Chemical Carcinogen Risk Assessment and Scientific Rationale" ("Guidelines"), was issued in November of 1985 although its development began in ______. The Foreword to the cancer policy states that: "The purpose of this document is to enumerate the guidelines used by the California Department of Health Services in performing human health risk assessments for potential chemical carcinogens. This document is not regulatory in nature. The scientific underpinnings of carcinogen risk assessment are changing too quickly to attempt placing guidelines into law or regulation." The Guidelines contains a section on the need to update the policy from time to time. The document states that: "Since the science that underlies carcinogen identification and dose - response assessment is rapidly changing, it is important to maintain flexibility in risk assessment policy. To this end, the DHS does not propose advancing these guidelines as regulation. The DHS will update these guidelines approximately every three years and more frequently if necessary." 9 SAL 00000107 A- 4. The Benzene Risk Estimate Was Adopted Bv ARB Without Change And Has Been Used Bv ARB And Other Agencies As A Regulation During the public hearing to consider whether to list benzene as a toxic air contaminant, neither the ARB staff nor the Board questioned the range of risk numbers developed by DHS although evaluation of the range of risk is required by section 39662(d). Thus, the risk numbers were, in effect ratified by the Board without comment. Risk estimates are an integral part of the ARB's entire air toxics regulatory process and, as stated above, they have a significant effect on decisions as to whether certain sources will be regulated and, if so, to what extent. Because of their importance to the process, it is vital that the estimates be as accurate as possible and not overstate risk. Overstating risk results in unnecessary regulation. Similarly, the unit risk number for benzene used by the South Coast AQMD in its proposed toxics new source review and its informal toxics review policy is the upper end of the range of risk (170) developed by DHS and approved by ARB. Again, as in the case with the ARB staff, the South Coast AQMD staff has not done any re- evaluation of the unit risk number but has simply relied upon the DHS1 expertise. Thus, permit applicants are given no opportunity to question the validity of the unit risk numbers when regulatory decisions are being made. Once ARB list a substance based on the health effects evaluation, ARB and other agencies treat the risk 11 SAL 000001075 prepared a statement of reasons, and has available all the information upon which the proposal is based. Gov't Code 11346.5(a)(10). Similarly, the initial statement of reasons must identify each technical, theoretical and empirical study or report upon which the ARB is relying. Gov't Code 11346.7(a) (3) . In the case of listing a toxic air contaminant, the regulation is based on the health effects report, including the range of risk factors, and this information must be made available to the public for review and comment. Following public comment, the agency must prepare a final statement of reasons to accompany the adopted regulation. The final statement of reasons must include a summary of each objection to the proposed listing, and an explanation of how the proposed regulation has been changed in response, or the reasons for making no change. Gov't Code 11346.7(b)(3). Thus, if a comnentcr objects to the proposed listing by challenging the range of risk factors developed by DHS which form the basis of the decision to list, the ARB must explain how they have changed the determination to list or otherwise explain why no change is necessary. Since ARB did not change the benzene range of risk, even though it was disputed by the Western Oil and Gas Association, WSPA's predecessor, the ARB clearly made a determination to adopt the range of risk. 13 SAL 000001076 The first limitation concerned the information about individual worker exposures over time. The EPA had to perform its analyses by grouping observations into exposure classes. In addition, information developed subsequent to the EPA assessment during OS HA hearings on benzene led to a consensus that several of the epidemiology studies relied on by EPA (i.e. Aksoy, Ott / Bond and Wong) were inadequate for quantitative risk assessment, due to a lack of a dose-response relationship between benzene exposure and the development of cancer, inherent design limitations and confounding factors such as exposure to mixtures of potential carcinogens. The Clement analysis has relied on the same epidemiology study as that selected by OSHA, that of the Goodyear pliofilm workers (Rinsky, et al) . The Rinsky data were further refined in the Clement analysis by inclusion of detailed work (exposure) histories on individual workers, correction of previous errors in job codings, and three additional years of worker follow up. This resulted in the generation of 1740 individual exposure profiles which are based on actual observations of the pliofilm workers and which provides a high degree of confidence for the new unit risk estimate. Second, in 1985 when the EPA performed its improved risk assessment, there was little information available concerning both the relationship between the time of exposure to benzene and the onset of leukemia (latency) and whether the increased risk following benzene was related to or independent of the background population risk of developing leukemia. Thus, the EPA was forced 15 QO0001077 SM- victims, mutagenicity studies on benzene and studies of genes involved in growth control and the differentiation of hematopoietic stem and progenitor cells. Based on these evaluations, Clement concluded that a non-linear (quadratic) model, predicting a multiple-hit mechanism (at a high dose) of benzene-induced leukemia, was the most plausible representation of actual risk associated with benzene exposure. While this finding of non-linearity may not be fully accepted by DHS - ARB staff scientists and reviewers without more extensive peer discussion, there should be little controversy over use of the more complete exposure information and the extensive, new statistical analyses which serve to provide a more accurate linear (one-stage) model. Such acceptance will not compromise the extremely conservative risk assessment policies which currently guide FPA and DHS. In fact, modifications to the model had only minor influences on this new unit risk estimate, since the modified model is linearized based on actually observed data. The lower risk estimate is primarily due to the use of the weighted cumulative form of latency distribution and the calculation of the transition rate from exact time-dependent exposures of each of the 1740 individuals in the cohort. The resulting unit risk estimate, based upon this modified linear model, is a number which is an order of magnitude lower than the initial EPA estimate. Based on these findings, the initial EPA unit risk estimate at 1 ppb of 26 x 10-6 is recalculated to 3.48 x 10-6 based on the more accurate, modified linear model. The quadratic (two-17 17 SAL 000001078 The preliminary draft was reviewed and the informal request for reevaluation of the DHS / ARB risk estimate was denied. The reasons given for the denial were the preliminary nature of the work and lack of peer review. Since that tine, the Clement report has been finalized, addressing the concerns raised, and the process of peer review has been initiated. We expect that the peer review will be concluded by WSPA believes that the Clement report, in its finalized form, is now at a stage to provide the basis for a formal petition for review pursuant to Health and Safety Code Section 39662. Accordingly, WSPA has filed this petition for review requesting that the ARB direct the DHS to re-evaluate its range of risk for benzene based upon the additional scientific evidence now available concerning the health effects of benzene -- evidence which was not available at the time of the original determination - and based upon the recognition that primary emphasis should be placed on human epidemiological data, rather than animal data, when adequate human data are available. In addition, WSPA requests that this review be expedited so that a revised range of risk is available for the Board's consideration prior to the hearing on the proposal to reduce the benzene content of gasoline. Respectfully submitted, McCLINTOCK, KIRWAN, BENSHOOF, ROCHEFORT & WESTON Sharon F. Rub^lcava 19 SAL 000001079 Benzene it a/hnajqt commodity chemical of great value to industry. It has long been recognized that overexposure to benzene /coulp result in damage to the blood-forming organs of the body. More recently, it has become pparent that chronic high levels of exposure are associated with the development of leukemia. Animal experimerjls haye also suggested that overexposure to benzene may result in certain reproductive risks. '/ Benzene in the workplace RICHARD S. BRIEF. JEREMIAH LYNCH*. TIBOR BERNATH and ROBERT A. SCALA Exxon Corporation, Medical Department. Research and Environmental Health Division, Box 235, East Millstone, NJ 08B73; AExxon Chemical Company, Medicine and Environmental Health Department. Box 235. East Millstone, NJ 08873 introduction Until recently the primary concern has been occupational a byproduct of steam-cracked naphtha and by dealkylation exposure to benzene. Now the possible environmental effects of benzene on the community are also of concern. of toluene. The remainder (6%) is produced as a byproduct of the coking process in steel-miiis. In 1976, ii billion Benzene is ubiquitous, since it is a natural constituent of crude oil as well as of a wide variety of manufactured chemicals and fuels. A measureable background of benzene exists worldwide, but at levels considered to be acceptable. pounds of benzene were produced in the U.S. and production is projected to increase as the demand for benzene derivatives increases. Industrial uses of benzene have included preparation of derivatives such as polymers, Higher concentrations capable of producing both reversible and non-reversible health effects may exist in industry and he risk to humans is a function of the concentration of jenzene in the air, the exposure time and the susceptibility of the individuals. However, the human risk can be controlled by a combination of control measures including ventilation, work practices, and personal protection. Methods of measuring worker exposure to benzene and benzene concentrations in ambient air have been developed. These methods have adequate sensitivity to measure benzene at levels well below those which are toxic, and detergents, pesticides, and intermediates in the chemical and pharmaceutical industries (95% of demand in the U.S.), preparation of chlorinated solvents, extraction and rectification, in the rubber industry, in cements and adhesives, as a component of inks in the priming industry, as a coatings thinner, and as a degreasing and cleaning agent. Benzene is also present in motor fuels, averaging less than 2 vol. % in the U.S. and 4-5% in Europe, although some European blends may run as high as 8 vol. % at times where steam-cracked components are regularly present. sampling strategies are available for a variety of exposure limits and work situations. Improved systems to minimize human exposure are needed since benzene will continue to be a valuable chemical commodity and a direct or indirect additive to a wide variety of materials found in industrial societies worldwide. properties and technology0'*1 Benzene (OHe) or benzol, as it is sometimes called, is the parent hydrocarbon of the aromatic group. Benzene is a colorless, clear liquid with a density of 0.87 g/cm3 (20 C) and a boiling point of 80.4 C. It has a melting point of 5.45.5 C, a vapor pressure of 74.6 mm Hg at 20 C and a flash point of 12 C. Benzene is slightly soluble in water and miscible with alcohol, chloroform, ether, carbon disulfide, acetone, glacial acetic acid and carbon tetrachloride. Its characteristic odor can be perceived at levels as low as 1 or 2 vppm. Its relatively high volatility allows concentrations potentially hazardous to workers and to other exposed persons to be reached when benzene is released into the environment in sufficient quantities. Benzene is produced primarily (94% of U.S. production) from petroleum by catalytic reforming of light naphthas, as toxicology12"41 uptake and elimination At least since 1900, benzene has been recognized as a toxic substance capable of causing acute or chronic effects. Inhalation is the primary route of entry into the body. Benzene diffuses rapidly through the lungs and is quickly absorbed into the blood with the rate of absorption greatest at the beginning of exposure. Benzene content of the circulating blood may reach as high as 70-80% of equilibrium levels with respect to the air content within the first 30 minutes, with an additional 2-3 days of exposure necessary to produce complete saturation. Vapor absorption through intact skin is of minor importance, but this route of entry may become a hazard when liquid benzene comes into direct contact with the skin. The benzene absorbed by the circulating blood is distributed throughout the body. Since benzene is liposoluble, it tends to accumulate in organs in proportion to their fat content. The highest levels are found in the bone marrow, followed by fatty and nervous tissues. The concentration of benzene in the expired air following benzene exposure falls along an exponential decay curve with three distinct phases.>M This elimination has been Coevrigta I MO, American lnduirial Mygian* Aaaocialion sis Am M Hyg Assoc. J(41) September 1980 SAL 00000108 described by a three-compartment model with biological half-times of 2.5, 28 and 90 hours and reflects a differential clearance of benzene from various tissues. For example, sixteen hours after cessation of exposure the compartment with a biological half-time of 28 hours contributes about 75% of the benzene concentration in the exhaled breath. In humans, pulmonary clearance accounts for 12-50% of the total absorbed dose of benzene. Benzene is metabolized by liver enzymes to derivatives which are more water soluble, thereby facilitating their removal by the kidneys, the first intermediate in the biotransformation of benzene is believed to be benzene epoxide, a highly reactive intermediate and one of several candidates suggested as the active agent responsible for the myelotoxicity of absorbed benzene. Phenol is the primary urinary metabolite, but hydroquinone, pyrocatechol and phenyl mercapturic acid may also be found as metabolites in the urine. scute toxicity *' The primary acute toxic effect of benzene is on the central nervous system and is seen initially at exposures above 250 ppm. Exposure to massive concentrations, around 2.5% by volume in air (about 25 000 ppm) is fatal within minutes. The prominent signs are central nervous system depression and convulsions with death usually following as a consequence of cardiovascular collapse. Fatalities have occurred after benzene inhalation in closed spaces such as tanks. Severe non-fatal cases exhibit similar signs, but recovery occurs after a period of unconsciousness. Milder exposures (4000 ppm) produce euphoria followed by giddiness, headache, nausea, staggering gait, and finally unconsciousness if exposure continues. Inhalation of lower concentrations (250-500 ppm) produces vertigo, drowsiness, headache and nausea, symptoms which clear rapidly once exposure ceases. Deaths from cardiac sensitization and cardiac arrhythmias have also been reported after benzene exposure to unknown concentrations. chronic toxicity1*"^ Exposures above about 50 ppm for extended periods may induce changes in the bone marrow which result in decreased levels of platelets, red blood cells or white blood cells. In its most severe form, the damage to the bone marrow results in aplastic anemia. About 13% of these cases of benzene-induced aplastic anemia are fatal. The effects of benzene on the bone marrow may become irreversible unless benzene exposure is stopped. The signs of chronic benzene poisoning can appear any time following a few weeks to several years of exposure. Typical symptoms are rather non specific: severe fatigue, headache, dizziness, nausea, vertigo, stomach pain, loss of appetite or feeling cold. Chronic or intermittent exposure to atmospheric benzene concentrations exceeding 100 ppm carries a high risk of reversible cytopenias and pancytopenias. Aplastic anemia is a less frequent complication. While the scarcity of data make it difficult to reach a firm conclusion on the doseresponse relationship between benzene exposure and bone American Industrial Hygiene Association JOURNAL (41) 9/80 marrow disorders, exposures to benzene concentrations greater than about 50 ppm benzene in air predictably will produce blood effects in proportion to the amount of exposure. Prolonged or repeated skin contact may produce a dry, scaly dermatitis, erythema, and blistering. leukemia While aplastic anemia is a major complication of benzene toxicity, acute leukemias of the marrow-formed blood elements are the most feared. The evidence for benzene-induced leukemia rests largely on epidemiological grounds.'3'6'** Increased incidence of leukemia was observed in some industries (shoemakers, certain rubber products, etc.) where benzene in high concentration mixtures with other solvents was handled indoors and in unventilated systems. The clearest relationship between benzene exposure and leukemia was demonstrated in studies of benzene exposure prior to 1960 when high benzene concentrations (> 200 ppm) in the air were likely. The most common form is acute myelogenous leukemia. On the other hand, no increased incidence of leukemia was observed among workers employed in the petrochemical industries (outdoor, enclosed systems) or in coke-oven byproduct workers, despite the fact that the latter group of workers may have been exposed to high levels of benzene from fugitive emissions. In all well documented cases of benzene-related leukemia, victims had developed a previously detectable decrease in blood levels of one or more of the cell lines. The implications of these observations for the relationship between benzene exposure and leukemia are two-fold: (1) chronic exposure to high concentrations of benzene appear to be required, and (2) decreases in blood concentrations of platelets, leukocytes and/or red blood cells may be an important early warning of leukemia risk in workers exposed to benzene. Differences in individual response related to sensitivity (hypersusceptibility) have been observed and current research efforts are directed toward finding indices associated with this phenomena. Several studies by Vigliani12'31 have indicated chromosomal changes (aberrations) in peripheral blood lymphocytes, but no definite correlation (specificity, doseresponse, reversibility) between the persistence of these abnormal aberrations and the degree of benzene poisoning can be established. Animal experiments at New York University sponsored by the American Petroleum Institute (API) (unpublished) did produce leukemia by the inhalation route after prolonged exposure to high levels of benzene. Also, Maltoni191 has reported hemolymphoreticular neoplasias (leukemias) in animals by the ingestion route using benzene in olive oil. Inhalation studies are now planned to further define threshold limits for hematological changes associated with low-level benzene exposures in animals. reproductive effects Less well-studied and given far less consideration are the potential reproductive risks associated with benzene SAL 000001091 617 Benzene measurements around U.S. refineries and chemical plants handling benzene or benzene-containing streams ranged from 0.3-125 ppb in areas inside these facilities, 0.03-150 ppb in the vicinity of chemical plants, and 0.5-259 ppb in the vicinity of refineries. In Western Europe, community air close to industrial installations has been found to have a concentration of benzene about 1 /30th of the concentration present in factory air. Fugitive emissions during production, storage, transport, and commercial use were estimated by OSH A to be 79 X 106 pounds (36 X 106 kg) per year (1976).(2> This approximates 68% of the total produced. OSHA considers that the fugitive emissions are largely derived from petroleum cracking facilities, although the API does not agree. A recent study by Foster D. Snell Inc.0M in fact showed that actual benzene emissions from refineries, olefin plants and alkyl benzene plants were about 40% of earlier EPA estimates.1171 In 1974 EPA0<> indicated an order of magnitude greater loss than OSHA from benzene production, transportation and commercial use. Materials containing small amounts of benzene such as glues, adhesives, solvents and some household cleaning products also contribute to benzene exposure. Inadequately controlled handling of materials containing benzene, fugitive emissions and benzene in gasoline appear to be the major sources of exposure to the general population. Natural degradation of benzene is rather a slow process due to its stability. Nevertheless, limited research081 seems to indicate that removal from the atmosphere can occur substantially by phenolic conjugation in plants. Benzene is considered to be a moderately persistent contaminant and the levels measured in the general environment seem to support this thesis. benzene in gasoline Benzene is present in gasoline as a result of its natural occurrence in crude oil as well as a byproduct of the catalytic cracking, coking and reforming processes used in oil refining to roughly double the yield of gasoline per barrel of crude oil. Runion091 has demonstrated a linear relationship between benzene volume percent levels in liquid and vapor phase of gasolines, and has found that the concentration in the hydrocarbon fraction of the vapor phase is less than onehalf of its concentration in the liquid phase. He concluded that it would be difficult to exceed an 8-hour exposure of 10 ppm for benzene from exposure to gasolines containing 5% or less benzene if the total gasoline vapor concentration is kept below its acceptable concentration, nominally 300 ppmAmbient air benzene concentration051 in gasoline service stations has been reported in the U.S. in the range of0.3-3.2 ppm in one study and 0-1.7 in another. Other studies at service stations have identified levels of benzene only in the range of .024-.24 ppm. Higher levels of benzene exposure have been reported in gasoline bulk loading facilities with levels anywhere from 1.4-9.9 ppm to a few exposures at 2030 ppm, and even some up to 100-250 ppm. These large American Industrial Hygiene Association JOURNAL (41) 9/30 variations are due to the type of bulk terminal, the ambient temperature, whether top or bottom loading was employed, and the presence or absence of a vapor recovery system. The trend to reduce organic lead anti-knock additives has created a need to reformulate the gasolines to meet anti knock requirements. As a result, more gasoline components containing aromatics have been blended into recent fuels. While total aromatic content of gasolines is increasing, no major changes in the exhaust composition are anticipated other than a tendency toward increased aerosol formation. industrial exposure The highest levels of human exposure to benzene occur in the industrial setting. The National Institute of Occupational Safety and Health (NIOSH) estimates that some two million workers in the United States have potential exposure to benzene. Historically, the levels of exposure varied greatly from process to process, depending on whether they were open or closed systems. Some industrial exposures are known to have been as high as 1001000 ppm on a routine basis. Now, however, in our judgment, industrial establishments with continuous levels over 50 ppm TWA must be very rare. In petroleum refineries during normal operations, there is a low probability (<5%) of benzene levels exceeding I ppm TWA and a negligible chance of exceeding 5 ppm. In petrochemical plants there is a somewhat higher probability of exceeding 1 ppm, but less than 8% probability of exceeding 5 ppm. This higher potential relative to refineries is related primarily to much higher benzene concentrations in the process streams and products. The likely activities wherein workers may be exposed to higher air concentrations would occur: by effluent treatment plants (such as API separators), during manual tank or stream sampling, during laboratory testing of the benzene-containing process materials, during maintenance when equipment containing benzene materials is opened or drained without adequate flushing, and during loading of ships, barges and trucks with gasoline or benzene rich streams, particularly if no vapor recovery or remote venting is employed. It is important to note that the available data tend to be biased on the high side because monitoring results often relate to activities where there are possibly higher than average exposures. With proper methods (engineering controls, personal protection and strict work practices) exposure to benzene can be reduced. Evidence in the refining and petrochemical industries indicate that a 10 ppm ceiling value can be achieved with few exceptions which can be managed by use of respirators. As a rule, unnecessary exposures to benzene could be eliminated or drastically reduced. Also, where benzene exists, its use in open systems, certain products (solvents, glues) and laboratories, especially under conditions of inadequate handling or without proper ventilation or other controls, should be avoided. SAL 00001082 619 The desorption methods are compared below. In eacn case the GC-FID method of separation and detection is used and the sampling tube contains a solid adsorbent. comparison of desorption techniques Solvent Desorption Heat Desorption The sample tubes ere used once Thetubecontemscanberepeat- edly analyzed Internal standards can be used Lends itself to automated analy sis Requires handling of toxic de sorbing chemicals Desorption efficiency must be determined for each batch of tubes The sample tubes are reusable The tube contents can be ana lyzed once or repeatedly de pending on the type of desorber used. Dosed tubes are closest approxi mation to internal standards Presently no automated method exists No chemicals are needed Desorption is essentially com plete Recently passive dosimeters based on free diffusion through a diffusion path or permeation across a membrane to an absorbant charcoal bed have become available commercially. From preliminary evaluations in our experience, passive dosimeters are less sensitive and not as accurate as the charcoal tubes when benzene is present in a mixture, but are useful for monitoring after the environment has been carefully evaluated with charcoal tubes. Passive dosimeters are more effectively applied to 8-hour average samples than 15-minute (ceiling) samples. The monitoring operation should be part ofa larger effort to contain and reduce benzene exposure. Other parts of a compliance policy should include engineering controls, protective clothing and equipment, respiratory protection, and appropriate medical surveillance. sampling strategy A sampling strategy130* devised for the OSHA standard of 10 ppm TWA is shown in Figure 1. For a 15-minute ceiling standard, the sampling strategy becomes more complicated due to the greater number of periods during which overexposure may occur. Since measurement of all possible exposure periods (thirty-two 15-minute samples per 8-hour day) is very difficult, several methods of reducing the sampling burden should be considered. The most direct method of finding the maximum 15minute exposure in an 8-hour day, short of measuring all possible periods, is to sample randomly some number of periods so as to be reasonably confident that the highest, or near highest, periods are measured. From statistics it is possible to estimate how many 15-minute samples must be taken per day to be sure, at a selected level of confidence, that at least one of the highest exposures that occurred during that 8-hour period is included in the sample. Specifically, if we wish to be 95% confident (only one chance in twenty of being wrong) that at least one of the top three 15-minute exposures occurring over eight hours were included, it would be necessary to collect 19 samples. To be only 90% confident (only one chance in ten of being wrong) 16 samples would be needed. While this is a reduction from. American Industrial Hygiene Association JOURNAL (41) 9/80 32 samples, it is still a very burdensome monitoring program. There is a relationship between levels of exposure found over one averaging time compared with those over other averaging times for log normal distributions. It has been found that most samples taken in industrial environments will approximate the log normal distribution (that is, the logarithms of the sampling data follow the normal distribution curve). Consider a 10 ppm ceiling limit and its relation with an 8hour time-weighted average. If only one 15-minute period reached 10 ppm during the workday and all others were zero, then the TWA would equal 10 X 15/480 = 0.31 ppm. Thus, if the TWA were below 0.31 ppm, the 10 ppm ceiling could not be exceeded. Actual industrial environments where benzene is present typically will show continuous variation in concentration over the day. Therefore, the maximum TWA for which it is unlikely that a 10 ppm ceiling would be exceeded in higher than 0.31 ppm. Extensive statistical evaluations of benzene measurements are available in the literature.The data fit a log-normal distribution with a geometric standard deviation (GSD) range of 1.5to4.5.The geometric standard deviation is the antilog of the standard deviation of the logarithm of the data. It can be calculated or obtained from a plot of the sampling data on log-probability graph paper. For example, in a refinery work situation with a GSD of 3.0, a TWA of 2.4 ppm would be expected when a 10 ppm ceiling was reached three times per shift. Consequently, if we can be confident that the TWA is below 2.4 ppm, then we would be equally confident that the 10 ppm ceiling was not exceeded more than three times per shift. Obviously, a lower TWA will provide greater confidence that this ceiling limit was not exceeded. The log normal distribution assumption has been found to fit observed industrial environments where exposures result from a multiplicity of small frequent events, but should never be assumed to predict infrequent events which may result in very high exposures. Thus, it is reasonable to augment control of ceiling exposure by keeping the TWA as low as feasible and by monitoring known unusual events which have the potential of causing high exposures using some number of 15-minute samples. worker exposure measurement Personal sampling of workers exposed to benzene is the preferred method of determining exposure. That is, the sampling device, either active (with its own pump drawing air near the breathing zone) or passive, is placed on the worker in order to integrate the sampling during the work day. This includes both work and rest periods and averages the concentration of benzene to which the worker is exposed. Area samples involve the sampling in work areas frequented by workers and then assessing the time that the worker spends in each of the areas. An adequate timeweighted average based on area samples can be obtained if there are adequate numbers of areas covered, the sampling is done frequently, and the time factors are accurately SAL 000001083 621 3.*Th National Research Council: Health Effects of Benzene. A Review. National Academy of Sciences. Washington, D.C. (1976). 4. A Critical Evaluation of Benzene Toxicity. Various Reviews. J. of Toxicology and Environ. Health 3:{Supplement) (1977). 5. Sharwood. R. J.: Criteria for Occupational Exposure to Benzene. Paper, International Workshop on Toxicology of Benzene. Paris (1976). 6. Jandl, J. H.: A Critique of EPA `s Assessment of Health Risk Associated with Atmospheric Exposure to Benzene. American Petroleum Institute. Washington. D.C. (1977). 7. Jandl, J. H.: A Proposal for a Program for Medical Surveillance to Detect Early and Reversible Changes Caused by Occupational Exposure to Benzene. Organization Resources Counselors. Inc., Washington, D.C. (1977). 8. Truheut, R. and R. Murray: Internat. Workshop on Toxicology of Benzene. Paris, November, 1976. Internet. Arch. Occup. Environ. Health 41:65-76 (1978). 9. Maltoni, C. and C. Scarnato: First Experimental Demonstration of the Carcinogenic Effects of Benzene. Med. Lavoro 5:352-357 (1979). 10 Wolf. M. A.. V. K. Rowe, D. D. McCollister, R. L. Hollingsworth and F. Ogen: Toxicology Studies of Certain Alkylated Benzenes and Benzene. Arch. Ind. Health 14.387398 (1956). 11. Teratology Study in Rats, Project No. 145-552. Final Report. Hazleton Laboratories America. Inc.. Vienna, Virginia (September 25, 1975). 12. Embryotoxicity of Inhaled Benzene in Mice and Rabbits. Report Code HET K-002661 -(11). Final Report. Dow Chemical U.S.A., Midland, Michigan (August 3. 1978). 13. Green, J. D., B. K. J. Leong and S. Laskin: Fetotoxicity of Inhaled Benzene in Rats. Toxicol. Appl. Pharmacol. 45:9-18 (1978). 14. Teratology Study in Rats. Project No. 20698-3. Final Report. Litton Bionetics, Inc., Kensington, Maryland (November, 1977). 15. Ollison. W. M.: Human Exposures to Atmospheric Benzene. A Review. American Petroleum Institute. Washington. D.C. (1977). 16. Gisser. P.: Benzene Emission Control Costs in Selected Segments of the Chemical Industry. Foster D. Snell. Inc.. Florham Park, N.V. (June 12.1978)(NTIS Report PB 283 781). 17. Atmospheric Benzene Emissions. EPA Publication No. EPA400/3-72029. EPA, Washington, D.C. (October. 1977). 18. Howard, P. H. and P. R. Durkin: Sources of Contamination. Ambient Levels, and Fate of Benzene in the Environment. EPA, Washington. D.C. (December. 1974). 19. Runion, H. E.: Benzene in Gasoline. Am. Ind. Hyg. Assoc. J. 36:338-350 (1975) and 36:391 -393 (1977). 20. Leidel, N. A.. K. A. Bush and J. R. Lynch: Occupational Exposure Sampling Strategy Manual. NIOSH Publ. No. 77173. NIOSH. Cincinnati, Ohio (January, 1977). 21. Jones, A. R. and R. S. Brief: Evaluating Benzene Exposures. Am. Ind. Hyg. Assoc. J. 32:610-613 (1971). 22. Hansen, D. A.: Survey of Benzene Occurrence in Ambient Air at Various Locations Throughout the United States American Petroleum institute Publication No. 4305, Washington, D.C. (December, 1976). 23. Lauwerys. R.: Review of the Biological Monitoring Methods for Evaluating Exposure to Benzene. Paper, international Workshop on Toxicology of Benzene. Paris (1976). 24. Piotrowski. J. K.: Exposure Tests for Organic Compounds in Industrial Toxicology. NIOSH, Cincinnati, Ohio (September. 1977). CALL FOR PAPERS The 21 st annual American Industrial Hygiene Conference for the 1981 will be held at the Memorial Coliseum, Portland, OR, May 24-29, 1981. American Forms for submission of titles and abstracts for papers may be Industrial obtained from the Managing Director's office, American Indus Hygiene trial Hygiene Association, 475 Wolf Ledges Parkway, Akron, OH Conference 44311 (216) 762-7294. All abstracts must be submitted no later than October 31, 1980. Papers will be presented from the platform or in poster sessions. If the author prefers a poster session, this should be indicated on the form provided. Depending on circumstances, it may be necessary to assign additional papers to the poster sessions, even though the author has indicated a preference for platform presentation. American industrial Hygiene Association JOURNAL (41) 9/SO ooooio0ii SAL o 23 ' -/ hygienic guide series f ; ;. American INDUSTRIAL HYGIENE ASSOCIATION Benzene (benzol) C6He CAS No. 71-43-2 Significant Physical Proportfes Benzene is a colorless, flammable hydrocarbon liquid having a pleasant, aromatic odor. Molecular weight: Melting poipt: Boiling point: Vapor pressure.: Solubility: Saturated air concentration: Specific gravity: Flash point: Conversion factors: (25 C and 760 mm Hg) 78.1 5.5C 80.IC 95 14 mm Hg at 25C 0.06% in water, infinitely soluble in alcohol, ether, and most organic solvents 125,000 ppm (39,600 mg; m3) at 25*C 0.879 at 20 C --12 to --10*C I mg/ m5 = 0.313 ppm I ppm m 0.32 mg/ m5 I. Hygienic Standards A. WORKDAY EXPOSURE CONCENTRA TIONS: Time-weighted average (TWA) concentrations (8 hours): 10 ppm ACGIH,"' OSHA (ANSI)0' 2 ppm USSR01 25 ppm Germany1" 1 ppm (NIOSH) revised recommended1*' B. Shortterm exposure concentra tion: SO ppm (10 min.) OSHA (ANSI) C. Ceiling concentration: 25 ppm OSHA (ANSI) D. Immediate lethal concentration: Single exposures to benzene vapor in air at 20,000 ppm may be fatal within 5-10 minutes.1 1 II. Toxic Proparties Benzene affects the hematopoietic system. There is some evidence that chronic exposures The Committee withes to tckaovMfe the NMsaec of Willard H. Baumans m the preparauea of this Hygieaie Guide. to benzene cause s progressively malignant disease of the blood-forming organs. Benzene affects the central nervous system Absorption of benzene through the skin is not an industrial problem A. INHALATION: Acute exposure concentra tions in excess of 3,000 ppm are irritating to the eyes, nose, and respiratory tract and upon continued exposure may cause exhilaration followed by dizziness, headache, nausea, and narcotic effects. The LC (4 hours) for rats is reported to be 16,000 ppm,11' and the minimum concentration causing death of a mouse, 14,100 ppm14' Rabbits exposed to 35,000 to 40,000 ppm exhibited excitation and tremor within 5 minutes and succumbed in 36 minutes.01 Repeated low-level chronic exposures have an injurious effect on the hematopoietic system. Human exposure to concentrations in excess of 150 ppm may cause head ache, weariness, loss o' appetite; and lassitude, with incipient blood effects including decreased red cell counts, mild lymphocytosis, cotinopenia. wtute cell count may remain unchanged.' `` At the condition progresKa, the blood atnionnaiities may be manifested first by anemia and leukopenia and tometimet macrocytotit and thrombocytopenia. There are considerable variations in both the individual tuaceptibility to benzene intoxication and the symptomatology, o that a "typical" blood picture or sequelae cannot be described.1 1 Excess chromo some aberrations among workers in England exposed to benzene have been reported.1" NJOSH, in their Update Criteria and Recommendations for a Revised Benzene Standard, i.e., 1 ppm, assert that sufficient evidence is available from clinical and epidemiological data to conclude that benzene is leukemogenic. Hence, they recommend, for regulatory purposes, that benzene be considered carcinogenic in man. With this recommendation, NIOSH takes the position that no safe exposure limit can be established at this time. Therefore, exposures should be kept as low as possible. B. SUN CONTACT. Dermal contact with the liquid ma cause erythema and blistering of the skin, and a dry, scaly dermatitis may develop on* prolonged or repeated exposure. It appears to be poorly absorbed through the intact skin. C. EYE CONTACT: Vapors art irritating and cause smarting, only at high concentra tions. Eye splash with the liquid produces a moderate burning sensation with only slight transient injury of the epithelial cells, and recovery is rapid. D. INGESTION. The acute oral LDm (rats) is reported to be 5.7 g/kg.**1 Aspiration following human ingestion ofa tablespoon (about 15 mL) has been known to cause collapse, bronchitis, and pneumonia. The ingested liquid will produce local irritation of the mucous membranes of the mouth, throat, and stomach. More seriously, ifthe ingested liquid is aspirated into the lungs, a chemical pneumonitis may result with pulmonary edema and local hemorrhag ing.'71 III. III. Industrial Hygisns Practice A. Industrial uses and occurrence: Benzene is produced primarily from the petroleum industry. It is also recovered as a by-product from coke oven operations. Benzene is used chiefly ns an intermediate in the production of other orgaoic chemicals such as phenol, cyclohexane, and styrene. Other uses are in the manufacture of detergents and pesticides. ---------- -- -w ill formulations of solvents and paint removal products. Benzene is present in gasolines consumed in the United States in the range of 0.3-2.0%.'101 It may also be a minor impurity in toluene and xylene and a significant constituent, i.e., 5% or more, of certain hydrocarbon solvents such as aromatic petroleum naphthas, with boiling ranges encompassing the boiling point of benzene.111,1,1 B. Evaluation of exposure: 1. Sensory Recognition: Odor thresh olds of4.7 ppm11" and l.3ppm<7'have been reported. Olfactory detection of levels at or in excess of the TLV is not reliable. 2. Air Sampling and Analysis: Benzene vapor in air is collected by drawing air at a measured flow rate through a packed tube containing activated charcoal granules.*14*1" The benzene is desorbed from the charcoal with carboo disulfide and an aliquot sample injected into a gas chromato graph equipped with flame ionization detectors. The charcoal tube, connected to a small battery-operated pump by means of a short piece of plastic tubing, can be worn by the worker over a measured period of time. Direct reading flekl instruments can be used to measure benzene concen trations in the workplace. Colori metric indicator11"171 tubes packed with chemically impregnated granules that produce a color change on contact with benzene vapor provide a quick, but semiquantitative, estimate of benzene concentration. Other commercially available instruments are: flame ionization meter, variable path infrared aoalyzer, and gas chromatograph. Direct reading instruments must be properly calibrated. Other substances that may be present in the test atmosphere should be examined for possible interference. 3. CUnital Monitoring: a. Urine: Excretion levels of urinary metabolites from benzene are used as indices of benzene exposure. Urine sulfate1111 ratios were considered to be a good measure of benzene exposures. However, more recent studies have shown sulfate ratios to be less specific than the measurement of urinary phenols. A level of 75 mg/L of phenol11*1 io urine 00595b QUANTITATIVE RE-EVALUATION OF THE HUMAN LEUKEMIA RISK ASSOCIATED WITH INHALATION EXPOSURE TO BENZENE: A CONDENSED VERSION EXTRACTED PROM THE FINAL REPORT Supported by: American Petroleum Institute 1220 L Street, N.V., Suite 900 Washington, DC 20005 Chemical Manufacturers Association, Inc. 2501 M St., N.W. Washington, DC Western Oil and Gas Association 505 North Brand Blvd., Suite 1400 Glendale, CA 91203 Prepared by: Clement Associates, Inc. 9300 Lee Highway Fairfax, VA 22031 September 198B SAL 000010Q7 EXECUTIVE SUMMARY AND CONCLUSIONS The purpose of this summary is to describe a condensed version of an assessment of quantitative human leukemia risk associated with inhalation of benzene. A more detailed analysis is provided in an accompanying report. The purpose of this assessment is to use new statistical methods and biological information to re-evaluate the benzene leukemia risk, and to expand on the U.S. Environmental Protection Agency's (EPA) interim 1985 benzene quantitative dose response extrapolation evaluation. Because of time constraints described in the introduction of the EPA interim report (EPA 1985), the quantitative unit risk estimates for benzene were based on data from a "secondary source" to be used until more extensive estimates could be completed. Furthermore, these estimates did not represent the "optimum use of the information" available to EPA at that time. The 1985 EPA evaluation was characterized by several factors: (1) When human data were available, usually there was very little information about the levels of exposure for each individual in the cohort. Consequently, statistical techniques were not developed to derive time-weighted average exposure curves and time to death for each individual for use in modeling. Therefore, these analyses generally were performed by grouping observations into exposure classes. (2) Given the limited exposure data, little could be deduced about the shape of the underlying dose response relationships, and the assumption of linearity could not be tested. (3) Biological data that defined the underlying mechanisms were rarely available; thus models were generally not biologically based. In light of these practices, the 1965 EPA risk estimate was a composite measure derived from three epidemiology studies, use of both the relative and absolute risk models, two different ways of calculating latency, and a transition factor derived from grouping the individuals in the study into six person year 1 SAL 000001088 it was not entirely clear at the time which of these two functions was the most appropriate. It is now clear that a weighted cumulative dose is more appropriate because the observations in the epidemiology studies are that the leukemia rate declines as members of the cohort age. This observation is further confirmed by data from several different epidemiology studies that were not included in the 1985 EPA study; the 1965 study used a rough approximation of the latency distribution observed in the Japanese leukemia deaths related to the atomic bomb-radiation exposure. This re-analysis has included data on leukemia from four studies of leukemia victims of radiation therapy and chemotherapy and three studies of benzene-induced leukemia to arrive at the decision that the weighted cumulative dose is the most precise description of the latency distribution. Data from one study, that of patients treated for ankylosing spondylitis with radiation therapy (Smith and Doll 1962), was used to derive a continuous function which expresses a more refined description of the actual latency distribution for use in the modeling exercise. It is important to recognize that since the latency distribution is related to the time to death from leukemia after the initial malignant event occurs, the radiation data is also useful for this particular determination. The use of this data in no way implies that the first malignant event is caused in the same way by radiation and benzene. In this re-analysis, the transition rate has been determined by taking the time-weighted exposure history and time of death for each of the 1,740 individuals in the Rinsky cohort to determine the transition rate, (l.e., the probability that a given benzene exposure level at a single point in time will result in the cell transformation that produces a malignant cell). This term was calculated in the 1985 EPA study by relying on an aggregation of data which 3 oooool-089 SM- involved in controlling growth and differentiating of henatopoietic stem and progenitor cells. In summary, the detailed re-analysis, which is presented in a separate document, incorporates more recently available information and uses statistical techniques made possible by the incorporation of additional data. This re-analysis significantly improves the linear dose response model over that of the combined EPA estimates presented in 1985. The effect of our modifications on the final risk estimates are presented below in Table 1. Individual modifications had only minor numerical Influences on the unit risk estimates even though they enhanced the credibility of the model. However, two modifications taken together had a relatively major effect on the risk estimate using a linear (one-hit) model: (1) use of a more refined latency distribution to obtain the exposure weighting function, and (2) use of an efficient statistical technique, which relied on individual exposure estimates and timeco-tumor data, to estimate the transition rate. In our view, the most reliable form of the linear (one-hit) model from this work decreases the risk estimate by approximately one order of magnitude at an exposure level of 1 ppm. At present, there are plausible reasons to regard the quadratic equation as the most likely representation of the actual risk associated with exposure to benzene. The empirical fit of the data to the quadratic equation and the available biological information provides a more plausible explanation for a two-hit mechanism (two molecules of benzene/metabolites interacting with DNA) than for a one-hit mechanism. Three or four hits may well be required for benzene to induce leukemia, given the existing information, but the most conservative of the multiple-hit types, the two hit model, is the most reasonable to present at this time. The linear-quadratic model, which is based 5 SAL 000001090 FIGURE 1 RELATIONSHIP BETWEEN EXPOSURE AND RISK ESTIMATE USING EPA (1985), LINEAR. QUADRAATIC. AND LI NEAR-QUADRATIC MODEL lo g Risk L09 Cspeavrv (ppm) o Owedmtie o cpa otas) A UnQr->Ou0drtjc 7 SAL 000001091 ^LUI IUUUJ Interoffice Communication TO: Distribution FROM: L. M. Sanchez, EO DATE: January 5, 1989 SUBJECT: WORKPLACE LABELING POR BENZENE Recently the following question was raised: Is the cancer warning language of the OSHA Benzene Standard required to be affixed to workplace containers, e.g., reactor vessels and gasoline storage tanks? The answer is no provided the labeling Information, i.e., the Identity and appropriate hazard warning, Including the warning "Danger Contains Benzene Cancer Hazard" is communicated to employees by "other appropriate forms of warning." It is my understanding that most of our operations satisfy workplace labeling by using a coding system that permits tracing to the appropriate MSDS, which contains the required Information. This method satisfies OSHA requirements, provided that the MSDSs are readily available to the employees in their work area, i.e., the employee can access the information without first asking for his/her supervisor's approval. The OSHA Benzene Standard requires that a MSDS specifically on benzene be used in employee training and made available to employees. Conoco workplaces generally have been using the benzene MSDS written by Cain Chemical Inc. Unfortunately, the Cain Chemical benzene MSDS does not include the specific label language. Therefore, please replace the Cain Chemical benzene MSDS with the attached Conoco version. Note that the Conoco MSDS contains the OSHA labeling language in Section XI. This MSDS satisfies both the Hazard Communication Standard and the Benzene Standard. EOHS will distribute the Conoco benzene MSDS to all workplaces actively participating In the Material Information (MI) System. Please communicate this change to all other sites. If you have questions, please call Sheila Ryan, Ext. 4261, who is my replacement as Hazard Communication Coordinator. /cJs Att DISTRIBUTION Safety & OH Advisory Council A. G. Bisso i-Wr D. Broddle L. D. DeBrie J. M. Lahey L. A. Legendre R. L. McCalip P. L. Youngblood SAL 000001092 MATERIAL SAFETY DATA SHEET BENZENE CONOCO INC. P.O. BOX 2197 HOUSTON, TX 77252 TELEPHONE NUMBERS: Emergency Medical l-(800) 441-3637 Transportation Emergency l-(800) 424-9300 (Chemtrec) General Information (713) 293-5550 I. MATERIAL IDENTIFICATION Product Name Benzene Shipping Name Benzene (Benzol) DOT Hazard Class Flammable liquid Chemical Name (Synonyms) Benzol, Phenylhydride CAS Registry Number 71-43-2 LD. Number UN 1114 IL HAZARDOUS COMPONENT(S) Hazardous Component(s) Benzene CAS Number 71-43-2 ACGIH TLV 10 ppm (T) OSHA PEL 1 ppm (T) 5 ppm (S) % >99 (T) 8 hr TWA; (S) = STEL Substances present at a concentration of 0.1% or more classified as a carcinogen by IARC, NTP OR OSHA: Benzene HI. PHYSICAL/CHEMICAL DATA * appearance and Odor Clear colorless liquid; Sweet (aromatic) odor Specific Gravity 0.S79 @ 60F Bolling Point 80C, 176F Volatile Content 100% Melting Point 5.5*C, 42*F Solubility in Water Negligible Vapor Pressure 95 mm @ 25C Vapor Density (Air = 1.0) 2.8 IV. FIRE AND EXPLOSION HAZARD DATA Flash Point (Method used): -11*C. 12F (TCP Autoignition Temperature: 498G 928F Flammable Limits In Ain LEL: 1.3 UEL: 7.9 Extinguishing Media: Use foam, dry chemical and carbon dioxide. Special Fire Fighting Instructions: Shut oft source of fuel, if possible and without risk. Use water spray to cool fire-exposed surfaces and to protect personnel. Keep personnel removed and upwind. Wear full protective clothing and self-contained breathing apparatus. Unosoal Fire, Explosion Hazards: Extremely flammable, will readily ignite at ambient temperatures. Vapor forms explosive mixture with air. MISP0016/December 1988 1 SAL 000001093 V. HAZARDOUS REACTIVITY Stable: X Unstable: Conditions to Avoid: High heat, sparks, open flames. Incompatibilities (Materials to Avoid): Strong oxidizing agents, concentrated mineral acids, pure oxygen. Hazardous Combustion/Decomposition Products: Incomplete combustion can generate carbon monoxide. Polymerization: Will not occur. VI. HEALTH HAZARD DATA Acute or Immediate Effects: Routes of Entry and Symptoms Inhalation: Acute exposure has been reported to cause dizziness, weakness, euphoria, headache, nmsea, blurred vision, respiratory irritation, pulmonary edema, tremors, irregular heartbeat, liver and kidney damage, paralysis and unconsciousness. Skin Contact: Irritation with possible redness, edema or drying of the skin. May cause dermatitn on prolonged or repeated contact Benzene can be absorbed through the skin, especially abraded skin. Eye Contact: Liquid and high vapor concentrations can cause irritation. Ingestion: Can cause gastrointestinal tract discomfort. Chronic and/or Other Effects: Chronic exposures have been reported to cause headache, loss of appetite, drowsiness, nervousness, pyschological disturbances and various blood disorders, including anemia, bone marrow changes, and leukemia. Medical Conditions Aggravated by Exposure: Personnel with pre-existing medical conditions including diseases of the heart, lung, kidney, liver, nervous system, or the blood, and those susceptible to dermatitis should avoid exposure to this material. vn. /IRST AID Inhalation: If inhaled, immediately remove the affected victim from exposure to fresh air. If breathing has stopped, give artificial respiration. If breathing is difficult, give oxygen. Get medical attention. Skin Contact: Flush immediately with large amounts of water, use soap if available. Remove contaminated clothing, including shoes, and launder before reuse. Eye Contact: Immediately flush eyes with plenty of water for at least 15 minutes. Call a physician. Ingestion: If swallowed, do not induce vomiting. Aspiration may cause chemical pneumonia. Get prompt medical attention. Vn. PROTECTION INFORMATION Ventilation: Local exhaust ventilation is recommended to control vapors. Respiratory Protection: Use MSHA/NIOSH-approved respiratory equipment - air purifying with organicsapor cartridges; air supplied - if other protective measures do not adequately control exposure to vapors. For emergencies and unknown concentration, use positive pressure self-contained breathing apparatus. Utilize respiratory protection equipment in accordance with 29 CFR 1910.134 (Respiratory Protection) and 29 CFR 1910.1028 (Benzene). Protective Clothing: Impervious gloves and/or body protection when splash or contact with material exist. Eye Protection: Face shield or chemical goggles if potential for splash is likely. Other Protective Equipment/Measures: Emergency eye wash fountains and safety showers should be available in the vicinity of any potential exposures. Do not breathe vapor or mist MISP0016/December 1988 2 SAL 000001094 IX. SPILL OR LEAK PROTECTION Steps To Be Taken If Material Is Spilled Or Leaked: Review Section IV. FIRE AND EXPLOSION HAZARD DATA and Section X. SPECIAL PRECAUTIONS OR OTHER COMMENTS before proceeding with cleanup. Use appropriate personal protective equipment/measures during cleanup. Eliminate sources of ignition. Keep upwind of material. Dike spill. Prevent liquid from entering sewers, water ways or low areas. Recover liquid for reuse or reclamation. Soak up with absorbent material. Waste Disposal Method: Recovered nonusable material is a RCRA Hazardous Waste. Treatment, storage, transportation and disposal must be in accordance with EPA or State regulations under the authority of the Resource Conservation and Recovery Act (40 CFR, Parts 260-271). Dispose nonusable free liquid in an approved and permitted incinerator. Recover contaminated water and dispose of in an approved and permitted biological treatment system or an approved and permitted deep well. Remove nonusable solid material and/or contaminated soil for disposal in an approved and permitted landfill. Do not flush to surface water or sanitary sewer system. X SPECIAL PRECAUTIONS OR OTHER COMMENTS General Control Measures and Precautions: Use only with adequate ventilation. Keep away from heat, sparks, and flames. Keep container in a cool place. Keep container tightly closed. Do not mix with strong oxidants. Do not consume food, drink, or tobacco in areas where they may become contaminated with this material. Storage Conditions: Store in well ventilated area. Do not store with strong oxidants. XL OSHA LABEL DANGER, CONTAINS BENZENE, CANCER HAZARD. Benzene may also be toxic to blood and bloodforming tissues. See Conoco MSDS for further information. MSDS Code: MISP0016 DATE OF LATEST REVISION/REVIEW: DEPARTMENT RESPONSIBLE FOR MSDS: PRODUCT INFORMATION CONTACT: 12/88 - Replaces MSDS dated 10/87 Environmental and Occupational Health Services MSDS Analyst Conoco Inc (713) 293-5550 The above data are based on tests, experience, and other information which Conoco believes reliable and are supplied for informational purposes only. However, some ingredients may have been purchased or obtained from third-party manufacturers. In these instances, Conoco, in good faith relies on information provided by those third parties. Since conditions of use are outside our control, CONOCO DISCLAIMS ANY LIABILITY FOR DAMAGE OR INJURY WHICH RESULTS FROM THE USE OF THE ABOVE DATA. NOTHING CONTAINED HEREIN SHALL CONSTITUTE A GUARANTEE, WARRANTY (INCLUDING WARRANTY OF MER CHANTABILITY) OR REPRESENTATION (INCLUDING FREEDOM FROM PATENT LIABILITY) BY CONOCO WITH RESPECT TO THE DATA, THE MATERIAL DESCRIBED, OR ITS USE FOR ANY SPECIFIC PURPOSE, EVEN IF THAT PURPOSE IS KNOWN TO CONOCO. MISPOOlfi/December 1988 3 000001095 SAL N ACCEPTED EXPOSURE-AND^RISK LEVELS FORCbENZENKN Airborne Benzene U.S. EPA unit risk, (95% UCL): 7 x 10" Unit risk is excess lifetime cancer risk from continuously breathing 1 jig/m^ of benzene (70 kg individual). Geometric average of 3 epidemiologic studies. Animal studies yield a unit risk Of ~ 7 X 10 Intent to regulate under 112 Clean Air Act Waterborne Benzene U.S. EPA water concentration for an individual lifetime cancer risk of 10"5 :6.60 pg/l. Guidelines under the Clean Water Act Pace 3 (800) $ April 17,1904 21 SAL 000001096 s DRAFT BENZENE HEALTH EFFECTS BACKGROUND t Benzene is one of the chemicals found in petroleum or at petroleum and petro chemical facilities for which reporting may be required under the superfund Amendments and Reauthorization Act (SARA) Title III, Emergency Planning and Community Right to Know. Benzene is a minor naturally occurring constituent of crude oil. It is also produced as a constituent of various process streams as crude is refined to high-octane unleaded gasoline. Most gasolines contain an average of about 2% benzene. Benzene often is also separated from these streams and sold as a raw material for processing to a broad range of other chemical products. Final products based on benzene include such household articles as aspirin and other drugs, nylon and polyester fibers, detergents, and a wide range of plastic and rubber products made from materials such as polystyrene, styrene-butadiene rubber, phenolic resins, and epoxy resins. Since benzene turns to a vapor at relatively low temperatures, it is one of the materials that may be vaporized and released to the air when gasoline is trans ferred from a refinery to a marketing terminal, or then to a service station and an automobile's fuel tank. Expensive specialized equipment (floating roof tanks with seals and vapor recovery systems) has been installed to keep these emissions from gasoline to a very small level. Benzene is also one of the light hydrocar bon materials that can escape through seals of valve stems, pump shafts, and other similar process equipment at our refining facilities. These losses, called fugative emissions, are similar to those of freon lost from a car's air conditioner. Individually, they are so small that they cannot be measured directly but must be estimated from correlations for each type of equipment. A better measure of the significance of these emissions is the concentration at the refinery fenceline. Recent data shows benzene concentrations in air typi cally run 1-4 parts per billion at our facilities fenceline. One part per billion is one molecule of benzene in 1 followed by nine zeros (1,000,000,000) molecules of air. That's equivalent to one second in 32 years. Data from the government indicates cities without heavy industry--Atlanta, Denver, Phoenix, etc., typically have 4-6 parts per billion benzene in the air. Benzene is one of the building blocks of life. Its chemical structure is found in several of the amino acids that make up protein in the human body as well as those in cattle, chicken (eggs) and tobacco. It is also in essential vitamins such as folic acid and the E and K groups, drugs such as penicillin and sulfa nilamide, and hormones such as adrenaline. Therefore, It is not surprising that benzene and its derivatives are found in complex fossil fuels such a petroleum and coal as well as foods and vegetation such as fruits, nuts, vegetables, dairy products, meat, fish and poultry, beverages, and tobacco products. Benzene is often produced when fuels or other products are burned or when food is cooked. Examples include burning natural gas, which forms benzene within the flame; combusting gasoline, other petroleum products and coal, which break complex aromatics down to benzene; cooking meat or eggs; and smoking cigarettes. The U.S. Environmental Protection Agency has published results from a series of studies conducted from 1979-1986. They show exposures to environmental pol lutants are about the same for people living In cities near petroleum refining SAL 000001097 2- and chemical plants as those in rural towns. (The Total exposure Assessment Methodology or TEAM study in New Jersey, California, North Carolina, and North Dakota.) Among the significant findings: _ There were no greater exposures or body burden between the areas _ Indoor air exposures were greater than outdoor ~ Sources of exposure seemed to be within the homes One of the pollutants studied was benzene. Specific findings from this study, along with a similar California study (U. of California, 1986, Journal of Toxicology and Environmental Health) and others by government and industry groups, indicate: _ The majority of benzene in outdoor air comes from combustion of motor fuels _ In states like California this is rivaled by agricultural burning and * other sources _ Indoor air has much more benzene than outdoor air--in most cases at least double __ Smokers' breath has at least twice the benzene as non-smokers, and the benzene in non-smokers' breath is usually twice that found outdoors _ Overall benzene exposures over a lifetime come primarily from food, indoor air, and smoking. Persons spending only 10% of their time outdoors would get only 2%-3% of their total benzene exposure directly from benzene in the outdoor air. Similarly, persons would only get 2%-3% of their total lifetime exposure drinking water that contained an exceptionally high level of benzene at 25 parts per billion* Benzene is considered a carcinogen primarily based on the experience of certain work groups exposed at very high levels. These workers usually showed signs of anemia, or low blood cell count, as a result of damage to the bone marrow cells. Some cases later progressed to leukemia, a form of blood cancer. There is no evidence that benzene increased total cancer rates. In the study most widely used, exposures of rubber film workers in the early 1940s are acknowledged to be at least 100 parts per million benzene, with some known excursions up to around 700 parts per million. These levels are around 50 thousand to half a million times the benzene levels seen outdoors. Because of the small number of cases and the uncertainty surrounding their level of exposure, it is very difficulty to extrapolate, or forecast, what the risk of benzene exposure is at low levels, except to say it is very low. Animal experiments have been run at high exposure levels, but the animals developed tumors In organs not found in humans, and did not get leukemia. Again, extrapolating these tests results to estimate human risk at minute parts per billion levels give a wide range of uncertainty about possible risks. Studies on large groups of refinery workers, chemical plant workers, and others who would have benzene exposures higher than the general public have not shown any increase In cancer overall or in leukemia. This, coupled with the estimate that the public's exposure to benzene in the outdoor air is only 2%-3% of their total exposure, and much less than that in water, suggests that petroleum operation emissions have no discernible effects on the public. SAL 000001098 -3- .xxon has studied workers and annuitants at its large Gulf Coast and East Coast refining and chemical plant locations (Baytown, Texas; Baton Rouge, Louisiana; Bay, New Jersey). Deaths overall and from all types of cancer were less than would be expected from national statistics (11% less for all causes, 6% less for cancer). The most significant result was that overall death rates and total cancer death rates for non-smokers were about half that of smokers. Since workers are closest to whatever hazards may be present in operations, these study results indicate neighbors would be unaffected by the operations. The first phase of this study was published in the highly regarded medical publi cation, the Journal of Occupational Medicine (April-May 1985). `Assumptions based on benzene of 5 ppb in outdoor air, 10 ppb in indoor air, and 5 ppb in drinking water; giving lifetime totals in grams of <0,1 for water, 0.4 for 10% of life in outdoor air, 6 for food, 7 for 90% of life in indoor air, and 10 for smoking. Note, however, a non-smoker living outdoors would be exposed to 60% less total benzene, but 40% of the remainder would come from outdoor air. Benzene in water at 25 ppb would increase lifetime totals to 0.4 grams for water. o. L. kw c i pr r s_ $ U- o> r ?5//`U / * i? 3t>% V/;a a7?> ?3% *2- RCR:gps 5/10/8B SAL 000001099 HYDROCARBON RISK ANALYSIS DRAFT The following compares various group evaluations of life time exposure levels that would provide "no effect" or low levels of excess risk for three aromatics on the SARA 313 list. Studv Group California DHS Animal Data Excess Risk Level 10-6 Lifetime Exposure ILevels, oob Benzene Toluene Xylenes 0.006 - - California Prop 65 OSHA Benzene Rule EPA (Original CAG) 1100-55 ID'6 10'6 0.03 0.3 0.02 0.04 . - - - . - - - ICF - Clements Linear CAG Update Quadratic Biological Based Model Houston Regional Monitoring i:f 10 5 io:f 10 * No Effect 0.5 5 50 100 20-70 - -- 200 - - _ - 200 o Except for the California DHS conservative animal data based estimates of total cancer risk, all other risk extrapolations models are based primarily on the Pliofilm rubber workers epidemiology studies of leukemia initiated by NIOSH. ICF-Clements has updated this analysis for better information on actual exposures (using a linear extrapolation to zero excess risk at zero exposure as do the earlier approaches) and then has modified the model using biological hypothesis and leukemia dose-response data from other sources that indicate a two-stage quadratic model provides a better data fit. o The Houston Regional Modeling consortium used a toxicology based approach which incorporated studies if no-effect levels from animal testing results and then applied appropriate conversion and safety factors. o The average risk or chance of dying from leukemia over a lifetime are around 1 to 1.5 In 1,000 for males, depending on whether childhood leukemia is included. The average annual leukemia mortality rate is about 1 in 10,000 for males, and about 0.5 In 10,000 for females. Female leukemia death rates in urban areas appear to be essentially the same as for non-urban areas, and show little variation throughout the United States. RCRtec 5/17/88 SAL OOOOOllOO Lifetime Risk of Leukemia Due to Continuous Benzene Exposure Predicted by Various Dose-Response Models $S2113-5d Exposure Level S4L OOOOOlloi BENZENE RISK ANALYSIS o Urban area ambient benzene ranges up to 10 ppb, with rural areas well under 1 ppb. Refineries seem similar to urban areas. Los Angeles, Houston, No. New Jersey Atlanta, Denver, Phoenix Rural, Remote Areas Refinery Fencellne 8 U.S. (API - 1978) New Jersey (1988) Houston Regional Monitoring Baytown (Refinery Fence Line) Houston (E. Loop) Baton Rouge Consortium Industry Fencellne (1988) State Capital (19B6) Ambient Benzene Mean ppb 2-8 4-6 <0.5 4 1-3 0.5-4 (2.0 Avg.) 3-12 (5.5 Avg.) 2-3 2.8 RCR:ec 5/17/88 Document No PB673-000 (Q-iUrrr^ DRAFT DO NOT cm OR QXXE A REVIEW AND EVALUATION OF RECENT LITERATURE CN AMflIFNT ODNONISATiatS, IMISSiCie, MODELING AND POPULATION EXPOSURE TO BEN2ENE, TOLUENE, AND XXLZNE prepared for: THE AMSUCAN EEIRDLELW INSTITUTE Decenoer 1962 prepared cy: Environmental Fesearcn and Tecnnology, Inc* (XTJ 1919 Pennsylvania Avenue, N.W., Suite 405 Washington, DC 20006 and 2625 TOwnsgate Road, Suite 360 Westlaice Village, CA 91361 SAL 000001103 (0*1) tftflO - | 1*001) fCl. - It lIOOll * ! W *urfoJ3 - If f*r| IMMUtfl | llOOl) *! 'wm iuwi IP (mil *! ) 'llinirn |9 (IflOII *! *m>wiii - fq MMunqUi||*-|Wia - * >H wnpiab --ioq |>p) Mj ipd* os/ot * mmm M|dMW JO MJfM - , Vf' #* i J } I p -p p 9 0 0 0 q q q H q w *** 4*0-0*0 0*0-00 *H*a re-0** o*(-o*o ro-o*o (*4-0*0 **4-0*0 (*0-0*0 *0-0*0 Mrz-ro# ri-ro l-is*e-i*o* 1 H)U*C-( *0 1 ro-9*o i-vtrt-ro rwi (-dj4*1-1*0 l-OU't-CO 0 . n-o* r*o* 4*i-o* 0*01-10* 0`01-lU* . o*(-oo* *c-io* *91-40* 1*1*00* o*9-io* 4*|-90* *o-oi>* r>-o* C0-90* i*ll-00* *1-0* 0*11-0* o*(i-r IC-10* ris-r rt-r roi-r rw (*(-{* ro(-r rc-i* rtz-r 1*0-1* 0*((-(* r** t*il OX 9*0 9*1 C*( *( C*0 0*1 * (*( 4*0 9*0 9*1 0*9 S*( 0*9 C*C 1*( C*4 (*C 1*9 (*1 1*4 (*( 0*9 4*9 44 o*on-i*9 01 (*04-0*0| IS 9*l-0*0 4t 0*19-0*0 9C ((1-0*0 (1 *(1-0*0 04 4*41-0*0 99-99 9*(-(*0 09 rsi-ri 19 0*09-0*0 9*0C-9*0l 9`09-i*C OC 4*C-0*0 01 (*0-0*0 It p*rc-ro* (9 0*C1-1*0. (9 0*40-0*0 0 0*91-0*0 0 (*99-9*0 0 (*19-9*0 II 1*0(-4*0 11 9'9(-0'l 01 4*9-1*0 01 ('49-0*1 t o*4i-ro 11 t*0C-4*0 Cl *(4-n (*9t 0*lt 9*1 0*0 0*9 0*9 9*1 9*( *9 (*( C*91 0*( 9*0 rz 9*0 9*1 0*( 9*9 0*( 0*0 *4 e*9 4*1 (*01 rc 9*0 ru 44 r*oc-o*o It 44 01 OIK-DO **( 01 14 9*((-0'0 14 4( (*9-0*0 C*l 4< 9 0*9-0'0 ri 9( (1 4*l-4*0 1*C (1 04 *9-0*0 0*0 04 99 4*(-t*0 (( 49 09 (*1(-4*0 0*4 09 99 (*(1-9*0 0*( (9 11 0*ll-0*( *4 11 0*9oe-o*( 9*40 1( o*oc-ri rot 9( *l (9 0*(-0*0 9*0 (9 09 *-0*0 9*1 9 99 0*01-1*0* (( 99 04 9*01-1*0* 1*1 04 94 o*zt-ro* (( 94 0 `-9*0 9 ( 0 0 9*99-9*0 0*4 0 0 0*01-1*0 1*9 0 II 0*11-4*0 0*9 11 11 o*tt-ro 9*9 11 Ot *4-1*0 9*1 01 01 ClC-0`0 *4 01 0 f'l-ro 9*1 0 IT 0*04-9*0 1*9 11 01 0*((-i*O 0*9 01 2 -S __ zwvx H*OI jCWI bmm fadd)jtmii |(|Virauiini l<fMTaciiioi gumwthYW wnu oof <[noi *mb<h jkihm# 1-c vna (0 ------------------------- N to *!** mrQ 10 10 10 10 10 SO HnWMO 10 ( *wn9 10 t-\0 10 l - is wnw 0( c - fiMrifra u ( plt> ( 1 - puaifea it nt <wfM3 41 Of `ww it ni iwtm *9 it m piinqi it m it m 'inaunin 10 11 *ota0|o ! 91 11 III <|M|*| Mini 00 00 go 00 CM 'lin>l *>8 00 u *Maqno|| a YJ *i**l *o 0( . tv it 93 Tiit imoan *# O o o o *c <s> TABLE J-J AVERAGE CONCENTRATIONS OF SELECTED ORGANIC VAPORS IN NEK JERSEY (ppto) (time period) sound RUTHERFORD NEKARK ELIZABETH AKBOY PINE BARRELS BATSTO CWCEN Benzene Toluene ortno Xyiene para/^neta Xylene 3.x6 8*40 1.32 3.72 1.70 2.62 1.06 2*52 7.20 7.04 1.78 5.10 1.38 2.24 0.45 1.21 0.61 0.50 0.14 0.27 1.75 5.97 2.14 6.44 SOURCE: Bozzellj, et al. (19R1) Crew, et al. (lACb 19B2) carried out a study to monitor selected nyorocarbons in ambient air at selected sites in tne Houston area. These are sftown in tne more detailed description of the study given in Appendix B. The hyorocaroons were measured by gas chromatography using a fiame ionization detector. A possiole proolem with tne study is tne fact tnat TE&X was used as tne soroent to concentrate all nyarocarcons witn a caroon number greater tnan CO. As stated aoove, 5ingn et al. (1962) have identified problems with the absorption and subsequent exutxon from TENAX. Additionally, wnile toluene and the xylenes were separated on the gas enrematagrapn, benzene eluted at the same time as 2-ana 3-metnylpentane. This fact maxes it ispossible to ootain a realistic value for ancient concentrations of benzene. Thus, this stuay xs of limited use in obtaining reliable and specific aznoient concentrations data for benzene* The probleas with the TS2AX comm may oe one reason wny tne ambient measurements reported in the Texas Air Control Board study are quite a bit lower than the mean values reported by Singh, et al*, although care oust be exercised In carparing data fran two different studies of sites which may not be truly oaiparaole in hours of possible inpact ty emission sources. 3-11 SAL 000001105 Ol Ol EPA-600/3-8 January 19B P063-156S35 MEASUREMENTS OF HAZARDOUS ORGANIC CHEMICALS IN THE AMBIENT ATMOSPHERE * H.B. Singh, LJ. Sala R. Stilt*, and H. ShigiiiKI Al/notphffic Seitnet Cantar SRI Imtrnational Mani Park, California 9402$ Cooperative Agreenent 005990 Projact Offtear LCupin Atmospharic Chamiatry and Phyiic* Laboratory RtMarch Triangn Park, North Carolina 27711 ENVIRONMENTAL SCIENCES RESEARCH LABORATORY OFFICE OF RESEARCH AND DEVELOPMENT U.S. ENVIRONMENTAL protection AGENCY RESEARCH TRIANGLE PARK. NORTH CAROLINA 27711 ateoctt <r NATIONAL TECHNICAL INFORMATION SERVICE a* Hna'Uw'tHLkti, a*t4.tofiaiuaiiu SAL 00001106 / 4 i s * rj*s Iiiiii.* ..*iJ F J 41 l IT 51 J ii t\ 1 k is. S > is.iu il.fi 2*.5=5 1=2=5 25.*2= . .2=1===. ..*****. ..!!====. 5 .*= .* |85 i *. Mi* !.*=.= = 11.- II 1 ,.**.= inin . ItlJU . SfilSX |*!21.. linn Hlinn ..in . , 8*f "" i . .** = ! ...Mj *l r :2j 1 fi l Ii J %i im j *, = . S ,|, . 2. = . 4 % r l r t\ It9 KI ii 1 = i .5 , I ! i 5 * 1 IMM s* .* = * I-** P.Sl* I*<155 I*-1K u .{iZ 5=1" Ii.I 22.1*5 ..si|==2. *it*i i . .1*1**-, Hi"=* i **a ..s=r*=. I.2S.S 2.H.* I.!*.* * *iis *11 " M!.* !iU--=11*2*1*1 mItsn*s-n!nnnn Minus \\niiii S!!!*!l 5 = = !2H iiiniit * *11 = .. .* ...H * *. i = 1 ...|! ..?i .. .** ii ...p ' * *s = t i ill! i {Ill at ,.!! list! jjj* nliiij Li"o"t lljlllll flii.i mm jiiii ]fssii] iiiiii! 1 II IIJIIIS jiiiiiirj ii . fi i u iiHi! u SAL 000001107 *U: n'iii iss|s** ,,*.* ifniiS* 'll sin iViil Mi*!*"* * ||m!li I Ui ill! jj*s r;i|fs iisjr I?ii iiis iriii l:^!***1 Mir* IH!**I* (!! ' ||IH'! | !* Hi* fl"l*s MS`*** * t'lism | 'it J|-: !!*{!! t*|a|s-sa **j|f .**' * lllllM | !|?! UP ifiis nj|.* i.p 1 i\i\nn i UP ||a||| !* s nu;m | *n lif |**t fs*| *:>***** 11*11' It1 * ii*n*si j"**. i>iisti ,! III* 1**11* HIT"1 ir I***st 1 IIIIHI! I'M1 151* !**il= **1*1**'* j-** iniiisi | -P ! I igi* Si'ii! Ml*!***1 **11** I** * t]!|!l!l { 12* IIP Is'j!* *l*I**fS **ig. *.* {i|: IPHi *2i:j*"i *!|jf* |*** iiiumi i *|5 innii! i *i*! m; i :u li if *i .1 lii'i.l 1 Ifss I!!* IIS* {sa: |r*JJ! t**l** ii*{:t *** I!i|*t:a **!*' titii:**: u*i'?* a*||* "*!l 'iiit' i * *:i * I** - * II*!** ISinill unit!! llimn I1**; | i* H:< kk. Hi* i|:U! It!! j>I * HiiriU ..J*; g* 8 !l [j:: :*its riiift u*n- - ||ta*it u ill' I!ll!!*:e !!ip! f**> 8 Uiltiii *!- \ *58* 1**111 2*1*1**** *ir * iimn* --h! | JJ !t* II`1II I*|*I>ss *|| l*` Igfliggi !!! 9 II | iiii'ii l|l|J jiiifi! 11, <!! id j lilili ill! jlaillill*.| * I'lfiiii 1 iliil 1 lUu lijllu jiiitei till 33 SAt 00000110 / / SAL 000001109 SURVEY OF BENZENE OCCURRENCE IN AMBIENT AIR AT VARIOUS LOCATIONS THROUGHOUT THE UNITED STATES ERT Document No. P-S341-3 Prepared for AMERICAN PETROLEUM INSTITUTE Environmental Affairs Department Washington, DC Prepared by D. Alan Hansen ENVIRONMENTAL RESEARCH 6 TECHNOLOGY, INC. 2625 Townsgate Road Westlake Village, California 91361 SAL OOOOOlllO 3E t Ttirooooo ivs -TT?a- / uTa ACM % SuaMry I f k a u n i Oecurrmc* In th i USA Durlnc Htr M77-7I *vrnn?*mn ! i =1 f f r II !? m 7aaf i il 5 1 s i zl 5 r <* ? 2? ssssss I im xm i m 73 fm a vi ft wif * % * 7^ 74^ p:h 7 .'-*C5_ ?* e * a a itfaf _ 4-> 'l *9 4J a^ A w .-.S2*2< * 2 ~ -9 oam* oa a c o--9 --4. c5--- srir 3* -V-?(9oA* '*?*^-- r*~----m7um>|5mm f 3* -* V ? C?C3. I ** taf?u ?a ra ?? s= v> s fs a * : * 9* -7 75 :c? n \vA\' cc aa a<--a%3__is y n <** v <-4i I t. 7 3 * % BENZENE RISK ANALYSIS 0 Total lifetime benzene exposure estimates suggest water and outdoor air overshadowed by Indoor air, food, smoking, and occupation Drinking water (5 ppb) Outdoor air (5 ppb, 10%-100% life) Indoor air (10 ppb, 90* life) Food Smoking Workplace (0.1 ppm TWA) (1.0 ppm TWA) Potential Exposure To Benzene q/lifetime <0.1 0.4-4 7 6 10 11 no SAL 000001112 HO-8 1-12-08 \ X Ambient Alr^ * Non-Urban Urban Indoor Alr^^ Urban Inoeatlon Hater, Typical (98%) Atypical Food Smoking >1 pack/day Occupational^^ Typical (<0.1 ppm) OSHA PEL Proposed (1 ppm) Currant (10 ppm) Past (100 ppm) TABLE I BENZENE EXPOSURE SOURCES Benzene Concentration PPb o/l Intake Exposure (7) ug/D mg/Yr MetabollzatIon Factor Benzene. Metabolic Dose' ' (8) palit . g/Llfatime <0.5 5 0.0015 0.015 33o0S:<<`>><3* 11 110 0.5 0.5 5 55 0.4 3.9 15 0.045 <0.5 250 - <0.5 250 - 900.*1**3* 330 0.5 <0?3)12) 3 4 5 6 708.12 160.'*' 60 250 90 <1.0 <1.0 1.0 160 0.1 60 90 11 0.007 4.2 6.3 -- 1,000 360 0.5 180 10 <100 1,000 10,000 100,000 0.3 3 30 300 2.000.<6><4 730 20,000* j ^) 7,300 200,000. 73,000 2,000,000.'' 730,000 0.5 0.5 0.5 0.5 370 3,700 37,000 370,000 11 no 1,100 11,000 SAL 000001113 (1) Baaed on CAG 20 M^/Da Average Resplraton Rate, i.e. Mild Activity (2) Baaed on 650 NL/Day Average Hater Ingestion (3) 24 Hra/D at Indicated Level, 365 Days/Yr (4) 8 Hra/D at Indicated Level, 240 Oaya/Yr (5) 1 ppm 3 mg/m 3 ug/1 for Benzene in Air (6) Based on CRG 20 N /Day x B/24 - 6.7 mJ/D (7) Rounded to Two Significant Figures (8) 70-Year Total Lifetime, 30 Years Occupational Exposure RCR:BR 10-2-86 Maca> ca> to (\j LT> -- CO m LT> Benzene In human breath re la te d to smoking, fo o d , o th e r Indoor o r In te rn a l sources not outdoor a ir -HO-7 1 12-88 r- c\j C\J CNJ cm m cm *-- SAL 000001114 CURRENT DEVELOPMENTS T3S5 Jamet Pendowski, manager of the Solid Waste Planning division, the agency is consulting with other state agencies, deluding the Illinois Department of Energy aod Natural Resources, to determine if the ruling should be appealed or the lav rewritten. Pendowski said the decision in the ease was Instructive because it set out in clear language what Deeded to be done to rectify the lew. A spokesman for the Illinois Attorney General's office said staff attorneys were in consultation with the IEPA. "While we probably are going to appeal ft, this decision has not been made." More than 910 million Id tipping fees beld in a special fund pending the outcome of the lawsuit are now at issue. A spokesman for the Illinois Attorney General's Office said, "We will fight any efforts by anyone to take this mooey away.** The IEPA, having provided a number of research and development grants before the cut-off in funds, is clearly worried that certain alternative waste management activi ties that have been undertaken might now fall by the wayside. No termination notices have been sent to grant recipients yet. Pendowski said, "but it is a very real possibility if we can't get something worked out." Genera/ PoUcy EDA STUDY SAYS EXPOSURE NEAR CHEMICAL. OIL PLANTS NO GREATER THAN IN RURAL AREAS Residents in small towns and areas with light-manufac turing seem to be exposed to fust as many environmental pollutants as people living in areas with heavy petroleum refining and chemical-manufacturing industries, according to a study released Sept. IS by the Environmental Protec tion Agency. People living close to major sources of pollutants in heavy industrial areas, according to the study, showed no greater exposure or body burden than those living far from such sources EPA said many activities that are common in all types of areas, such as smoking, driving, painting, and pumping gas. were shown to increase exposures to toxic air pollutants dramatically Other activities listed were, using air freshen ers. visiting a dry cleaner, and taking a hot shower. The findings were unveiled in a research study conducted by EPA* Total Exposure Assessment Methodolop group. The study, conducted in phases from 1979-1989. provides EPA't fust direct measurement of ordinary citizens' expo sure to many environmental pollutants, according to the agency. Exposure by residents was measured In Us Angeles Calif., Bayonne sod Qlxabeth, NJ; Greensboro, N.C; and Devils Lake, N.D. The first three areas are heavy petroleum refining and manufacturing areas aad the last two are a light industrial dtp aad rani tow*. Subjocta Carried Ak tHanhere Tbe three-volume study examined more than 100 subjects selected to represent more than 700,001 residents. tody participants carried as air monitor for two consecutive 10hour periods aad provided a breath sample and drinkingwater sample at the end of each period Outdoor air saaplao were collected is tbe backyards of about 100 nbjoern. Answers to questionnaires supplemented the field taeta. One of the more significant findings, EPA said, was that Indoor levels of target chemicals were moch greater than outdoor levels Exposure to about a dozen volatile organic chemicals, such ss beoxene. chloroform, sod other solvents, were usually greater -- often moch greater -- than outdoor concentrations, EPA said. Tbe source of tbe measured expo sures often seemed to be In tbe homes- The TEAM study said U seems probable that consumer products such as paints, cleansers, propellants, plaxtio. cosmetics, and building materials (adhesives, fixers, resins, end Insulation) comprise mijor sources. A limited Dumber of copies of tbe full TEAM ftugy ere available from the Center for Environmental Research IdfortaaUoo, 29 West SL Clair St_ Cincinnati, Ohio, 493U. Ground W$fr HOUSE SCIENCE, ENERGY PANELS APPROVE BILLS BOOSTING USGS, EPA GROUND WATER RESEARCH Legislation to establish a federal ground water research program advanced a step in the House when two subcom mittees approved the measure Sept. 19. By a unanimous voice vote, the Science Committee's Subcommittee on Natural Resources. Agriculture Research, and Environment approved legislation combining portions of two previously introduced bills. HR 732, introduced by Rep. Sam Gejdenson (D-Conn). and HR 2253. introduced by subcommittee Chairman James H Scheuer (D-NYV Tbe resulting measure, the National Ground Water Re search sod Protection Assistance Act of 1987 (bill number not yet assigned), would establish a comprehensive, coordi nated ground water research program involving the Envi ronmental Protection Agency and the VS. Geological Survey. Within one year of enactment USGS would be required to report to Congress on the adequacy of existing ground water information systems and federal data collection and moni toring programs, and to make recommendations for improvements. USGS would be required to establish a National Ground Water Characterization Program to assure that federal, state, and local governments have information to assess ground water resources for protecting and managing them. In addition, USGS would have to establish a national clearinghouse to catalog and disseminate ground water information. The Science pane! bill also would establish a research program at EPA to support agency regulatory activities and to help states protect, manage, and clean up ground water. EPA would further be required to conduct a nsk assess ment analysis for each significant ground water cootamiaaat Tbe agency would have to publish analyses for 90 contaminants within two yean after enactment, and an additional SO contaminants within three yean after enactment According to a subcommittee side, tbe risk assessment provisions would stop short of requiring EPA to set ground water contamination limits for sack of tbe contaminants, leaving it up to each state to Judge for itself what constitutes an acceptable level of risk for each contaminant la addition. EPA would be directed to carry out pro gram to develop aod demonstrate technologies that may be effective la controlling source or potential sources of ground water contaminants or la mitigating ground water contamination. e-is-ar tniwww Ndm mts-mtww/eo-as SAL 000001H5 Test results reassuring Hazardous pollutants in coastal air 'surprisingly' low, study discovers By Harofd Scartft_________ EPS* MV'aQNVNT WWtTCW 3 _________________ `" A major study by the Texas Air Control Board staff showed a "surprising" absence of hazardous pollut ants in the air along the Upper Gulf Coast, air board members were told Friday at an Austin meeting. "The levels we found did not pose a public health risk." said Eli Bell, air board executive director. "We think that's good news. In the study, the air board staff set up automated monitoring stations in Harris. Galveston. Jefferson and Orange counties to determine the degree of public exposure to 10 toxic substances. The monitors sampled the air from October 1985 to `The levels we found did not September 1986 for acrylonitrile, ar senic. benzene, epi- chlorohydrin, ethyl ene oxide, formaldehyde, lead, ELI SELL Air Board aiecutfv* director PCBs and their combustion prod ucts of dioxins and furaru, polyaromatic hydrocarbons and vinyl chlorides. Dr. James Price, who headed the study, said the "most striking and surprising thing" about it was the complete absence of any trace of four widely used organic chemicals -- acrylonitrile, epichlorohydrin. ethylene oxide and vinyl chloride. "All were chosen because we expected them to be a possible health hazard," he said. "I think their absence indicates we don't have a pervasive, areawide problem that some of the public have been concerned about." Price said the remaining hazardous substances were found in ranges typical of major urban areas. None was found in levels considered a health risk, he said. The most common substance found was benzene. Price said, and it turned up in just about every sample taken. Sources of benzene vapors range from neigh borhood gas stations to major refineries and chemical piants. "We did a health impact review of all the substances and samples," Price said, "and the only thing foend setting up toward the marginal level of concern was a benzene sample taken by a monitoring station in the Cloverleaf area of Houston, on I-10 north of the'Ship Channel." He said that sample measured 18 microgTamf *of benzene per cubic meter of air. k> ffb Harris County had two monitors, both set up in the same location to see if they would vary in test resiflts. and the other counties had one each Price acknowl edged the sampling network was not elaborate. r "This study doesn't mean there can't be hot spots elsewhere in the immediate vicinity of some plants." he said. "But we put these monitors where we were expecting the worst situations, and we feel we have a pretty accurate picture of areas that you would thmk are heavily impacted by industrial emissions." Board member Dick Whittington called the nsiilts "reassuring'' and said, "People in the coastal part of the state ought to find comfort in this." In other action, the air board approved administra tive penalties totaling $56,000 on six Houston-area companies for air pollution violations. The companies agreed to the penalties. The largest penalty, $30,000, went to the Doty Sand Pit, a commercial Undfiil at 12000 Bissonnet. which was charged with 43 excessive odor emissions. The landfill has had repeated run-ins with pollution offi cials over the years Other penalties were: $10,000 on the Occidental Chemical Corp vinyl chloride plant in La Porte for violating vinyl chloride emission standards. nd $10,000 against the Occidental plant in Deer Park lor the same offense. j;- AJso, $4,000 on Paktank Gulf Coast Inc., a Ixjwd bulk storage facility at 2759 Battleground Road In Deer Park, for failing to keep required records on benzene, $1,900 on Patterson Truck Une lnc., 439 South Sheldon Road in Channelview, for operating a facility without a permit; and $ 1,000 against intermed ia Inc., a pacemaker manufacturer in FreeporTjor constructing and operating ethylene oxide steriligfwn chamben without a permit SAL 000001U6 OpinionS^Comment CancerPrevention-AreWe Getting OurMoney's Worth? These comments art based on an article that appeared m the American Council of Science and Health's News end Views lor Nowcmber/December 1967. Mrs. Napier received her B.S. degree in nutrition tram the Vnh. of Minnttote and her metier of public health degree, with a concentration A* environmental health audiei. from Yale Unit. School Medicine. She hat aba done graduate mark in fwrfir toeteehttg at Cate Urgent Jtrifm Vnh. n 1987, the federal government spent more than $2.8 billion on cancer prevention. IWere these dollars spent wisely? I believe the answer is no. Far too much of it was spent on misguided battles against environmental agents which are, at most minor causes of cancer. Far too little was spent on effective campaigns. Cancer prevention is part of the agenda of two key federal agencies, the National Cancer Institute (NCI) and the Environmental Protection Agency (EPA). NCI has a yearly budget of $1.21 billion to address every aspect of cancer cause, prevention, and cure. For prevention programs, NCI has allocated a mere $0,064 billion. EPA, on the other hand, devotes at least $2.77 billion out of an annual budget of $4.88 billion to keeping chemicals out of the environment -- an effort widely regarded as devoted prin cipally to cancer prevention. The best scientific evidence indicates that diet, viruses, sexual practices, alcohol, and. especially, tobacco account for the bulk of reported cancers. Substances targeted by EPA, including carcinogens in the workplace, account for fewer than 8% of American cancer deaths. No one is at all certain what EPA is achieving from its expenditures. After decades of advances in the understanding of cancer etiology, scientific consen sus began to point to the importance of life-style factors in cancer causation. By the mid-1950s, scientists began to dismiss the role of genera! chemical exposure in causing cancer. Ironically, at the very time epidemiologists were making major headways in identifying the true risk factors for cancer, a few verbal and well-publicized individuals began to popularize the notion that we are surrounded by a virtual sea of industrial carcinogens and that our only hope of survival was an all-out war against chemicals, particularly those of industrial origin. Legislators were convinced by scientific zealots predicting environmental doom. They actually built into legislation the principal assumptions of people like Rachel Carson. Samuel Epstein, and Thomas Corbet One decade of American legislation appears more closely aligned with public opinion than with sound estimates of risk. There is no scientific evidence demanding that our environment be chemical-free. The payoff in cancer prevention simply is not there. Neither is there ecological justifica tion to purge every man-made chemical from the environment A major reallocation of this nation's cancer prevention fund appears grossly overdue. May 1968 Kristine Napier, M.P.H., R.D. an. **%! b> maid . Ik vt-vraantt nimiitf thu Ann AAtfrctt twn^ndrm to tfw tt*or (hw / AMuinrmqp f+grrts. iUS K 47 SI. few V.a* NV 10017 SAL 000001117 S EPA - /<7F0 FINAL DRAFT REPORT py M'e A'->e *- -/v f EXECUTIVE CONCLUSIONS1 r* ( / ; V / f Excessive occupational exposure to benzene has been shown to be associated with leukemia, end other serious blood diseases. Acute toxicity Involves central nervous system effects vhleh can result In death# Environmental exposures are at least 100 fold below the minlmums thus far shown to be associated with toxicity from occupational expo sures. However, prudent public health policy, by not recognizing thres holds for carcinogenic effects, would anticipate some risk at such levels. Conservatively applying the EPA Cancer Assessaent Croup's linear nonthreshold extrapolation to low exposures, the effect of benzene expo sure routes on the potential cancer incidence In the total U.S. popula tion would be estimated as shown below: Route Ambient Air Drinking Water Food Cigarettes Comparison of Benzene Exposure Routes (EPA Exposure and Risk Estimates) Average Benzene Level 3.3 - 6.5 yg/m3 t.i - {fB** 0.025 - 0.17 yg/1 Average Excess tlfetlne Risk Nationwide Incidence (cancers/vear) 2xl0-5 - 5xl0-5 75 - 150 4xl0~8 - 2xl0"7 0.1 - 0.8 possibly 250 yg/day 90 yg/cigarette possibly greater than air 10~3 800 The assumptions incorporated Into the EPA cancer risk extrapolation suggest that these estimates may exceed the actual risks from the above tabulated exposure levels (as discussed In Chapters 5 and 7)# The above estimates (or range of estiaates) for the population mean do not reveal the distribution of individual exposures within the population. Individual exposures may be two orders of magnitude higher than the cieans, as described In Chapter 5. Nevertheless, these estimates pro vide some indication of the possible overall importance of benzene In the environment, since for linear nonthreshold risk extrapolations, incidence Is determined by the arithmetic mean exposure# (The above estimated meens and the Chapter 5 and 7 estiaates for specific scenarios are Intended to complement each other#) Prepared ly EPA Technical Project Officer based in part on program considerations# 111 SAL 000001H8 FINAL DRAFT REPORT le Is apparent chat cigarettes, food, and ambient air constitute the most important exposure routes for the non-occupatioaally exposed general population. Drinking water appears to comprise less than one percent of average exposure. Because the food data la very Halted, the exposure via food la uncertain. While Its presence st very low levels may represent a phase equilibrium with contaminated air. Its presence at higher levels, such as In eggs. Is believed to occur naturally. Due to benzene's low potential for bloeoncentratlon, expo- ' sure to waterborne benzene via contaminated fish la expected to be less than via drinking watsr. Relatively little risk to aquatic life can be expected to result from current environmental levels. Benzene Is acutely toxic to some fish and aquatic invertebrates st concentrations above about 5000 ug/1. Although there is insufficient data to establish a chronic toxicity criterion, limited data suggest that chronic toxicity to fish may soaetlaes occur at concentrations in the range of 100-1000 yg/l. Of 185 ambient water neasurecents recorded in 5T0RET, nose exceed 1000 Ug/1, and only 5 percent exceed 100 yg/1. No fish kills on file for the last decade have been attributed to benzene spills or discharges. Although benzene is s naturally occurring substance, its global production and environmental burden have been Increased by human activ ities. Approximately 11 million metric tons of benzene per year are bandied within the U.S. economic system. One half of this Is essen tially pure benzene, mostly produced from petroleum by catalytic or thermal reactions, and used almost entirely as s feedstock to synthe size other ehemleals. The other half Is a constituent of hydrocarbon mixtures, primarily gasoline and other fuels. Nearly all known environmental releases e`f benzene are to air, primarily from gasoline combustion. Less than one percent of the known releases Is to water, primarily from solvent users, petroleum refiners, and chemical plants. Benzene disposal to land appears to be negligible; however, the content of some potentially Important solid wastes Is not known. It may be noted that the relative pro portions of water and air disposal are very roughly equivalent to the relative proportions of average water and air exposures. In soil the fate of benzene wastes la somewhat uncertain, and may Involve volatilization, biodegradation, or leaching. In most surface vateri volatilization Is expected to dominate ever degradation, thereby bringing benzene Into the atmosphere, where it Is oxidized. Water In equilibria with contaminated urban sir having 10 ug/m^ benzene would have only 0.044 ug/1, and would represent negligible exposure compared Co Che air concentration. Nevertheless, such equilibrium may not be approached quickly, but may requlra a distance of a few miles to many dozsns of miles, depending on a stream's depth and turbultnea. The absence of substantial levels of benzene In ambient water Is thus con sistent with both the sparsity of discharges and the high fugaelty of waterborne benzene. Iv SAL 000001119 FINAL DRAFT REPORT Overall, It can be concluded from Che assessment of benzene die* posal, face, exposure, and risk that: 1) Population aggregated exposure through waterborne routes (drinking water and eating fish) it small compared with exposure through either air, smoking, or possibly food. 2) Water discharges of benzene ere small compared with air emissions, and thus, even when volatilised, do not sub* tantially increase nationwide air concentrations* 3) Air contamination with benzene does not cause serious con* Semination of water, as through ralnout. 4) The potential for aquatic life problems downstream of most benzene dischargers appears to be quite low* 5) Due to benzene** multi-media exposure potential, removal from one medium (such as water) by transfer to another (such as air) may not necessarily be of benefit. Notes on Tabulated Cancer Bisk Estimates: 1) Unit risk (dose*response) is taken from E?A (1980), referenced in Chapter 3* Other unit risk estimates are described In Chapter 5. a) Lifetime Ingestion of 13.3 ug/day would result in 10 ^ risk. Drinking water Intake Is assumed to be 2 1/day, although this may be high (Appendix C) b) Lifetime Inhalation of 1.35 ug/m^ with 501 absorption efficiency would result in 10~5 risk. c) Annual Incidence Is for the entire U.5. population (220 million persons), assuming a 70 year average lifespan* 2) Two estimates are provided for the air concentration averaged over the entire population. The lover Is from Mara and Lee (1978), as referenced in Chapter 4; the higher is from Chapter 5* 3) The drinking water mean concentration is assumed to be represented by the National Organic Monitoring Survey* The range of estimates for the average was generated by assuming either: a) Benzene not detected Implies zero concentrations; b) Benzene not detected Implies a concentration Just below the detection Halt* V SAL 000001120 FINAL DRAFT REPORT TABLE 5-11. SUtttART OF ESTIMATED BENZDfl EXPOSURE AND ROUTES \ Route and Activity Ingestion Veter Food* Mean Dally Intake (mg/day) 0.004 0.250 Inhalation -- Nonoccupational Urban Suburban Rural Near Emission Sources Caa Station Use Cigarette Smoking 0.1 0.05 0.03 0.01-0.05 0.01 1*4 Inhalation -- Occupational Outdoor In-traffic Jobs Industrial Caj Station Employees At Occupational Standard Per cutaneous Occupational -- Liquid Occupational -- Vapor Residential -- Liquid 0.05 20 l.S 153 Worst Case (mg/day) 40 0.9 <1.0 Estimated Exposure Population (millions)b, 220 150 70 isable to estimate 220 54 million (1978) cm able to estlsate unable Co estimate unable to estimate unable to estimate an undeterminate sub s* of 0.1 million subpopulation ir, known but quite small *There are as yet Insufficient data to determine truly typical values. These data are the NCI's (1977) "conservative estimate." ^Populations based on 1970 Census Data (U.S. Bureau of the Census 1979). 5-38 SAL 000001121 BENZENE IN FLORIDA GROUNDWATER AN ASSESSMENT OF THE SIGNIFICANCE TO HUMAN HEALTH Florida Petroleum Council A Division of the American Petroleum Institute OC-TcB&L SAL 000001122 i ffra** PART TWO: HAZARD ASSESSMENT fomsr B Thomas. Ph. D. Shell DevtbpmefU Company Houston. Texas M toxicological effects of benzene 2-1.1 Introduction Several excellent reviews of the toxicological properties of benzene have been published recently: Fishbein (Ref. 2*1.9(14]}. 5ynder(Ref. 2-1.9(32]). Aksoy (Ref. 2-1.9(l]) and Mehlman (Ref. 2-1.9(22]). This section will therefore address only selected aspects of the extremely large toxi cological data base available for this compound in order to provide a perspective from which to evaluate other parts of this document. 2-1.2 Major Sources of Human Benzene Exposure It must be appreciated that benzene is ubiquitous. According to estimates from the National Research Council (Ref 2-1.9 (24]). the dietary intake of benzene may be as high as 2S0 Mg daily, perhaps explaining ben zene concentrations of 6-20 ppb in the breath of individu als with no known exposure to this compound. The ben zene content of specific foods is reported to range from 2 ppb for canned beef to 2100 ppb for a boiled egg (Ref. 2*1 9 (23]l Recent results from the National Toxicology Program (Ref 2-1.9 (25]) indicate that virtually 100% of benzene administered orally is absorbed into the body. Benzene concentrations in ambient air(urban and rural) have been estimated to range from 1-100 ppb (Ref. 2-1.9 (17]) Urban air is reported to contain higher levels than rural air. presumably due to the contribution of automo tive emissions of benzene (Ref. 2-1.9 (5]) After reviewing these data, the National Research Council (1980) calcu lated that an individual living in an urban environment containing a mean atmospheric benzene concentration of 16 ppb (50 *jg m5) w ho breathes an average of 24 m3 of air per day and absorbs approximately 50% of the dose (i.e., equilibrium state) will absorb approximately 600 Mg of benzene daily. [16 ppb 50 Mg'ro3 x 24 m3/day x 50% absorption s 600 fig'day] Benzene is present in cigarette smoke at levels of 47-64 ppm. leading to estimates of the amount of benzene inhaled from a single cigarettes ranging from 10-31 Mg Using the upper estimate, a person smoking two peeks (i.e., 40 cigarettes) per day will absorb up to 992 m| of benzene (assumes 605 of dose is absorbed, non-equili brium state). [Note; This discussion will not consider the contribution of secondary inhalation of cigarette smoke to the overall benzene exposure of a non-smoker.] [40 cigarettes/day x 31 Mg benzene/cigarette x 10% absorption * 992 Mg/day] The solubility of benzene in water is reported to be 1760 mgrI at 25 C (Ref. 2-1.9 [2]) In a report issued by the EPA Office of Drinking Water (Ref. 2-1.9 [11]). it was estimated that 97.7% of the population served by public water systems is receiving water either free of benzene contamination or having levels less than 0.5 Mg I Esti mates of daily human water consumption range from 0.8 to 2 I/day. Assuming that the average adult consumes 2 liters of water daily, it can be calculated that drinking water with a benzene content of 0.5 Mg' 1 would contrib ute 1 Mg of benzene to the average daily dose (100% absorption assumed). [0.5ms'1x2 J/day = 1.0 Mg'day] Summarizing the above calculations for what are consid ered major sources of human benzene exposure: Non-Smoker Smoker Food Air Cigarettes Water TOTAL 250 Mg'day 600 Mg. day 1 mZ day 851 Mg/day 250 Mg day 600 Mg day 992 Mg day l Mg da> 1843 Mg day 2-1.3 The Pharmacokinetics of Benzene The primary routes of benzene exposure are considered to be oral and inhalation. W'hile there are data that benzene applied as a liquid or in solution to human skin can be absorbed fairly rapidly (Ref. 2-1.9 [4]), this route is gener ally discounted as being significant because of the rapid evaporation of benzene which effectively reduces the time of skin contact. Recent data from the National Toxicology Program (Ref. 2-1.9 [26]) indicates that virtually all of an oral dose of benzene dissolved in vegetable oil is absorbed in rats and mice. It is reasonable to assume that dietary fiber content may reduce both the rate and efficiency of ben zene absorption somewhat by eomplexing the hydrocar bon, but experimental evidence for this is unavailable. To be conservative, 100% absorption of benzene from food and water was assumed in the above calculations. The respiratory absorption of a hydrocarbon vapor such as benzene is a complex process which has only partially been characterized. Initially, when an animal (or man) is placed into an atmosphere containing benzene vapor, virtually all of the hydrocarbon is absorbed into the blood Stream and then distributed to the various tissues of the body. Each tissue will absorb some of the benzene from the blood with some tissues (e.g., those having a high 7 SAL 000001123 phasize that although all three species possess similar metabolic pathways, glucuronidation predominates in the mouse, whereas sulfation predominates in the rat and man- It should also be noted from these data that the specific metabolites which are formed at high doses may be substantially different from those formed at lower (environmentally relevant?) doses, and as a result, it would not be surprising to find entirely different toxic profiles under the two conditions. Similar arguments can be made even between tissues with the same animal. The liter, for example, is known to be capable of metabolizing benzene to a wide variety of reactive derivatives, but it is not considered to be a target organ for benzene toxicity. The reasons for this insensitiv ity are undoubtedly complex, but could be due to the effective shunting of potentially toxic benzene metabo lites into various conjugation pathways which effectively detoxify such metaboiites. In contrast, the cells of the bone marrow appear to be exceptionally sensitive to the toxic effects of benzene, reflecting perhaps a greater emphasis on certain actu ation pathways in marrow cells or less effective detoxification by enzymatic conjugation, or less effective repair of cellular damage. Future research may provide a clearer understanding of the biological basis of such differences. 2-1.4 Toxicity to Blood Formation `'`oxic effects have long been recognized in the bone mar,w of animals and man exposed repeatedly to high levels of benzene vapor (Ref. 2-1.9 (27)) This organ is located in the hollow spaces of s arious bones and is the primary site of blood formation. In simple terms, the bone marrow can be viewed as a tii&uc filling a container of fixed volume, comprising a dynamic mixture of cells which are in various stages of becoming mature red blood cells (RBCs) and white blood cells (WBCs). See Figure 2-1.8 in Most commonly, benzene toxicity is expressed as a decreased formation of various types of blood cells; and therefore, decreased concentrations of these cells are found in the circulating blood (i e., anemia, pancytope nia, etc.) Severe cases of benzene imoxifieaiion may pro gress to a fatal condition where all blood formation essen tially ceases (i.e., aplastic anemia). The mechanism(s) by which benzene affects bone mar row suppression is incompletely understood, but is known to be complex. Much of this uncertainty is perhaps due to the biological complexity of the bone marrow itself. In the clinical and toxicological literature, for example, one of the common early manifestations of benzene toxicity is a decrease in the number of circulating lymphocytes (i.e., lymphocytopenia), suggesting that the lymphocytic stem cell line may be particularly sensitive to the cytotoxic/cy tostatic effects of benzene. Of interest, increased circulat ing levels of other cel) types may also be seen at the same ime as lymphocytopenia (e g., an increase in the number of eosinophilic granulocytes in the blood). It is not clear whether this increase in circulating eosinophils should tnosi appropriately be considered a direct manifestation of benzene toxicity or simply the compensatory prolifera tion of eosinophilic WBC precursors into the bone mar row space made vacant by the killing of lymphocyte pre cursors b> benzene. A similar phenomenon is seen in the anemia of leukemic crisis, which develops when the bone marrow becomes filled with malignant leukemia cells leaving no room for the proliferation of other types of blood cells. It should be noted that in many cases of severe bone marrow suppression, other tissues (c.g., liver and spleen) may be observed to reassume their embryonic functions of blood formation (i.e., extramedullary hemopoiesis.) 2*1.5 Benzene and Leukemia A relationship between repeated high-level benzene expo sure and the occurrence of leukemia in man was recog nized as early as 1928 (Ref. 2-1.9(9]). Acute myelogenous leukemia (AML), and to a lesser extent its variants (e.g., acute erythroleukemia, acute myelomonoeytic leukemia), are the types of leukemia most commonly associated with occupational exposures to high levels of benzene vapor, suggesting that the myeloid, erythroid stem cell line may be particularly sensitive to the ieukemogenic effect of benzene. (See Figure 2-1.8 [2]). Other types of leukemia (e.g., acute lymphocytic leukemia and chronic leukemias of various cell types) are less clearly linked to benzene. Leukemia is characterized by the uncontrolled prolifera tion of a specific type of blood cell, and the term was originally derived from the increased number of circulat ing WBCs or leukocytes (i.e.. leuk ) in the blood (i.e.. -emia). Nonetheless, leukemias are considered by most scientists to be neoplastic diseases of the bone marrow and other blood-forming organs. Leukemias which manifest themselves predominantly in tissues other than the bone marrow are commonly referred to as lympho mas. It should be appreciated that the diagnostic distinc tion between leukemia and lymphoma is an artifact of medical history. The two terms, however, persist in the clinical, epidemiological literature to reflect whether the disease was first diagnosed in the bone marrow or in extramedullary sites. Of significance to epidemiological evaluations, the true incidences of specific leukemias are often clouded since the transformation of leukemia into lymphoma, and vice versa, is commonly encountered in the clinic. The distinction bet ween the leukemias and nonleukemic malignant neoplasms has been the subject of long stand ing debate among scientists, although the most popular paradigm would classify leukemias as cancers. The debate, however, is not complete, and there is consider able evidence to suggest that leukemogrnesis and car cinogenesis represent two highly distinct biological pro cesses. Dameshek (Ref. 2-1.9 (7J) and Wasserman (Ref. 2-1.9 (36]). for example, suggested that myelogenous leukemias are specific manifestations of a more general condition which was termed the "myeloproliferative syn drome." According to these authors, this syndrome is manifested not only as leukemia, but also as such neoplas tic conditions as polycythemia vera. aplastic anemia, or agnogcnic myeloid metaplasia. Walsh (Ref. 2-1.9 [35]) provides an excellent discussion of myeloproliferative syndrome and notes that leukemia is the terminal compli cation in 109c to 159c of patients with polycythemia vera. SAL 000001124- ? ' that an association of acute leukemia with agnogenic i, iOid metaplasia has also been reported. As an alter native mechanism. Dames he k (Ref. 2-1.9 [8]) and Sinkovics n el. (Ref. 2-1.9 [31]) have suggested that certain leukemias may be a particular clinical manifestation of autoimmune disease. Also of interest is the report of Battiforaero/. (Ref. 2-1.9[3]) that myelogenous leukemia is "induced" in rats by a dietary mineral deficiency (mag nesium). Such observations tend to emphasize leukemogenesis as a biological process which may be distinct from our current models of carcinogenesis. If that be the case, then the mathematical models commonly assumed to estimate human cancer risk may be highly inappropriate for use with leukemia. Until recently, attempts to induce leukemia/lymphoma in experimental animals with benzene had been unsuc cessful. However.several investigators have now reported the induction of a lymphoma in the thymus of C57BL mice and derivatives of that strain by a number of chemi cals including benzene. This lymphoma is characterized by the proliferation of T-lymphocytes, and is not believed to be the result of a direct "carcinogenic" effect of benzene on T-cell precursors. Rather this tumor may be the secon dary result of benzene associated activation of a latent endogenous virus (MuLV) which is known to be carried by this strain of mouse. While similar viruses are known to occur in man. available evidence links these human viruses also with leukemias involving the Tslymphocyte. t significant that it is myeloid, not lymphocytic leuke mias. which have been associated with high level benzene exposures in man. Therefore, the significance, if any. of murine leukemia and of benzene associated vtraJ activa tion to human health is unclear. No evidence of viral involvement in human AML has been identified to my knowledge. In this regard, Cronkite and his colleagues at the Brookhaven National Labora tory (unpublished data) have recently identified AML in CBA/Ca mice treated with benzene. This strain is being characterized in a number of laboratories and may even tually prove to be a suitable animal model for benzene leukemogenesis. 2-1.6 Benzene and Solid Turnon Maltoni and his colleagues at the Institute of Oncology in Bologna have conducted a number of studies on benzene which they summarized in 1983 (Ref. 2-1.9 (21)). Begin ning in 1977, they reported that a wide variety of solid tumors had been observed (Experiment BT901) in Sprague-Dawley rats (13 weeks old at the start of the study) receiving SO or 250 mg!kg of benzene dissolved in olive oil by gavage daily, 4-3 days/ week for 52 weeks, then held until spontaneous death. These tumors included car cinomas of the Zymbaf gland (females only at both doses) and oral cavity (females at high dose only), as well as increases in the incidence of mammary tumors (type 'inspecified; suggestive increase in females at high dose >n!y) and non-thymic hemolymphorcticular neoplasms (type unspecified; males only at high dose). It should be noted that Maltoni et et. report only crude tumor inciden ces from their studies and do not provide results of statiatical evaluations of their data. In a separate experiment (BT902,906). Maltoni et el. administered benzene in olive oil b> gavage at a daily dose of 500 mg/kg to 7-wcek-old Sprague Dawley rats, 4-5 days/week, for 104 weeks, which were then held until spontaneous death. According to the authors, under the conditions of this bioassay, benzene caused an increased incidence of a number of tumors: ZymbaJ gland carcinomas (equally distributed among males and females) Carcinomas of the oral cavity (equally distributed among males and females) Carcinomas of the nasal cavities (suggestive increase in males only) Skin carcinomas (males only) Forestomach dysplasias (males and females) and fore stomach tumors (females only) Hepaiocarcinomas (reported by authors but do not appear to be increased to this reviewer) Liver angiosarcomas (males and females) Increase in the number of other malignant tumors, some of which are extremely rare in the SpragueDawley rat, such as lung adenocarcinomas (tumor observed in one male) and soft tissue liposarcomas (tumor observed in two males). In addition, benzene caused a decrease in circulating WBCs. due primarily to a decrease in circulating lympho cytes (males and females) when determined during the 84ih week of the experiment. Increases in the incidence of mammary tumors and non-thymic hemolymphoreticular neoplasms (seen at the lower doses given in BT 901) were not seen in this study. Maltoni et et. suggest that the differences between the results of experiments BT 901 and BT 902,906 must be correlated to the different doses (daily dose and length of treatment) of administered ben zene. rather than to differences in the age of the animals at the start of each experiment. The technical basis for this statement, however, is not clear. Once again it should be noted that the conclusions from this study are subject to technical debate because of the lack of statistical evaluation. Maltoni et et. began in 1983 a study using 6-week-old Wistar rats (BT907) and Swiss mice (BT908) exposed by gavage to benzene in olive oil at a daily dose of 500 mg kg, 4-5 days/week for 104 weeks (rat) and 78 weeks (mouse). Preliminary information from these studies was included in Maltoni era/.. 1985. In the Wistar rat. ZymbaJ gland carcinomas (male and female), non-thymic hemolymphoreiicular neoplasias (suggestive increase in fe males), and an increase in total malignant tumors (sales and females) were observed. In the Swiss mouse, ZymbaJ gland dysplasias (males and females) and carcinomas (males only), mammary carcinomas (females only), pul monary ademonas (males and females), and an increase in total malignant tumors (suggestive increase in females) are reported. Results of statistical evaluations are not reported. 10 SAL 000001125 National Toxicology Program has conducted two-year The studies of Maltoni ei oi (1985) and the National - ology and carcinogenesis studies of benzene in F344 Toxicology Program (1986) have demonstrated without rats and B6C3FI mice. Male F344 rats were administered question that high level benzene exposures can produce benzene in corn oil by gavage at daily doses of 0.50, 100, or 200 mg' kg. 5days/ week, 103 weeks. Female F344 rats and male and female B6C3F1 mice were administered an increased incidence of a wide variety of tumors in rats and mice. It is somewhat more complicated, however, to conclude that these effects are due to a direct carcinogenic benzene in corn oil by gavage at daily doses of 0,25,50, or effect of benzene on these highly diverse tissues, and that 100 mg kg. 5 days,'week, 103 weeks. In rats, increased these animal data are appropriate for quantitative risk tumor incidences were seen for the Zymbal gland (males modeling for extrapolation to environmentally relevant and females), ora) cavity (males and females), and skin levels of benzene exposure in man. (males only). In the benzene treated mice, increased Before current models can be applied, three confound tumor incidences were reported for Zymbal gland (males ing factors must be considered further: and females), lymphoma, (males and females), lung (males and females), Harderian gland (males, marginal in females), ovary (females), and liver (males, marginal in females) (NTP, 1986). Maltoni and his colleagues have also evaluated the car* cinogenic potential of benzene vapor via inhalation. In experiments BT4004 4006. 13-week-old pregnant female Sprague-Dawley rats (gestation day 12 at sun of study) were exposed to benzene vapor at the following concen trations: 200 ppm 4 hours day, 5 days'week, 7 weeks: then exposed at 200 ppm, 7 hours day, 5 days week, 12 weeks: then at 300 ppm. 7 hours day, 5 days'week, 85 weeks, giving a total of 104 weeks of benzene exposure (Group 0 These animals were then observed until spon taneous death. The offspring from the above rats were As discussed above, recent data from the National Toxicology Program (1986) indicated that all of the dosages of benzene utilized in the above cancer bioas says have been at levels where the usual metabolic pathways may have been "wholly or partially satu rated Therefore, it is possible that benzene in these animats was forced into metabolic pathways which would not normally be significant in defining the toxic profile of this compound. The role of murine leukemia virus in the development of thymic lymphoma in the B6C3F1 mouse was dis cussed above. It is not clear whether or not current risk modeling techniques are appropriate for virally med iated neoplasia. exposed to benzene vapor as follows: transplacental!) ring the prenatal period (Note: gestation in the rat is ^proximately 21 days): by inhalation and probably by ingestion (via milk) during weaning: and afterward by inhalation as for the parental animals (Group ]J). One group of offspring was removed from further exposure Benzene is well known to be immunosuppressive, such that it is possible that all of the tumors reported by Maltoni ei oi (1985) and by NTP (1986) are the secon dary result of benzene-induced inability of the animal lo monitor and destroy spontaneously occurring trans formed cells. Certainly, this type of mechanism would after the 15th week of the above treatment schedule (Group II!). The offspring in Groups 1! and 111 were also held for observation until spontaneous death. The results in these three treatment groups will be discussed explain the occurrence of tumors of the oral cavity in the NTP benzene inhalation study, as well as the development of carcinomas of the skin in the benzene gavage studies. separately. Among the benzene treated pregnant rats (Group 1). 2-1.7 Conclusions suggestive increases in Zymbal gland carcinoma (3/53 * As discussed above, the biology of leukemia, bone mar 5.79c in treated rats vs. 1/60 * 1.79c) and malignant row function, and carcinogenesis as relates to benzene mammary tumors (6 54 * 11.19c vs. 2/60 * 3.3^) were seen. Increases in other types of tumors were seen near the exposure is extremely complex. The methods of quantita tive risk modeling have only recently been applied to end of the study but are of unclear significance due to the biological phenomena such as carcinogenesis, and be lo number of surviving animals. cause it is such a young science, it is not surprising that Among the offspring exposed to benzene vapor for 15 current models of quantitative risk extrapolation depend w-eeks (Group 1H). an increased incidence of Zymbal gland carcinomas (male and female), oral cavity carcino mas (female, suggestive in males), carcinomas of the nasal on assumptions w hich are well recognized as being sim plistic in the extreme. Nonetheless, such methods are now , and will continue to be, used to assist in the formula cavity (female), malignant mammary tumors (suggestive tion of human health policy and regulation, since a more in female), and hemal omas (female) were observed. In the definitive understanding of the mechanisms of benzene offspring exposed to benzene vapor for 104 weeks (Group II), an increased incidence of Zymbal gland carcinoma (males and females), carcinomas of the oral cavity associated toxicity and the relevance of such mechanisms to human health may not be sufficiently developed in the near future to offer an acceptable alternative to the risk (female, suggestive in male), nasal cavity carcinomas (reported by the authors, but considered only suggestive by this reviewer), and malignant mammary tumors (sug gestive in females) were reported. Increased incidences of other tumors were seen near the end of the study, but again the low number of surviving animals makes difficult the interpretation of the biological significance of such observations. manager. It is imperative that those who perform risk modeling recognize the limitations of our biological understanding and document fully the various simplifying assumptions made and resulting uncertainties when esti mating by extrapolation the risks to human health due to environmental benzene exposures. It is also important that as new biological understanding becomes avail- II SAL 000001126 able the risk models be improved and previous decisions be reevaluated. In 1980, the EPA Office of Water Regulations and Standards (Ref. 2-t .9[I3]) issued an ambient water qual ity criterion for benzene of 0.66 s*g/l which, at their calculations, corresponded to a risk of one additional cancer for every million people exposed for their lifetime to this concentration of benzene in their drinking water. This value was in fact based on a quantitative risk assess* ment performed in 1978 by the EPA Carcinogen Assess ment Croup (CAC) (Ref. 2-1.9 [12]) using occupational leukemia data from three epidemiological studies of workers exposed to high levels of benzene vapor. The 1980 water criterion assumes several simplifications which would be questioned on the basis of our present know ledge of benzene: The CAG risk calculation assumed that the relative risk of leukemia is "independent of the duration" of exposure, but is simply dependent on the total expo sure. That is. CAG assumed that exposure to 1 ppm of benzene vapor for 10 years (equivalent to 10 ppmyears) would have the same toxicity as would exposure to 3650 ppm for I day (also equivalent to 10 ppmyears). This does not agree with the available clinical experience with benzene. During the past few months, better estimates of the actual benzene exposures seen by the cohort used in one of the critical epidemiological studies modeled by CAG have become available. These suggest that the levels of benzene exposure assumed by CAG were substantially lower than those actually experienced by the worker, and that as a result, the calculated risk is overestimated by the CAG calculations. The authors of the water quality criteria document assumed that benzene is as equally toxic by the oral route as by the inhalation route. This simplification fails to recognize that blood drains from the gastroin testinal tract to the liver which is the primary site of benzene metabolism. In contrast, inhaled benzene is distributed throughout the body prior to metabolism by liver enzymes. The authors of the water quality criteria document did not consider fully the relative contribution of the multi-media sources of normal benzene exposure. Using the formulas in (he criteria document, it is inter esting to note that while the leukemia risk associated with the daily ingestion of water containing 0 66 jif/l of benzene (1.32 Mg/day) is ! per million, the risk associated with eating a boiled egg every day is 79.5 per million. 12 SAL 000001127 FIGURE 2-1-8 [I] MAMMALIAN METABOLISM OF BENZENE 0 o OH Benzene __ Hydroxy- _ cyclohexadienyl Radical Muconaldehyde FIGURE M.8 [2] SCHEMATIC OF BLOOD CELL DIFFERENTIATION AND MATURATION Multipotential Stem Cell tflyeioiO/Eryihroid Siem Cells I | Granulocytic WBCs I L--Megakaryocytic Stem Cell-^- Platelet 1 Eryihroid Stem Cell--*- Mature RBC Macrophage/Monocytic Stem Ceil I m Macrophage/Monocyte Lymphocytic Stem Celt T-Lymphocytes B-Lymphocytes Other Lymphocytes 13 SAL 000001128 2-1,9 REFERENCES: TOXICOLOGICAL EFFECTS OF BENZENE -[I, Aksoy. M. "Benzene as a Leukemogenic and Car* cinogenic Agent". Amer. / Indus. Med. 8:9-20, 1985. [2] Andelman. J. B . Suess. M. J. "Polynuclear Aro matic Hydrocarbons in (he Water Environment**. Bull. WHO 43:479-508. 1970. [.1] Battifora. H. A., McCreary. P. A.. Hahneman.B. M..- Laing. G. H.. Hass. G. M. "Chronic Magne sium Deficiency in the Rat Studies of Chronic Myelogenous Leukemia**, Arch. Pathol 86 610 f/., (968. [4] Blank, I. H . McAuliffe, D. J. "Penetration of Ben zene through Human Skin" Invest. Dermatol. 85.522-526. (985. [5} Brief. R. 5 . Lynch, J.. Bernath. T., Scala, R. A., "Benzene in the Workplace". Amer. Ind. Hyg. Assn. J. 41:616-623. 1980. (6] Cornish. H .. Ryan, R. "Metabolism of Benzene in Nonfasted. Fasted.and Aryl-hydroxylase Inhibited Rats." Toxicol. Appl Pharmacol. 7:767-771, 1965. (7] Dameshek. W. "Some Speculations on the Myelo proliferative Svndrome". (editonal) Blood 6:372 ff.. 1951. 18] Dameshek. W. "Certain Forms of Leukemia as Immunoproliferame Disorders." In Carcinogene sis: A Broad Critique. Williams and Wilkins Com pany. Baltimore. Maryland, pp 141 ff.. (970. J Delore. P.. Bcrgamano, J. "Leucemie Aique en Cours d'intoxicaiion Bezenique", J. Med. Lvon 9 227-233. 1928. [ 10] Environmental Protection Agency, Ambient Water Quality Criteria for Benzene. (PB81-117293), 1980. [11] Environmental Protection Agency. Benzene: Occur* rence in Drinking Water. Food, and Air, (Prepared by JRB Associates). 1983. [12] Environmental Protection Agency, Carcinogen Assessment Croup's Final Report on Population Risk to Ambient Benzene Exposures, (P83^)134), 1978. [13] Environmental Protection Agency. "Notice of Water Quality Criteria Documents". Federal Register 45:79326, November 28. 1980 [14] Fishbein. L. "An Overview of Environmental and Toxicological Aspects of Aromatic Hydrocarbons. I. Benzene." Science Total Environ. 40:189-218, 1984. [15] Goldstein. B D , Witz. G , Javid, J.. Amuroso, M. A., Rossman, T.. Wolder. B. "Muconaidehyde. a Potential Toxic Intermediate of Benzene Metabo lism.**, Adv. Exp Biol. Med. 136AJ3I. 1981. [16] Greenlee, W, F.,Sun,J. D.. Bus, J. S."AProposed Mechanism of Benzene Toxicity: Formation of Reactive Intermediates from Polyphenol Metabo lites.", Toxicol. Appl. Pharmacol 59:187-195, 1981. [17] International Agency for Research on Cancer ((ARC). /ARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, Lyon, France. 29:93-148. May. (982. [18] Irons, R. D. "Quinones as Toxic Metabolites of Benzene", / Toxicol Environ. Health 16:673-678. 1985. [19] Jernina. D , Daly, J.. Whitkop. B . ZaltzmanNirenbcrg, P., Udenfriend, S. "Role of Arene Oxide-Oxepin System in the Metabolism of Aro matic Substrates. 1. In Vitro Conversion of Benzene Oxide to a Premercapturic Acid and a Dihydrodiol". Arch. Biochtm. Biophys. 128:176-183, 1968. [20] Johansson. I., Ingelman-Sundberg, M. "Hydroxyl Radical-Mediated. Cytochrome P-450-dependent Metabolic Activation of Benzene in Microsomes and Reconstituted Enzyme Systems from Rabbit Liver.*, / Biol Chem. 258:7311-7316, 1983. [21] Malioni. C., Conti, B.. Cotti, G., Belpoggi, F. "Experimental Studies on Benzene Carcinogenicity at the Bologna Institute of Oncology: Current Results and Ongoing Research." Amer. J Indus. Med. 7:415-446, 1985. [22] Mehlman. M. A., ed. Benzene: Scientific Debate. Proceedings of the International Conference on Benzene Sponsored by the Collegium Ramazzmi, Sew York On . November 3-4. 1983, Alan R. Liss, New York, 1985. [23] National Research Council Drinking Water end Health, Vol. 3, National Academy of Sciences. W ashington, D C.. (980. [24] National Research Council. Health Effects of Ben zene: A Review, National Academy of Sciences, Washington. D.C.. (976. [25] National Toxicology Program. Toxicology and Carcinogenesis Studies of Benzene (CAS So. 7143-2) in F344/N Rats and B6C3FJ Mice (Gavage Studies). Technical Report No. 269 (galley draft). National Toxicology Program, W ashington. D C. February. 1986. [26] Sabourin, P. J., Chen T-H. Lucier. G.. Birnbaum. L. S., Fisher,E.. Henderson. R. F. "Effect of Dose on the Absorption and Excretion of UC-Benzene Administered Orally or by Inhalation in Rats and Mice." Toxicol. Appl Pharmacol. (Submitted for publication), 1986. [27] Samesson. C. G. "Uber Chronische Vergiftung mit Steinkohlentheerbenzin; vier Todefalle." Arch. Hvg Berl. 31:336-376, 1897. [28] Sawahata. T., Ricken, D.E., Greenlee, W. F "Metabolism of Benzene and its Metabolites in Bone Marrow." In Toxicology of the Blood and Bone Marrow, Irons R. D..ed., Raven Press, New [29] York, pp. 141-148. 1985. Selling, L. "Benzol as a Leucotoxin. Studies on the Degeneration and Regeneration of the Blood and Haematopoietic Organs.* Johns Hopkins Hasp. Reports 17:83-148, 1916. [30] Sherwood, R. J. "The Interpretation of Monitoring Results", Ann. Oceup. Hyg. 15:409-421, 1972. [31] Sinkovics. J. G., Trujillo, J. M., Piema, R. J., Abeam, M. J. "Leukemogenesis Stemming from Autoimmune Disease", In Genetic Concepts and 14 sal 000001129 3.1.9 REFERENCES; TOXICOLOGICAL EFFECTS OF BENZENE (Continued) Seoplosio, Williams and Wilkins Company, Bilti* more, pp 138 ff- 1970. [32] Snyder, R. "The Benzene Problem in Historical Perspective**, Fund Appl. Toxicol. 4:692-699.1984. J33J Snyder, R. "Relation of Benzene Metabolism to Benzene Toxicity." In Symposium on Toxicology of Benzene and Alky/benzenes. Braun, D., cd., Industrial Health Foundation, Pittsburgh, pp. 4453. 1974. [34] Tenney, S. M. "Respiration in Mammals * In Duke's Physiology of Domestic Animals, 9th Edi tion, Swenson, M. J.,ed., Cornell University Press. Ithaca. New York, pp. 175-209, 1977. [35] Walsh, J. R. "Polycythemia Vera: Diagnosis, Treatment, and Relationship to Leukemia" Ceriei* e/33:6 J-69. 1978. [36] Wasserman, L. R. "Polycythemia Vera -- Its Course and Treatment: Relation to Myeloid Meta plasia and Leukemia", Bull A. Y Acad. Med. 30.343 ff., 1954. SAL 000001130 15 %Xi of benzene exposure (on the ordinate). Based on this plot an exponential function was obtained which implied g-threshold" of 10 0 ppm for cyiopenic effects. However, among the 18 workers exposed to 10 to 20 ppm of benzene in the study, no hematologic toxicity was observed. As aoird by Snyder (1984). a major problem in understand ing this study is the lack of information about the defini tion of work exposure confidence concentrations for individual employees. 3-U Leukemia As is true for pancytopenia, the association of benzene with leukemia has a long history. Summarization of this history has been complicated by the fact that hematolo gists differ in how they define leukemia subtypes. There art differences not only in terms of the evolution of crite ria over time, but also because standards differ in differ ent countries. Nosology is particularly important in leukemia because there are major differences between the various subtypes in terms of the frequency of occurrence, the clinical course, the prognosis, and possibly the etiologic mechanism. In summarizing the literature for the present report, the classification as developed by Gold stein (Ref. 2-2.9 [59]) is used. Leukemia is defined as a neoplastic disease w ith increased numbers of white cell or white cell precursors in the blood or bone marrow. Leukemias are usually subdivided depending on whether hey are acute or chronic and in terms of the cell type evolved. Acute myelogenous leukemia is the most com mon form of adult leukemia and is the form of this disease that has been most frequently related to benzene. In this disease, there is a proliferation of cells which are morpho logically related to the normal myeloblast, which is the precursor of granulocy tic blood ceils. There are several variants of acute myeloblastic leukemia, the one most frequently reported in association with benzene being eryihroleukemia Acute myelomonocytic leukemia, in which the precursor is a myeloblast which has the mor phological appearance of a monocyte, and acute promyeiocync leukemia, morphologically a somewhat more mature leukemic cell, have also been associated with ben zene, but to a lesser extent. True monocytic leukemias are rare, but have also been associated with benzene expo sure. Another uncommon form of acute leukemia, usu ally called stem cell leukemia, is defined by proliferation of very immature bone marrow precursor cells. Chronic myelogenous leukemia and possibly related diseases, including essential thrombocythemia, myelofi brosis with myeloid metaplasia are often lumped together under the heading of myeloproliferative syndrome. This reflects their presumed origin in the same precursor cell. Controversy persists, however, concerning the relation ship of these disorders to each other. Lymphocytic leukemias are also classified as acute and chronic. Acute lymphoblastic leukemia is the most com mon form of childhood leukemia. Chronic lymphocytic leukemia usually occurs in late adult life where it is often slowly progressive and not a cause of death. Studies relating benzene exposure to leukemia art sum marized in Table 2-2.8 [2]. As noted by Snyder (1984),the support that these case reports five to the idea of a causal relationship between benzene and leukemia is only partly due to the number of cases involved. With respect to acute znyeloblastic leukemia, the relatively common finding of a worker with aplastic anemia associated with benzene exposure who passes through a pre-leukemic phase into frank acute leukemia is especially impressive (Refs. 2-2.9 [2], [6], [56], [91], and [140]). It is also of note (Snyder. 1984) that there is a relatively high frequency of associa tion between eryihroleukemia and benzene exposure since this is a relatively rare variant of acute myelogenous leukemia. As was true with respect to pancytopenia and aplastic anemia, further support for the association between benzene and leukemia is provided by the diverse occupational and geographical settings from which these reports originate. Despite the diversity, benzene seems to be the common thread. As regards chronic myelogenous leukemia and its possi bly related disorders, including essential thrombocythemia and myelofibrosis with myeloid metaplasia, there ere scattered case reports in the literature; but they form a less impressive body of evidence than the group of studies relating benzene exposure to acute myelogenous leu kemia. There are only a few scattered reports relating acute lymphoblastic leukemia to benzene. The same is generally true for chronic lymphocytic leukemia. The strongest support for an association between benzene and chronic myelogenous and. or chronic lymphoid leukemia comes from France. Specifically, Coguel ft el. (Refs 2-2.9 [57]. [58]) reported 50 cases of leukemia in benzene workers near Paris between I960 and 1965. Among the 44 new cases in this group, there were 13 with chronic myeloge nous leukemia, 8 with chronic lymphoid leukemia. The relatively high proportion of these types of leukemia, however, has not been replicated in other case series. While case repons and case series can provide circum stantial evidence of an association between an exposure of interest (in this case, benzene) and a panicular disease, such investigations cannot provide a scientific test of the hypothesis that the exposure of interest is associated with increased risk of the disease. Such hypothesis testing is in the realm of analytic epidemiology. Such studies have been done among shoemakers in Istanbul and among workers in the rubber industry, the printing industry, xnd in the petroleum and petrochemical industries. Addition ally, a case control study has been done among patients with blood diseases in a hospital in Lyon, Franee. In general, while these studies tended to support the idea that exposure to benzene is causally related to the occur rence of leukemia, many of the investigations have been severely criticized. Controversy has been particularly strong regarding the low limits of benzene exposure which may be associated with the development of leuke mia. A specific discussion of these studies follows. Aksoy and co-workers reported on leukemia among workers in small shoemaking shops in Istanbul. Between I9SS and I960, a solvent with high levels of benzene was introduced into the Turkish shoe industry. The first cases ofaplastic anemia were observed in these workers in 1961, and leukemia appeared in 1967 (Snyder, 1984). Between 1967 and 1975 among 28,300 shoemakers in Istanbul, the 17 SAL 000001131 e tied incidence of leukemia was estimated to be 13 pe* 100,000/year in contrast to the incidence in the general population which was estimated to be 6 per 100.000/year. The concentration of bcniene in the air of the workrooms of the shoemakers was estimated to be 150 ppm. and the exposure had lasted from four months to 17 yean (Ref. 2-2.9(3]). Benzene was banned as a solvent in 1969, and the incidence of leukemia, after peaking in 1973, decreased in 1974 and 1973. No cases were reported in 1976,1977, or 1978 (Ref. 2-2.91150]). Snyder (1984) noted several methodoiogicshoncominp in Aksoy^i work. Specifically, Snyder pointed out that the definition of occupation used for workers with leukemia differed from that used for the official records. It was possible that a worker with leukemia was called a shoe worker whereas the same person appeared on the official record as having another occupation. Additionally, there was no follow-up of the 26,500 workers exposed to ben zene, and it was possible that some cases ofleukemia were missed. Further, the stated incidence rate of 6 per 100,000 year for the general population was for an unknown location and an unknown time, and no age standardization was done in making the comparison between the incidence rate for the general population and that for the shoe workers. Finally, the exposure levels reported by Aksoy aod co-workers represented occa sional random measurements taken in. what was in *sence, a cottage industry. several cohorts of rubber workers have been studied including the investigations of Pagnotto c/c/. (Refs. 2-2.9 [104], [105]), McMichaei et al (Refs. 2-2.9 [94], (95), [96]), Andjelkovic ei al. (Refs 2-2.9 [9J. [10]). Monson and Nakano (Refs. 2-2.9 [97], [98]), and Infante et al. (Ref. 2-2.9 [74]). These investigations have been summarized and criti cally reviewed by van Raalie and Crasso (Ref. 2-2.9 [ISO]). In their review, van Raalte and Crasso note that Pagnotto et at. (1961) performed a survey in a rubber coating industry where a benzene worker had died from panmyelophthisis. In a follow-up study 18 years later (Pagnotto et al. 1979). which cited 36 workers who were exposed for 1 to 24 years at a level of 10 to 50 ppm(PWA) with short term peaks which were higher, there was no occurrence of either blood dyscrasia or leukemia. In the study by McMichaei*/ al. (1974), a threefold excess mor tality from leukemia was found though the workers exposed to solvent had a sevenfold excess of death from lymphatic leukemia with six of eight deaths resulting from chronic lymphatic leukemia. In contrast, only a twofold excess mortality was detected for myeloid leuke mia. Subsequent studies by this group confirmed the excess risk of leukemia among solvent exposed workers. An historic prospective study in a cohort of rubber workers over the period 1964 through 1973 was done by Andjelkovic et al (1976). While increased risks for neoplasms of the hematopoietic and lymphatic systems were found for white males, white females did not experience excess mortality. Wolf */ al (Ref. 2-2.9 [JS7]) were noted to have performed a case control study involving 72 workers with leukemia which had occurred between 1964 and 1973 in four rubber and tire companies with moder ate levels of benzene exposure. While increased risk for lymphatic leukemia was identified, no increased risk was detected for myelogenous leukemia. Monson and col leagues (1976, 1981) reported on mortality among 29,087 men and women who had worked in a rubber plant at least two years within the periods from 1940 through 1974, and 1974 through 1978, respectively. In both instances, an excess mortality from leukemia was found. Van Raalte and Crasso were particularly critical of the studies performed by Infante and co-workers in the rubber industry. In 1977, Infante eiel reported a fivefold increase of all leukemias and a tenfold increase in the combined incidence of myeloid and monocytic leuke mias. It was stated that "the benzene levels themselves were generally below the limits recommended at the time of their measurements,** (referring to threshold limit values in force at the time: exposure lOOppmin 1941 to 10 ppm in I97|)andthat exposure levels from 1969 onward were, "in most instances ranging fromO to 10 or IS ppm" (van Raalte and Crasso, 1982). This statement appeared to be contradicted by Infante (1977) during OSHA ben zene hearings in November and December, 1977. Specifi cally, at the hearings, it was indicated that the leukemia cases were more probably related to unknown but appar ently quite high levels (in excess of 100 ppm) of benzene exposure. In 1981, Rinsky */ al published a follow-up to Infante's 1977 report. The identical cohort was used in the follow up study but it was based upon 989c vital status identifica tion of the study group versus 75% in the 1977 report. There were seven deaths due to leukemia among 748 workers who had at least one day of exposure to benzene between 1940 and 1950. The leukemia cell types involved were myelocytic or monocytic. In contrast to the seven cases identified in the follow-up study, comparable Unit ed States death rates standardized for age, sex, and calendar time period were expected to yield only 1.25 leukemia deaths. This Standardized Mortality Ratio (SMR) is equal to $60, p <0.001. The mean duration of benzene exposure in the cohort was less than one year. For workers exposed to benzene for five or more yean, leukemia deaths produced an SMR of 2,100. Four addi tional cases were excluded from the analyses. These included a 67 year old man with a latency for acute myelogenous leukemia of 37 years, an individual who was among salaried employees not in the original cohort, an individual with acute lymphocytic or aleukemic leuke mia, and an individual who was diagnosed by a hematol ogist as having acute myelocytic leukemia but whose death certificate listed the cause as aplastic anemia. While Snyder (1984) felt that Rinsky1* investigation indicated that benzene is a human carcinogen at levels not greatly above the curtent legal standard, van Raalte and Grasso (1982) advanoed an argument which reached the opposite conclusion. Specifically, van Raalte and Grasso noted that one ofthe cases in Rinsky*> group ofseven was a worker with chronic myelogenous leukemia which had developed after only one month of exposure to benzene. This is at variance with most clinical experience and suggested that other faciors besides benzene may have been involved. Additionally, all cases included in Rin- * SAL 000001132 group of seven occurred between 1950 and 1961,and the only exception among the total of 12 eases identified was that worker for whom the period of latency was 57 years. Further, van Raihe and Grasso pointed out that there wert no new cases at all in employees who were first exposed after 1951. On the contrary, the period of exposure for all eases started in the first 13 years since the plants opened, that is from 1937 through 1950. Moreover, with the exception of the aforementioned unusual case of chronic leukemia with only one month of exposure, the two cases with the most recent onset had the shortest latency period, three and nc-half and four years, respec tively. In other words, patients exposed to higher concen trations of benzene have a longer latency. This, they argue, is inconsistent with both general clinical expe rience and experimental precedent. Finally, all of the cases in Rinsky *s primary set ofseven had a latency period of less than 22 years. Since the plant closed in 1976, there were only two possible (or suspect) cases noted in 26 years of employee exposure between 1950 and 1976 plus five subsequent years of follow-up through 1981. Even grant ing these two cases, van Raalte and Grasso feel that Rmsky's data shows a decline in the incidence of leukemia which parallels the decline in benzene exposure at the factories in question. Far from indicating an association between leukemia and low level exposure to benzene, van Raalte and Grasso suggest that Rinsky's data is more onsistent with the interpretation that low levels of ben zene exposure show no excess in leukemia mortality. Turning to studies in the printing industry. Lloyd et of (Ref. 2-2.9 [87]) found an increase in the number ofdeaths from leukemia among priming pressmen, eight observed versus 5.1 expected. Green et al (Ref. 2-2.9 [63]) performedacancermortality among male U.S. Government Printing Office employees who had worked during the period January, 1948 through April, 1977. A significantly higher proportion of deaths were related to multiple mye loma, leukemia, and Hodgkin's disease. Although the excess leukemia deaths occurred primarily in binders whose benzene exposure was ended in the early 1960s, there was little or no change in leukemia mortality after the discontinuance of benzene. As such, the low level exposures to benzene may not have been associated with an excess incidence of leukemia (van Raalte and Grasso, 1982). Paganini et ol (Ref. 2-2.9 [103]) performed a mortality study in Los Angeles among 1,361 web pressmen with one or more years ofexposure during the period 1949 through 1965. Seven eases of leukemia were observed versus 2.8 expected in a comparable U.S. white male population. Six of the seven cases were of the myetomonocytic type. Additionally, myelogenous leukemia was mentioned in a secondary role in one case and another man had myelofi brosis (van Raalte and Grasso, 1982). As regards the petrochemical industry, Ott et /. (Ref. 2-2.9 (102)) and Townsend et ol (Ref. 2-2.9 (147)) per formed a mortality study among 594 workers involved in three production areas on or after January I, 1940 through January 1,1974. Because of limited information available regarding the work place, exposure assessment was limited to data collected between 1953 and 1972. During this time, the time-weighted average exposure to benzene was estimated to be generally less than 10 ppm although some exposures in excess of 30 ppm occurred, ineluding occasional higher values with a peak of 937 ppm. Among all workers studied, there were 102 deaths versus 128.2 expected on the basis of age-time specific rates for white males in the United States. There were two deaths from leukemia while 1.0 was expected. A third death occurred and was attributed to pneumonia al though the individual had acute myetoblastic leukemia. Both van Raalte and Grasso (1982) and Snyder (1984) point to the relatively small size of this study population in suggesting that the data are insufficient to provide a reliable and independent estimate of the relationship between benzene and the risk of developing leukemia. In addition to the mortality studies. Townsend (1978) performed a health examination study among 282 work ers from this cohort. There was no indication of adverse benzene effects in this group. Another investigation, by Thorpe (Ref. 2-2.9 [143)). involved a much larger population, 38,000 persons employed or on pension from large oil company during the period from 1962 through 1974. Over a ten year period. 18 cases of leukemia were recorded versus an expected value of 23.2. Precise statements of exposure levels to benzene were unavailable. Several other investi gations in the petrochemical industry include studies by Theniam and Goulet (Ref. 2-2.9 [141]), Hanis et ol (Ref. 2-2.9 [68]), Thomas et el (Ref. 2-2.9 [142]), and Rushton and Alderson (Refs. 2-2.9(123). [124]). In only one case was an excess ofdeaths associated with leukemia demon strated. Theniam and Goulet (1979) studied the mortality of 1,205 men employed for more than five years in a Canadian oil refinery in East Montreal between 1928 and 1976. Three deaths from leukemia and lymphoma were identified from death certificates versus 2.36 expected. Hanis tt ol (1979) studied employees of Imperial Oil Company exposed to petroleum products from 1964 to 1973. The mortality of the exposed group was compared with that of a non-exposed group concerning cancer of the lymphatic and hematopoietic systems. Seven deaths were identified in the exposed group and 15 in the nonexposed group. Thomas et ol (1980) studied 3,105 union members in Texas who worked from 1947 through 1977. Although the study was small, an increased relative fre quency of leukemia and multiple myeloma was demon strated among white males with more than 10 years of membership. Rushton and Alderson (1980,1981) studied 35,000 workers with more than one year of service at eight oil refineries in the United Kingdom between January. 1950 and October, 1975. There were 30 cases of leukemia identified, but this was relatively less than would have been expected in comparison with national rates. Addi tionally, these authors formed a case control study on the same population using two lets of refinery controls per case. One set of controls was matched for length of ser vice. Industrial hygienists classified exposure as low, medium, or high. In no case was a statistically significant association demonstrated between benzene exposure and leukemia, although the risk of medium plus high expo sure workers taken together, relative to the risk of those 19 SAL 000001133 2-4 )NDRINK1NG-WATER EXPOSURE David H. Powell Ph.D. in households containing one or more smokers. These William A. Tucker. Ph D. households exhibit at least 50 percent greater concentra Environmental Science and Engineering. Inc. tions than households of nonsmokers. One cigarette can Gainesville. Florida generate approximately 90 micrograms (Mg) of benzene (Ref. 2-4.4 [3]). The portion of the benzene in the main stream smoke is predominantly absorbed by the smoker 2-4.1 Occurrence and not exhaled. Mainstream smoke is that which the 2-4.1(1) Food smoker inhales; however, the sidestream smoke which is reteased to the room often contains twice the quantity of Dau on the occurrence of benzene in food are limited. some chemicals as the mainstream smoke (Ref.2-4 4 [6]) Mara and Lee (Ref. 2-4.4 (11]) reported that benzene Therefore, of the 90 m8 of benzene released from each occurs naturally in fruits, fish, vegetables, nuts, dairy cigarette, possibly 60 Mg is released to the smoker's envi products, beverages, and eggs. These authors report con ronment through the sidestream smoke. centrations ranging from 2 micrograms per kilogram (Mg/kg) for canned beef to 2,100 Mg.'kg for eggs. Cooked 2-4.2 Exposure meats are reported to have higher benzene levels than raw Reported benzene concentrations in foods do not involve meats, and it is postulated that the increased benzene all food groups. It is not known how representative these levels observed after cooking meats is due to the break concentrations are of the concentrations in foods in down of.aromatic amino acids such and tyrosine (Ref. general Dietary intake of benzene has been estimated to 2-4.4 (5)). be as high as 230 micrograms per day (m day) from beef, Low levels (<!0 Mg kg) of benzene in food could be due eggs, and rum alone (Ref. 2-4 4(13]). Assuming that the to a partitioning from the ambient levels of atmospheric average adult male weighs 70 kg. an intake of 250 Mg day benzene. The high levels observed in eggs indicate an would be equivalent to 3.6 mtcrograms per kilogram per intrinsic mechanism for the biochemical formation of day (Mg kg day), fn the absence of further data. Letfcie- t ene. Table 2-4.3 [1] summarizes the reported occur- uicz et at (Ref. 2-4.4 (S]) assumed the dietary intake of Tv.-.c of benzene in foods. benzene was at that level. Gilbert et al (Ref. 2-4 4 {$]) 2-4.1(2) Air estimated the ingestion due to only those foods with reported benzene concentrations (i.e.. butter, cooked The materials balance for benzene indicates that 93 per beef. eggs, and haddock), resulting in a daily ingestion cent of environmental releases of benzene are to the intake of 31 to 108 Mg'day. atmosphere, and three-quarters of this release is asso Exposure to benzene in the atmosphere is highly varia ciated with fuel combustion (Ref. 2-4 4 [5]) As a result of ble. reported levels range between low parts-per-biliion these emissions.it is not surprising that ambient air levels values in outside air to low parts-per-milhon in certain of benzene have been correlated with traffic volumes industrial settings Median air concentrations of benzene (Ref. 2-4 4(2]). have been calculated by Brodzinsky and Singh (Ref. 2-4 4 Atmospheric benzene is ubiquitous; remote regions have (3]) for rurali remote areas (4.5 Mg m1). urban'suburban measured concentrations usually ranging from i to 3.3 areas (8 9 MgmJ). and source-dominated areas (9.6 micrograms per cubic meter (pg/m'). Higher levels are Mg/mJ). Thus, in urban ' suburban areas, people inhale observed in urban and industrial environments. Table approximately 180 m8 of benzene each day (at 20 cubic 2-4.3 (2] summarizes benzene concentration ranges and meters, m\ of air inhaled each day). As a comparison, a averages for various atmospheric environments. one-pack-per-day smoker inhales approximately 600 Indoor benzene levels have been studied in industrial Mg/day of benzene from mainstream smoke. Exposure by settings Inside chemical plants, reported concentrations these routes is substantia), but highly variable in the range from 2.000 to 10,000 pg/m>. The current Occupa- genera) population. tionaJ Safety and Health Administration (OSH A) regula Average annual atmospheric benzene concentrations tion on workplaceexposure is 32.000Mg/mJ (10 parts per and the size of exposed populations have been calculated million, ppm) for the time-weighted average (TWA)con- by Mara and Lee (Ref. 2-2.4 [ 11]) based on air dispersion centration for an 8 hour exposure with a peak maximum models. Approximately half of the population of the concentration of 160.000 Ml/mJ (50 ppm) for any 15 United States was estimated to be exposed to average minute period during an 8 hour day (Ref.2-4.4 ()]). atmospheric benzene concentrations between 3.5 and 13 Indoor benzene levels in residences have been reported Mg/m1. Sample and Gilbert (Ref. 2-4.4 [14]) to have a median A newborn, formula-fed infant's respiratory intake of ilue of 15.0 jig/m* and an arithmetic mean of 25.8 benzene can be expected to range from 1.0 to 2.2 MS/m1 for 353 nighttime observations of benzene. There Ml! kg/day. whereas the intake of a nonsmoking. 70- is a minimal correlation between indoor concentrations kilogram (kg) adult male may vary between 1.5 to 360 and outside ambient levels. The impact of smoking on Ml/kg.' day, depending on ambient benzene concentra indoor benzene concentrations appears to be important tions (Ref. 2-4.4 [8]), 60 sal O0OZ134 fABLE 2-4J [1] Foods Reported to Contain Benzene Fruits* Apple Citrus Fruit Cranberry and Bilberry Currants Guava Pineapple Strawberry Tomato Nuts* Ftlben. roosted Peanut, roosted Macademia Nut Vegetables' Bean Leek Mushroom Onion, roasted Parsley Potato Soya Bean Trassi, cooked Dairy Products Butter (0.5 pg 'kg)* Blue Cheese* Cheddar Cheese* Other Cheese* 4 Ref. 2- 4 f if] 4 Ref 2-44115) * Ref 2-4 4(1?] Ref. 2-4 4(12) ` Reft. 2-4(9). 110) 1 Irradiated and non-ifradiated haddock, respectively * Rel 2-4 4(7] 4 Ref 2-44(11) Source: Ref 2-4 4 (5] Meat, Fish, and Poultry Cooked beef (2 to 19 Mg'kg)' Chicken (<10 Mg kg)4 Egg. hard boiled (500 to 1.900 Mg kg)* Egg, uncooked (2100 Mg/kg)4 Haddock (100 to 200 Mg'kg)' Lamb, heated 10 ug'kgr Mutton, heated J0 Mg kg)4 Veal, heated (<10 Mg'kg)4 Beverages Cocoa* Coffee* Jamaican Rum (120 Mg kg)' Tea* Whiskey* TABLE 2*43 |2J Su/nmir> of Benzene Occurrence in Air Cnsironmeni Rcntent Concentration (Mt/n,>) Remote (Range) Urban (Range) Residential -- Remote from Traffic (Average) Near Chemical Plant (Average) Near Refineries (Average) Gas Stations (Range) I to 2.5 4 to 160 4.5 14 9 <!to32 Sources: Refs. 2-4 4 (5). (8) 2^/J * lfP*= 6) SAL 000001135 4.< "TERENCES: NONDRINKING-WATER EXPOSURE t 1] American Conference of Governmental Industrial Hygienists (ACCIH), Threshold Limit Values for Chemical Substances and Physical Agents in the Work Room Environment, Cincinnati.Ohio, 1985. 2] Battclle, Environmental Monitoring -- Benzene, Battclle Columbus Laboratories, Columbus, Ohio, 1979.. 3] Brodzinsky, R., Singh, H. B. Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data, prepared by SRI International, Menlo Park, California for Environmental Scien ces Research Laboratory, Office of Research and Development, V. S. Environmental Protection Agency. Research Triangle Park, No. Carolina, EPA-440. 4-79-029b, 1982. [4} Drill, S., Thomas R. Environmental Sources of Benzene Exposure: Source Contribution Factors. Prepared by Mitre Corporation for the U. S. Envi ronmental Protection Agency, EPA-570/9-79-004, 1979. [5] Gilbert. D., Byrne. M , Harris. J., Steber, W.. Woodruff. C. An Exposure and Risk Assessment for Benzene, Final Draft. Report, Prepared by Arthur D. Little. Inc. for U. S. Environmental Pro tection Agency Office of Water and Waste Man agement. Washington, D. C. PA Contract No. s8-01-5949, 1982. 16] Johnson. W R., Hale, R. W , Nedlock, J. W.. Grubbs. H. J..and Powell. D. H."The Distribution of Products between Mainstream and Sidestream Smoke", Tobacco Science 17:141-144. 1973. J7J Leibich. H. M.. Koenig. Wr. A., Bayer. E. "Analysis of the Flavor of Rum by Gas-Liquid Chromato graphs and Mass Spectrometry" J. Chromato. Sci. 8:527-533, 1970. 18] Letkiewicz, F., Johnston. P., Macaluso, C., Elder, R., Yu.W., Bason. C. Occurrence of Benzene in Drinking Water. Food, and Air, Prepared by JRB Associates for U. S. Environmental Protection Agency Office of Drinking Water, Contract No. 68-01-6388, 1983. 19] MacLeod. A. J.. Personal Communication to H. I. Chinn. (Cited in Drill. S., Thomas, R., Environ mental Sources of Benzene Exposure: Source Con tribution Factors, 1979), 1977. JIO] MacLeod, A. J., Cave, S. J. "Variations in the Volatile Flavour Components of Eggs" J. Sci. Food Agric. 27:799-806. 1976. [11] Mara. S. J,, Lee, 5. S. Assessment ofHuman Expo sure to Atmospheric Benzene, U. S. Environmental Protection Agency, Research Triangle Park, No. Carolina, EPA-450,3-78-031,1978. (12] Merritt, C. "Qualitative and Quantitative Aspects of Trace Volatile Components in Irradiated Foods and Food Substances". Radiation Res. Rev. 3:353368, 1972. 113] National Cancer Institute (NCI). On Occurrence, Metabolism, and Toxicity Including Reported Car cinogenicity of Benzene. Summary Report, Wash ington, D. C., 1977. [14] Sample, C.J., Gilbert, D. Indoor Ambient Benzene Concentrations: An Assessment ofFactors Related to Indoor Air Quality. American Petroleum Insti tute, Washington, D. C., 1985. [15] Siek, T. J., Lindsey. R. C."Semiquantitative Anal ysis of Fresh Sweet Cream Butter Volatiles", Jour nal of Dairy Sciences 53(6):700-703, 1970. [16] Van Straiten, S., Editor. Volotile Compounds in Food, 4th Edition. Supplement 1, Central Institute for Nutrition and Food Research TNO, Zeist, The Netherlands, 1977. 62 SAL 000001136 'r0P . J8 UPDATED: 1989/03 TOXICITY HAZARD INFORMATION FOR MSDS BENZENE CAS# 71-43-2 EXPOSURE LIMITS: AEL (DU PUNT): TLV (ACGIH) : PEL (OSHA): WEEL (AIHA): 1 ppm (8 & 12 hr TWA) 5 ppm (15 minute TWA) 10 ppm, 30 mg/m3, A2 1 ppm, 3.2 mg/m3 (8 hr. TWA), 5 ppm (short term exposure limit), 0.5 ppm (action level' not established CARCINOGENICITY LISTING: Listed by the International Agency for Research on Cancer having sufficient evidence from epidemiologic studies to support a causal association between exposure and cancer, (IARC GROUP 1). Listed by the National Toxicology Program as a known c a r c i n o g e n. Controlled by Liu Pont as a potential carcinogen. Regulated by OSHA as a carcinogen. as AQUATIC TOXICITY: The compound is moderately toxic. 96 hour LC50, fathead minnows: 35 mg/L. HEALTH HAZARD INFORMATION: Ex cess ive b enz e n e e X P os u r e m a y caus e r e d u ce d red and wh ite b loo d ce 1 1 f o r m at i on a n d lung i r r i t at ion wi th CO ugh, d is c omf o r t. s h or tne 53 o f bre a th a n d pulmon a ry ed ema. It may c au s e he a rt i r r e gula r it l e s w i t h s u dden de a t h. Ch r oni c ov e r ex P os ur e Hi ay c a us e b on e m a r r ow in ,]ur y l *P 1 ast 1 c a n e m i a an d 1 u k errii a w i t h s ymptoms of lightheadedness, loss of appetite, abdominal discomfort, blurring of vision, shortness of breath, pale skin, easy bruising, nose bleeds, bleeding from gums and excessive menstrual flow. Gross overexposure may cause death. Ingestion or inhalation may cause nausea, vomiting, weakness, dizziness, headache, confusion, tremors, incoordination, convulsions and loss of consciousness. It is a skin, eye, nose and throat irritant. absorbed through the skin in toxic amounts. It can be SAL 000001137 FIRST AID t. INSTRUCTIONS TO PHYSICIANS INHALATION: If large amounts are inhaled, remove not breathing, give breathing is difficult, give oxygen, physician. to fresh and call air. a If SKIN CONTACT: In case of contact, immediately flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes. Call a physician. EYE CONTACT: In case of contact, immediately flush eyes with plenty of water for at least 15 minutes. Call a physician. INGESTION: If swallowed, do not induce vomiting. Immediately give two glasses of water, or activated charcoal slurry. Never give anything by mouth to an unconscious person. Call a physician. NOTES TO PHYSICIANS: To prepare activated charcoal slurry suspend 50 g activated charcoal m 400 mL water in plastic bottle shake well. Administer 5 mL/kg, or 350 mL for an average adult. and SAL 000001138 HUMAN HEALTH EFFECTS OF OVEREXPOSURE BY: Skin contact may initially include: skin irritation with discomfort or rash. Evidence suggests that skin permeation can occur in amounts capable of producing the effects of systemic toxicity. Eye contact may initially include: eye irritation with discomfort, tearing, or blurring of vision. Inhalation may initially include: irritation of upper respiratory passages, with coughing and discomfort. the Ingestion or inhalation may initially include: temporary nervous system depression with anaesthetic effects such as dizziness, headache, confusion, incoordination, and loss of consciousness; or nonspecific discomfort, such as nausea, headache, or weakness. Higher exposures may lead to these effects: reduced white blood cell production; aplastic anemia or leukemia with symptoms of lightheadedness, loss of appetite, abdominal discomfort, blurring of vision, shortness of breath, pale skin, easy bruising, nose bleeds, bleeding from gums and excessive menstrual flow; temporary lung irritation effects with cough, discomfort, difficulty breathing, or shortness of breath; temporary alteration of the heart's electrical activity with irregular pulse, palpitations, or inadequate circulation; or fatality from gross overexposure. Epidemiologic studies suggest that this compound may pose a risk of aplastic anemia and certain types of leukemia to humans. Individuals with preexisting diseases of the bone marrow may have increased susceptibility to the toxicity of excessive exposures. 0000011^9 SAL ANIMAL DATA: Inhalation 4 hour LC50: 13,700 ppm in rats (Very toxicity by inhalation) Skin absorption LD50: no information found Oral LD50: 930 mg/kg in rats (Slightly toxic by ingestion) low The compound is a skin and eye irritant, but is not a skin sensitizer in animals. Inhalation: Toxic effects described in animals from repeated exposures by inhalation include bone marrow supression with decreased red and white blood cells, narcosis, and liver, spleen, thymus, hematological, ovarian and testicular changes, growth and immune system depression, and kidney weight effects. Long term exposure produced hematological changes, bone marrow supression, narcosis, organ weight affected for the spleen and testes; kidney, and testes changes, immune system depression, and decreased survival time. Ingestion: Long term administration of the compoun d oral dosing resulted in effects on the blood formin Q system with decreases in white blood cells; ovarian changes; mammary, zymbal, adrenal, harderian and preputal glands chnages; lung, liver and forestomac h changes; tremors, and decreased bod/ weight. by Tests in some animals demonstrate carcinogenic activity. Tests in some animals indicate that the compound may have developmental toxicity but only at maternally toxic dose levels. Tests in female animals for reproductive effects have not been performed. Tests in male animals demonstrate reproductive toxicity. The compound does produce genetic damage m animals and bacterial and mammalian cell cultures. It did not produce heritable genetic damage. SAL 000001140 American Petroleum Institute 1220 L Street. Northwest Washington. D C. 20005 202-682-8000 V 3 April 8r 1988 TO: --BENZENE -KBfiHEff GROUP FROM: R.P. STRICTER RE: LEE THOMAS LETTER CONCERNING BENZENE REMAND AND API COMMENTS TO ATSDR ON BENZENE TOXICITY PROFILE Enclosed for you information is a letter by Lee Thomas to EPA Assistant Administrators and the EPA General Counsel addressing EPA strategy on the Section 112 remand of the benzene decisions. A cover letter by Cosmo DiPerna further addresses the ramifications of this letter. ICF/Clement has completed Phase I of the Benzene Dose Response Research Project. A draft has been reviewed by the BIG project team and other members and staff. A final report is due early next week and will be submitted to EPA for their consideration in addressing the benzene Section 112 remand. EPA is expected to issue proposed benzene rules in June. Other activities to support the benzene risk assessment effort are also underway. These include pharmacokinetic modeling efforts with Oak Ridge Lab; exposure assessment efforts with Jim Sample and PEI Assoc.; and a project to define acceptable risk levels with Environ Corp. The ICF/Clement Phase II effort has been approved by management and is now in final stages of contracting. CMA has agreed to contribute $100,000 to the project. CMA members and staff to the Benzene Program Panel deserve recognition for their ability to expeditiously review and make a timely decision on this important effort. Completion of the project is expected in June in time to address the EPA benzene remand proposal and the EPA public hearings anticipated in late summer 1988. Also enclosed for your records is a copy of the final API comments to ATSDR on the draft Benzene Toxicological Profile. xc: BIG mailing list 4/27/88 FYI 005407 TO: TACTF, PROPOSITION 65 TF, BCG FROM: MICHAEL WANG An equal opportunity employer SAL 000001141 American Petroleum Institute 1220 L Street. Northwest Washington. D C 20005 202-682-6000 April 8, 1968 Benzene Issues Group and Benzene Litigation Steering Committee EPA BENZENE NESHAP DECISION Attached is EPA's proposed benzene NESHAP decision in response to the D.C. Circuit's opinion on the vinyl chloride case. While the "bottom" line is favorable for the petroleum industry and follows the principles API has been suggesting to the Agency/ the road by which EPA arrived at the decision could lead to court attack by environmentalists/ e.g. The letter by Lee Thomas suggests that the safety determination under Section 112 of the Clean Air Act is substantially different than for other programs. Environmental groups are likely to contend the distinction made by Lee Thomas is without merit. For the first time/ EPA suggest that non-leukemia cancers should be considered/ but they have not been modeled for this rulemaking, Page 6 of the attachment to the Lee Thomas letter. The obvious question is why weren't the non-leukemia cancers modeled, when risk assessments such as those developed by California are available. API needs to continue its efforts on developing more realistic benzene risk assessments that will give EPA greater flexibility in considering the first stage of the two step NESHAP decision process. An API report with an update of the 1985 CAG benzene assessment (linear model) is scheduled to be delivered to EPA next week, with a new biologically based, quadratic model to be provided in mid-June. API also planned to examine the non-leukemia cancer incidence of the Ohio Pliofilm cohort this year. We need to accelerate the work so that the findings will be available for the benzene NESHAP rulemaking during the summer. Attachment C. J. DiPerna An equal opportunity employer 000001142 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON 0 C 20460 Hls-|s-v MEMORANDUM tmE A*Mis;STB*09 SUBJECT: Proposed benzene NESHAP decisions and limitation of issue to Section 112 of the Clean Air Act FROM: Administrator TO: Addressees One of the most difficult decisions confronting the Agency is how to respond to the D.C. Circuit's opinion in the vinvl Chloride case, in which the court remanded EPA's National Emissions Standard for Hazardous Air Pollutants (NESHAP) for vinyl chloride. The first NESHAP that will be issued after Vinvl Chloride is that for benzene. Over the past few months, I have received numerous detailed briefings on all aspects of the decision-making on benzene. After careful consideration, I have decided on a regulatory approach, which is summarized in the attached decision outline. I am directing the Assistant Administrator for Air and Radiation and his staff to incorporate this approach into a Federal Register notice that will serve as the vehicle for my proposed decision on reconsideration of the NESHAP. In previous meetings and discussions, a number of representatives of other programs have expressed their concern that the decisions I reach regarding "acceptable" risk levels for NESHAPs will drive the decisions that other offices must make when they regulate risks. The General Counsel has advised me, however, that as a legal matter the decisions I make on "acceptable" risk for NESHAP purposes do not control judgments that I must make under other statutes that regulate risk. As a policy matter, for the reasons set out below, I see NESHAP judgments as unique and limited to the peculiar context of Section 112 of the Clean Air Act. Section 112 requires the Administrator to establish standards at "the level which in his judgment provides an ample margin of safety to protect public health." Prior to the decision in the vinyl chloride case, judgments under this statutory prescription had generally been made in an integrated manner, considering a range of health, risk, and other factors, including costs and feasibility. As a result, the final decision did not separately weigh the factors in arriving at a judgment. SAL 000001143 3 Each regulatory statute contains specific tests for regulatory action; none of these resemble the requirements of Section 112. Because of the unique features of the Clean Air Act*s NESHAP provisions, I believe that no other statutory riskbased regulatory determinations provide an appropriate model for identifying "acceptable risk," and that NESHAP "acceptable risk" findings have little value in making risk judgments under other statutes, or even under other provisions of the Clean Air Act. Indeed, because I am free to issue rules that drive even lower those risks that I find "acceptable," it may sometimes be appropriate for an "acceptable" risk to be somewhat higher than the target risk ranges EPA has used when implementing statutes that do not provide for the second, more protective, step called for by the Vinvl [Chloride opinion. I know you and your staffs have spent considerable time, thought, and energy assisting me with this decision. I believe that the approach outlined in the attachment will provide for environmental protection as called for in Section 112 of the Act, as interpreted in the Vinvl Chloride decision. I also believe that for both legal and policy reasons, the decision is unique and you should vjew it only in the narrow context of Section 112. ADDRESSEES: | I Assistant Administrators General Counsej SAL 0000011AA BENZENE RE2-WE I. Process Used in Reconsideration II. General Conclusions Regarding Ft) 1 icy for Section 112 Decisions A. General Conclusions B. Approach to Deciding Acceptable Risks C. Approacn to Deciding Ample Margin of Safety III. Specific Decisions - Acceptable Risks IV. Specific Decisions - Ample Margin of Safety OOOOOll^5 SAL 3 :i. genesxl gammas* equct rer sEcnra n- dscisicis A. General Considerations Eath case niist be decided on its own merits (i.e. , case-by-case). o ihere are no precise criteria or bright lines used m making, decisions on individual cases; rather, I believe the individual facts of each case mist be weighed together. Decisions should always be made in 2 separate steps. -- First, decide the level that represents an acceptable risk as a starting point for further analysis. -- Then, decide the level that provides an anple margin of safety to protect public health. I believe the Court's references to driving and breathing city air should not be vi e-red as quantitative guidance on acceptable risk levels; but, rather only as support for the position that this is not a risk free society. Furthermore, because everyday life is not risk free, I believe the appropriate judgment in the first step analysis is on the question, "What is an acceptable level of exposure and risk?" Not on "vhat is safe?" As a general approach, I am inclined to want to see risks in the range of 10-4 or less. When estimated risks exceed this, I oe..eve it is important as a next step to look at the aggravating arc mitigating factors. 0 I recognize that there is considerable urcertainty in risk assessments. 0 In this decision process, it is accepted that there may be situations where sltitdowns result fran the decisions. 5. Arcmach fn rtaririina ArrPPf^lP Risks As a method of approaching these decisions, it is appropriate to: -- Begin by considering: (1) Maxiirtsn E2qsed Individual (MET) (2) Incidence (In this, the greatest arphasis siould be placed zr. incidsice associated with lifetime risks of 10-5 arC higher; incidffce associated with populations exposed to lifetime SAL 000001146 5 III. c^ppriTtr mgQB-yrTTWJ! Riaa Maleic Anhydride o sirce benzene is no longer used to manufacture NK. there are ro health risks fran beizene. Therefore, the question is root. P^^henzene and__Stvrene Process Vents The estimated MET of 2 x 10-5 is within the 10-4 and lower range. The estimated annual inciderce of 0.004 case/yr is low and most of the ircideroe (all hut 0.0002 case/yr) is associated with lifetime risks of 10-6 and lower. Modeled exposures are carparable to (and less than) background exposures to benzene ample DECISION: Baseline risks are low and acceptable as a starting point for further analysis to reach a level for regulation that protects public health with an margin of safety. Benzene Storage Tanks The estimated JNO of 4 x 10-5 to 4 x 10-4 is within the 10-4 and lc*wer range. -- the upper range of the MO estimates is based on particularly conservative assumptions. The estimated annual incidence (0.05 to 0.1 case/yr: is lew and -- essentially all of the incidaice (0.1 case/yr) is associated with lifetime risks of 10-6 or less; -- only 0.004 case/yr is associated with lifetime risks of 1 x 10-5 and higher. Modeled exposures are carparable to background exposures to benzene 0 DBClSlCNr Baseline risks are low and acceptable as a starting point for further analysis to reach a level for regulation that protect public health with an ample rrargin of safety. SAL 000001147 7 cake By-Product Plants The estimated MET of 6 x 10-3 falls outside the 10-4 or less range. The estimated annual incidsice is 3 cases/yr and -- about one half (1.4 case/yr) occurs in population exposed at lifetime risks of 1 x 10-5 and higher. In light of these estimates, it is important to examine the aggravating and mitigating factors: -- The overall weight of evidence for benzene carcinogenicity is strong. The risk estimates are based on human data. -- The maxunm modeled exposure level is an order of magnitude below the lcwest level associated with adverse health effects in occupational populations. -- The conservative nature of the linear nonthreshold model, especially at the leaver end of the extrapolations, noting that higher and lower estimates have been made by other risk models. -- NOn-leukrua cancers have not been modeled, but should be considered. -- Emission and exposure estimates are conservative and probably overstated, for example, these estimates are based or. all plants operating at full capacity for 70 years. In fart, this is not the case new and the declining demesne coke rrarket rakes this very unlikely in the future. -- Dispersion models for area sources of this type irclude additional uncertainties. -- Majority of incidence (2 out of 3 case/yr) is associated with modeled exposures which are carparable to backgroirti. CEEL2IRL After consideration of the risks and all the ron-ccst and non-technology factors, I concluded that risks at baseline are acceptable as a starting point for further analysis to reach a level for regulation that protects public health with an anple margin of safety. 0000011*8 SAL 9 rokP Rv-Product Plants Additional mission and risk reduction is feasible. -- 80 to 98% reductions in incidence are feasible at cost of about 1 to 30 million $/yr -- MHZ can be reduced to 10-4 -- Number of people at Higher risk levels can be reduced substantial ly 0 nnrTSTfriS: Select Option 3* as level of control that protects the public health with an anple margin of safety. This decision is based on consideration of: -- with these controls, the MET is reduced to 10-4 and the population at risk is substantially reduced. -- Dqposures axe reduced such that* only 0.035 case/yr are associated with population at risks of 1 x 10-5 and higher. -- Majority of incidmce is associated with exposures at risk levels of 10-6 and lewer. These exposures are ccnparable to background exposures to benzene. -- Control costs are reasonable considering the health protection and \C emission reduction benefits. 0 Options more restrictive than Option 3 were rot recarmended because additional reductions are not warranted considering the snail risk reductions, the snail additional \OC redL^xions, and the substantially greater control costs. Option 3 controls 24 of the 30 onission points; 7 of the 24 are controlled to a level less stringent than the maxurum feasible control level. SAL OOOOOUA9 Ms. Georgi Jones March 5, 1988 Page 2 Please feel free to contact Robert Strieter (202/682-6337) of my staff should you have any questions regarding these comments. Sincerely# S*L Ooooil5o COMMENTS OF THE AMERICAN PETROLEUM INSTITUTE ON THE ATSDR DRAFT TOXICOLOGICAL PROFILE FOR BENZENE I. SUMMARY OF COMMENTS Overall, the benzene toxicological profile provides a relatively complete summary of available information concerning potential health effects. The draft document is a reasonable overview on available health information for benzene, and in general uses a balanced approach in presenting the data available in the various sections of the report. However, certain areas are in need of improvement, including need for more critical evaluation of studies, and an evaluation of the "adequacy of data" instead of the more narrow identification of "data gaps" as is currently provided in the draft report. Specific comments and recommendations included herein address the treatment of risk assessment issues, assessment of data gaps, and the treatment of animal toxicological data. A. Treatment of Risk Assessment Issues The treatment of risk assessment issues in the ATSDR benzene document draft is not located in a single section of the report. Instead risk assessment issues are dispersed through several sections of the report, obfuscating available risk information concerning benzene. We feel that the benzene profile would be more useful if risk assessment issues were contained in a separate section of the report. SAL 000001151 3 methods to convert inhalation doses for different species into a "human dose equivalent" using existing pharmacokinetic models for benzene. These toxicology issues, as well as a number of additional specific comments pertaining to various sections of the ATSDR draft, are further addressed below. II. COMMENTS ON ATSDR * S TREATMENT OF RISK ASSESSMENT ISSUES A. Organization of ATSDR Toxicity Profile The ATSDR Draft Toxicity Profile on Benzene contains relatively little discussion of issues of risk assessment, and what little there is, is not located in a single section of the profile. Risk assessment is alluded to at several points in the report, including the sections on carcinogenicity (inhalation, 4.3.6.2) and general discussion, 4.3.6.5) and advisory status (9.1, 9.2). This disjointed approach detracts from the utility of the profile. The profile would be more useful if it contained a separate section dealing specifically with issues of risk assessment. B. Specific Comments on Risk Assessment Issues As noted above, the ATSDR draft profile contains little discussion of risk assessment issues. In the inhalation portions of the carcinogenicity section (4.3.6.2) the profile mentions which studies EPA's Carcinogen Assessment Group used for quantitative risk assessment, but provides no critical evaluation. It also mentions the more recent risk assessment by OOOOOl152 SM- 5 advisory for benzene in water is 0.354 mg/liter; while the National Research Council's 7-day suggested no--adverse-response level (SNARL) for benzene in water is 12.6 mg/liter, about 36-times higher. There seems little justification for such disparate values, but ATSDR makes no comment on which, if either, is more appropriate. Section 9 of the ATSDR profile contains a subsection entitled "Carcinogenic potency" in which a single EPA estimate is listed that is described as being "an average derived from several mathematical models" applied to three different data sets. We would encourage ATSDR to illustrate the uncertainty in this estimate by describing the range of individual estimates from which the average they report is derived. ATSDR also does not refer in Section 9 to any other estimates of carcinogenic potency, though many other estimates have been produced. It does not mention the estimates produced by OSHA or by groups challenging OSHA, though it cites the Federal Register notice that contains references to those other estimates. ATSDR does not describe in the draft profile any risk estimates based on animal data, though the California Department of Health Services relies on such an estimate (ATSDR notes that "regulations and advisory guidance from the states were still being compiled at the time of printing" of the draft profile). We urge ATSDR not to rely on estimates, as California has done, based on tumor types that are not relevant to humans (preputial gland tumors) from a study involving a method of administration (oral gavage) that is not comparable to normal human exposure.OOOOOll OOOOOll5^ SAL 7 benzene will be developed by ATSDR, NTP, and EPA in the future." The current presentation of the extent of the available data base on the health effects of benzene* however, may be misconstrued by certain audiences to represent data "needs," rather than data "gaps," and may suggest the need for more testing than is necessary to reliably assess the potential risks associated with benzene exposure. The following comments and suggestions are intended to clarify the characterization of the adequacy of the data base for benzene. A. Inconsistencies in the Characterization of Data Gaps A comparison of the toxicological data presented in Section 4 of the "Toxicological Profile for Benzene" with the bar graph presented in Figure 2.7 (Adequacy of the data base on health effects of benzene) and text accompanying the graphs (Section 2.3.2.2) reveals several inconsistencies. It appears that the bar graphs of intermediate inhalation system toxicity and developmental toxicity and reproductive toxicity via oral exposure do not accurately reflect the available data base for benzene. Section 4 of the toxicological profile summarizes several studies that investigated the subchronic toxicity of benzene via inhalation (see pp. 50-51 of the toxicological profile). These studies include a 13-week study in mice and rats (Ward et al. 1975), a repeated-exposure study in rats, rabbits, and guinea pigs (Wolf et al. 1956), a 2 to 16-weeks and studt in mice (Cronkite et al. 1985), and two studies of 9.5 weeks and 4 weeks SAL 000001154 9 that "no studies are available" on reproductive effects of oral benzene exposure. A possible explanation for the inconsistencies in both developmental and reproductive toxicity data is that an error was made in preparing the bar graph of data gaps, and the bar of half height in the oral reproductive toxicity exposure position belongs in the oral developmental toxicity position. ATSDR should carefully review Figure 2.7 and the text discussing data gaps for consistency with the summary of toxicity data in Section 4 of the toxicological profile to resolve the inconsistencies identified here. B. Prediction of NOAELs from Other Routes and Durations of Exposure In establishing levels of significant exposure for benzene or any other substance, the optimum situation would be to have data on the species (i.e., human) and exposure routes of concern for all relevant durations of exposure. Unfortunately, this is unrealistic. Accordingly, procedures have been developed by various regulatory agencies and expert groups to utilize data from other species and other routes and durations of exposure to assess safe levels for human exposure. Data on systemic toxicity occurring from exposure via one route can be used to predict the toxic effects of exposure via another route, provided fundamental principles of toxicology and metabolism are considered. Data on the relative degree of absorption of the substance via the routes of interest are particularly useful. If unavailable, these data can sometimes be SAL 000001155 11 monitored. They found that for 95% of the studies, the 90-day maximum effect level was only 6 times larger than the 2-year maximum effect level. McNamara (1976) examined data on 122 substances for which subchronic and chronic studies were available. Of these# only 2.5% produced previously unnoted toxic effects after 3 months of exposure. For another 6.5% of the compounds# effects were found in less than 3 months at the highest dose# but effects at a lower dose were then seen after 3 months. In almost all cases, new effects# not found before 3 months of exposure# did not appear after longer periods of exposure. McNamara also estimated the relationship between the chronic and subchronic NOAELs. He reported that# for 95% of the chemicals# the subchronic NOAEL will be less than ten times larger than the chronic NOAEL. McNamara concluded that the 90-day subchronic NOAEL could reliably predict chronic toxicity and the chronic NOAEL. It should be noted that this finding may more simply reflect the relative design characteristics (specifically# dose-spacing) of subchronic and chronic studies. Of course# the findings remain useful as long as the two types of studies continue to be designed as they have been and now are. Thus# retrospective examinations of toxicity data have consistently shown that# for the majority of chemicals# chronic NOAELs can be reliably predicted from subchronic NOAELs by application of a factor of 10. In the case of benzene, these studies of the relationship of toxicity and duration of exposure provide scientific support for $Al 0oOll 56 15 separate document. Since this separate document was not obtained, it is not possible to comment on the derivation of this value. However, we believe that an explanation of the 1000 fold safety factor used by ATSDR to develop the MRL should be included in the Toxicological Profile. C. Issues Concerning Characterization and Classification of Leukemia Figure 2.1 plots data on two individuals who reportedly developed cancer (leukemia) after being exposed to benzene vapor for 14 years and 18 months, respectively. This is both inappropriate and misleading since such exposures cannot clearly be etiologically related to benzene. The authors often report cancer data simply as "leukemia" without regard to the cell type involved. The only type of leukemia clearly associated with benzene exposure is Acute Myelogenous Leukemia and its variants. Since leukemias occur with frequency in the general population (i.e., in people not exposed to inordinate levels of benzene), it is technically improper to "lump" leukemias/lymphomas of different cell lineages D. Inappropriate Equating of Inhaled Dose of Benzene Between Species API believes that it is inappropriate to equate the body dose of inhaled benzene in rats, mice, and humans exposed to the same airborne concentration of benzene vapor. Mice breathe much more rapidly than humans, therefore a mouse will inhale 7 to 10 SAL 000001158 17 References Agency for Toxic Substances and Disease Registry (ATSDR) and Environmental Protection Agency (PA). 1987. Availability of toxicological profiles. Fed. Reg. 52:38340-38341. McNamara, B.P. 1976. Concepts in health evaluation of commercial and industrial chemicals. In Mehlman, M.A., R.E. Shapiro, and E. Blumenthol, eds. New Concepts in Safety Evaluation. Advances in Modern Toxicology, Volume 1, Part 1, Washington, D.C.: Hemisphere. pp. 61-140. Weil, C.S., and D.D. McCollister. 1963. Relationship between short- and long-term feeding studies in designing an effective toxicity test. Aqric. Food Chem. 11:486-491. SAL 000001159 1 HAZARD ASSESSMENT Forrest B. Thoaas, Ph.D. Shell Development Company 2-1 TOXICOLOGICAL EFFECTS OF BENZENE Several excellent reviews of the toxicological properties of benzene have recently been published iFishbein, I 9 B 4 j Snyder ft, 19 S 4; Aksoy, 19E5; fiehltnan, i?B5). This section will therefore address only selected aspects of the extremely large toxicological database available for this compound, in order to provide a perspective from which to evaluate ofcher^ parts of this document. v 2-1.1 MAJOR SOURCES OF HUMAN BENZENE EXPOSURE It oust be appreciated that bencene is ubiquitous. According to/ estimates from the National Research Council (1978), the dietary intake cf benzene may be as high as 250 ug daily, perhaps explaining benzene concentrations cf E-20 ppb in the breath of individuals with jo known exposure to this compound (XXX). The bencene content of specific foods is reported to range froa 2 ppb for canned beef to 2100 ppb f(Natioral Research Council, 19B0)! Recent results froa the National Toxicology Program (Sabourin et a1., in press) indicate virtually 1001 of benzene administered orally is absorbed into the body. Bencene concentrations in ambient air (urban and rural) have been estimated to range froa 1 - 100 ppb (IARC 1932a). Urban air is reported to contain higher levels than rural air, presumeably due to the contribution of automotive emissions of bencene (Brief et al. 1930). After reviewing these data, the National Research Council (1930) calculated that an individual, living in an urban environment containing a mean atmospheric bencene concentation of 16 ppb (50 ug/<n3), who breathes an average of 25 m3 of air per day, and absorbs approximately 501 Df the dose (i.e., equilibrium state), will absorb approximately 600 ug of benzene daily. C1 i ppb = 50 ug/itio x 25 a3/dy x 502 absorption * 625 ug/davl levels of 47 - Bencene is pr ssent in cigarette smoke at 64 ppffr^Ieading to Estimates cf the amount of bencene inh aisd from a si ngle cigarette ringing from 10 - 31 ug. Using the upper estimate, a person sacking 2 packs (i.e., 40 cigarettes) per day will absorb up to 992 ug of bencene (assumes SOI of doss is absorbed; nen-equi1ihriua state). SAL 000001X60 2 140 zicar 11ss/dsy :: 31 ug b enz sr.e/c i gar et t e s BO/, at i or p t i c n 972 ug/lay ] g e n : s n e is slightly soluble in water (520 ug/1 = 220 p p b at 20 C according to the national Research Council, 1920). [Check alternative values with Bruce Bastian...the CPA draft drinking water criteria document of April 19S5 reported the solubility of benzene in water as 1.3 o/L at 25 C and that it forms a two-phase, cinieua-boiling azeotrope with water at a benzene concentration of 911 by weight!. In a report issued by the EF'A Office of Drinking Water U9S3>, it was estimated that 97.71 of the population served by public water systems are receiving water either free of benzene contami nati cn7 or Having levers- less triTrP 0.5 ug/L. Assup ing that the average adult consumes 2 L ol water da* i 1 y, it can be calculated that drinking water with a benzene content of 0.5 ug/L would contribute 1 ug of benzene to the average daily dose (100Z absorption assumed). CO.5 ug/L x 2 L/day = 1.0 ug/dayl Summarizing the above calculations for what are considered major sources of human benzene exposure; Non-Booker Smoker Fc-c-d 250 ug/day 250 ug/day Air 625 ug/day 625 ug/day Cigarettes 992 ug/day Water 1 uc/dav 1 uo /day TOTAL 876 ug/day 1S69 ug/day 2-1.2 THE PHARMACOKINETICS OF BENZENE The primary routes of benzene exposure are considered to be oral and inhalation. While there are data that benzene applied as a liquid or solution to human skin can be absorbed fairly rapidly (Blank fc McAuliffe, 19351 , this route is generally discounted "as being significant because of the rapid evaporation of benzene which effectively reduces the time of skin contact. in Recent data from the National Toxicology Program (N7P; Sabcurin et a1.., in press) indicates that virtually all of an oral dose of benzene dissolved in vegetable oil is absorbed by rats and mice. It is reasonable to assume that dietary fiber content may reduce both ^he-rats and efficiency cf benzene absorption somewhat by completing the hydrocarbon, but experimental evidence for this is unavailable. To be conservative, 1007. absorption of benzene from food and water was assumed in the above calculations. SAL 000001161 3 Ths respiratory absorptizn : f s hydrocarbon vspor such 5 benzene is a complex process which has cnly partially been characteri:ed. Si gni f i c art differences in the respiratory characteristics of commonly used laboratory aniff.s's exist. Small aniafils, with their high metabolic rate, must have a large oxygen supply (Swenson, 1977)* The Lovelace Inhalation Toxicology Research Institute UTRI) under contract with NIP have characteri:ed the respiratory paraaeters of the B6C3F1 mouse and the F344 rat (unpublished information from the butadiene research prograa). Recording to ITRI data, the average B6C3F1 mouse weighed 27.5 g and breathed 35 ol of air per minute (i.e., minute volume); the average F344 rat weighed 392 g and had a minute volume of 289.7 al. Expressed on a kilogram body weight basis, the minute volume of the mouse is 1274 al/kg and of the rat is 737 ml/kg. From this perspective it is understandable why Sabourin et al. (in press) concluded that at siailar exposure levels of benzene vapor, alee received 150r2C0Z of the dose received by rats per kilogram body weight, suen differences in respiratory mechanics between species must be considered in the quantitative aodelling of animal inhalation data for estimation of human health risks. In particular, if one assumes a 70 kg man who breaths 7500 ml of air per minute, it can be calculated that the human minute vclume/kg body weight is about one-seventh that of the rat, and about one-twelfth that of the mouse. Initially, when art animal (or man) is placed into an atmosphere containing benesne vapor, cost of the hydrocarbon is absorbed into ths blood stream and then distributed to the various tissues of the bedy. Each tissue will absorb some of the benzene from the blood, with some tissues (e.g., those having a high content of fat) absorbing relatively greater proportions of benzene compared to other tissues. The benzene absorbed by each tissue may be sequestered, released back to the blood unchanged, or processed by the specific metabolic enzymes which characterize the cells of that tissue. In time, a state of dynamic equilibrium is established between the air, blood and other body compartments, as more benzene is absorbed from the air, some of the previously absorbed benzene i.s exhaled unchanged from the body, some :s metabolized to specific derivatives (which may be further metabolized even in other distant tissues), and some is removed by the kidneys and excreted in the urine. It is during this state of dynamic equilibrium that estimates of the efficiency of benzene absorption are commonly measured, such as the SOX absorption value used in the exposure calculations above (see Section 2-1.1). This should be interpreted as meaning that considering the amount of benzene vapor absorbed from the inspired air, less the amount of previously absorbed benzene exhaled unchanged, the net influx of benzene into the body is SOX of the total inhaled dose of benzene. Recent data from the NTr (Sabourin et al., in press) indicate that frea a 6-hour exposure to 11 ppm of benzEne vapor, the apparent absorption of benzene in mice is SOX, whersas at 1000 ppai the apparent absorption is 9,73, Values for similarly exposed rats are 332 absorption at 13 ppa, and 152 absorption at 870 ppm. A siailar picture of the dynamic equilibrium can be developed for benzene absorbed from the gastrointestinal tract. As noted above, S4t 00ooll6z 4 recent data froa NTP (Sabourin gt a 1 . , in press) suggest that essentially all of a dose of benzene (dissolved in corn oil) administered by gavaoe is absorbed by rats and mice. Two points should be emphasized with regard to oral exposures. First, the concentration of benzene in the blood as a result of the administration of an oral bolus is seen to be a transient peak or spike. Dissolving benzene in a vehicle such as corn oil essentially results in a retardation in the absorption of benzene into the blood stream, such that all of the benzene is eventually absorbed, but it requires a longer period of time, produces a spike of benzene in the blood Benzene is metabolized via a number of possible pathways (summarized in Figure 1). Available information indicates that benzene must be metabolized in order to exert its toxic effects. However, it is not clear at the present time which of the vario~us metabolic pathways activate benzene to more toxic derivatives, and which pathways result in detoxification. Various investigators have suggested that toxicity may be the result of covalent binding of benzene metabolites to cellular macromolscules such as DMA and protein, and a reactive benzene epoxide has been postulated to be formed during the metabolism of benzene by the cytochrome P-450 enzyme system. Irons and his colleagues at the Chemical Industry Institute of Toxicology suggest that polyphenol derivatives (e.g., hydroquincne and 1,2,4-benzenetriol) autzoxidize to fora highly reactive radicals which may be responsible for the toxic effects of benzene. Goldstein et al. suggest that the benzene ring is cleaved eetabolical1y forming muconaldehyde which is also capable of reacting with essential eacromolecules. In extrapolating toxicological data in animals to human health, consideration must be given to the significant qualitative and quantitative differences in the specific metabolic pathways for benzene which are seen between species. The phenolic metabolites in the urine of benzene-treated mice, for example, have been found to comprise 50-632 clucuronide conjugates. 26-397. sulfate conjugates, and approximately 37. unccnjugated phenol (Snyder 1974...ref B8B in lasfcin). In contrast, Cornish and Ryan (XXX) observed that approximately 70Z of the phenolic metabolites found in the urine of benzene-treated rats were sal fate conjugates. In man, virtually all of the phenolic compounds in the urine following benzene exposure exist as sulfate conjugates, until the concentration of phenol in the urine reaches approximately 400 mg/L when the sulfate pathway has apparently been saturated and products of glucuronide conjugation begin to appear <Sherwood 1972...ref 291 in Laskin). Such data emphasize the although while all three species possess similar metabolic pathways, glucuronidation predominates in the mouse, whereas sulfation predominates in the rat and man. It should also be noted from these data that the specific metabolites which are formed at high doses, may be substantially different from those formed at lower (environment aiy relevant?) doses, and as a result, it would not be surprizing to find entirely different toxic profiles under tTre -t>io conditions. Similar arguments can be oade even between tissues within the same animal. The liver, for example, is known to be capable of metabolizing benzene to a wide variety of reactive derivatives, but is not considered 0000011*3 SM- 5 to be a target organ for benzene toxicity. This is perhaps because of the elective shunting of these potentially tcxic metabolites into various conjugation pathways which effectively detoxify such metabolites. In contrast, the cells of the tone marrow appear to be exceptionally sensitive to the toxic effect's of benzene, reflecting perhaps a greater eophasis on certain detoxification pathways in asrrcw cells, or less effective detoxification by enzymatic conjugation. Future research aay provide a clearer understanding of the biological basis of such differences. 2-1.3 TOXICITY TO BLOOD FORMATION Toxic effects have long been recognized in the bone a a r r o w of anioals and cian exposed repeatedly to high levels of benzene vapor (Santesscn 1BB7). This organ is located in the hollow spaces of various bones and is the primary site of blood formation. In siople terms, the bone marrow can be viewed as a tissue filling a container of fixed volute, comprisinging a dynamic mixture of cells which are in various stages of becoaing aature red blood cells iFiBCs) and white blood cells (HBCs). Figure 2; Schematic of Blood Cell Differentiation and Maturation I--> Myeloid/Erythroid Stea Cells II 14 ! \ !-- > Granulocytic KBCs rtultipotential Stea Cell ! It 5 ii ! J \ --> i !-->Megakaryocytic Stea Cell lt --> Platelet !--> Kacrophagic Stea Cell -->Macrophage ti i--> Erythroid Stea Cel! --> Mature RBC Monocytic Stem Cell ! II PI !--> I -- > Monocyte Lyaphocytic Stea Cell lI ! -- > T-Lynphocytes I 9-Lymphocytss Ia Other Lyaphccytes Most commonly benzene toxicity is expressed as a decreased formation of various types of blood cells and therefore decreased concentrations of these cells are found in the circulating blood (i.e., aneaia, SAL 000001264 6 pancytopenia, etc.). _ $_e_v srs cases of benzene intoxication may p- r o g r e s s to a fatal condition whs re all blood f or mat ion essentially ceases (i. eT ~ aplastic anemia). " *" ---------------------- The mechanises) by which benzene effects bene marrow suppression is incompleiely understood, but is known to be complex. Much of this uncertainty is perhaps due to the biological complexity of the bone marrow itself. In the clinical and toxicological literature, for example, one of the common early manifestations of benzene tcxicity is a decrease in the number of circulating lymphocytes (i.e. , lymphocytopenia), suggesting tfiat the lymphocytic stem cell line may be particularly sensitive to the cytotoxic/cytostatic effects of benzene. Of interest, increased circulating levels of other cell types may also be seen at the same time as lymphocytopenia (e.g., an increased in the number of eosinophilic granulocytes in the blood). It is not clear whether this increase in circulating eosinophils should most appropriately be considered a direct manifestation of benzene toxicity, or simply the compensatory proliferation of eosinophilic WBC precursors into the bone marrow space made vacant by the killing of lymphocyte precursors by benzene, ft similar phenomenon is seen in the ar.eaia of leukemic crisis, which develops when the bone carrow^ecomes filled ~wfh" malignant leukemia cells, leaving no room for the proliferation of other types of blood cells. 2-1.4 BENZENE AND LEUKEMIA A relationship between repeated high-level benzene exposure and the occurrence of leukemia in man was recognized as early as 1923 (Delore & Bergamono). Acute Myelogenous Leukemia (AML), and to a lesser extent its variants (e.g., Acute Erythroleukeoia, Acute Myeloaonocytic Leukemia) are the types of leukemia most commonly associated with occupational exposures to high levels of benzene vapor, suggesting that the myeloid/erythroid stem cell line may be particularly sensitive to the leukeaogenic effect of benzene [see figure 21. Other types of i leukemia te.g., Acute Lymphocytic Leukemia and chronic leukemias of various cell types are less clearly linked to benzene. Leukemia is characterized by the uncontrolled proliferation of a specific type of blood cell, and the term was originally derived from the increased number of circulating WBCs or leukocytes (i.e,, leuk-) in the blood (i.e., -eoia). Nonetheless, leukemias are considered by most scientists to be neoplastic diseases of the bone marrow and other b 1 ocd-f or aing * or g an s. Leukemias^ which manifest themselves predominantly in tissues other than the bene marrow are commonly referred to a lymphomas. It should be appreciated that the diagnostic distinctions often become clouded in the clinical/epideaio!og:cal literature since a leukemic presentation of lymphoma, or a lymphematous presentation of leukemia, as well as the occurrence of an aleukemic leukemia are commonly encountered in the clinic. The distinction between the leukemias and nonleukemic malignant neoplasms has been the subject of long-standing debate among scientists. SAL 000001165 7 although ths most papular par&giga would classify leukemias as cancers. The d e b a te, however , is net complete, ana there is cc*n si aeT'&tol 5 57Td = r.T5 to suggest that Ieukesegenesis and carcinogenesis represent two highly distinct physiological processes. Cameshek (19511 and WassErman (1954), for example, suggested that myelogenous leukemias were specific manifestations of a more general-'ccnd i tion "whiclT'wfas termed the "myeloproliferative syndrome.' According to these authors, this conditions could alternatively be manifested as such nonneoplastic conditions as polycythemia vera, aplastic anemia, or agnothic myeloid metaplasia. Similarly, Dameshek < 196i>> and Sinkovics et al. (1970) have suggested that certain leukemias may be a particular clinical manifestation of autoimmune disease. Also pf interest is the report of Battifora et al. (1968) that myelogenous leukemia is 'induced* in rats by a dietary mineral deficiency (magnesium}. Such observations tend to emphasize 1eukesogenesis as a biological process which may be distinct froa our current models of carcinogenesis. Until recently attempts to induce 1eukeaia/lymphoaa in experimental animals with benzene had been unsuccessful. However, several investigators have now reported the induction of a lymphoma in the thymus of C57BL mice and derivatives of that strain by a number of chemicals including benzene. This lymphoma is characterized by the proliferation of T-lymphocytes, and is not believed to be the result of a direct 'carcinogenic* effect of benienY en T-cell precursors." Rat her this tutor is believed to be the secondary result of benzene-associated activation of a latent virus which is known to be carried by this strain of mouse. While similar viruses are known to occur in man, available evidence links these human viruses also with T-cell leukemias. It may be significant therefore that lymphocytic leukemias have not been clearly associated with high-level benzene exposure, and the significance of this murine leukemia to human health is unclear. No evidence of viral involvement in human AML has been identified to cny knowledge. In this regard, Cronkite and his colleagues at the Brookhaven National Laboratory (unpublished data) have recently identified AML in CBA/Ca mice treated with benzene. This strain is being characterized in a number of laboratories and may eventually prove to be a suitable animal model for benzene 1eukesogenesis. 2-1.5 BENZENE AND SOLID TUMORS Maltoni and his colleagues at the Institute of Oncology in Bolgna have conducted a number of studies on benzene which they summarized in 1935 [Maltoni et al. 19S53. Beginning in 1977 they reported that a wide variety of solid tumors had been observed (Experiment BT901) in Sprague-Dawley rats (13-weeks-old at the start of the study) receiving 50 or 250 mo/kc of benzene dissolved in olive oil by gavage daHy., -4-5 days/week for 52. weeks, then held until spontaneous death. These tutors included carcinomas of the Zymbal gland (feaales only at both doses) and oral cavity (feoales at high do3e only), as well as increases in ths incidence of mammary tumors (type unspecified: suggestive increase in feaales at high dose only) and non-thyaic hemolymphoreticular neoplasms SAL 00001166 8 (type unspecified; Sales only it high dose). It should be noted thet ft a 11 o n i st al. report only crude tumor incidences from their studies, and do not provide results c-f statistical evaluations of their data. I In a separate experiment (ET9Q2/706), f!al t Oft i et al. administered (by gavage) benzene in olive oil at a daily dose of 500 ao/kn to 7-week-old Sprague-Dawley rats, 4-5 days/week, for 104 weeks, which were then held until spontaneous death. According to the authors, under the conditions of this bioassay benzene caused Zymbal gland carcinomas (equally distributed between M tc FI, carcinomas of the oral cavity (equally distributed between tt fc F), carcinomas of the nasal cavities (suggestive increase in H only), skin carcinomas (H only), forestosach dysplasias (fl b F) and forestoaach tumors (F only), hepatocarcinomas (reported by authors, but do not appear to be increased to this reviewer), liver angiosarcomas (11 & Fl, and an increase in the number of other malignant tumors, soae of which are extremely rare in the Sprague-Dawley rat, such as lung adenocarcinomas (tumor observed in 1 K) and soft tissue liposarcomas (tumor observed in 2 11). In addition, benzene caused a decrease in circulating WBCs, due primarily to a decrease in circulating lymphocytes CM t F), when determined during the 84th week of the experiment. Increases in the incidence of mammary tumors and non-thysic hemolyophoreticular neoplasms (seen at the lower doses given in BT9C1) were not seen in this study. Kaltor.i et al. suggest that the differences between the results of experiments BT901 and BT902/906 must be correlated to the different doses (daily dose and length of treatment) of administered benzene, rather than to differences in the age of the animals at the start of each experiment. The technical basis for this statement, however, is not clear. Once again it should be noted that the conclusions from this study are subject to technical debate because of the lack of statistical evaluation. Maltoni et al. began in 19S3 a study using 6-week-old Nistar rats (BT907) and Swiss mice (BT90B) exposed by gavage to benzene in olive oil at a daily dose of 500 og/bg, 4-5 days/week, for 104 weeks (rat) and 73 weeks (mouse). Preliminary information from these studies were included in Kaltoni et al. Cl985J. In the Wistar rat, ZymbaJ gland carcinomas (-1 k F) , non-tbyoic hemolymphoreticular neoplasias (suggestive increase in F) , and an increase in total malignant tumors (M 6 F) were observed. In the Swiss mouse, Zymbal gland dysplasias (M t F) and carcinomas (fl only), mammary carcinomas (F only), pulmonary adenomas (M & F), and an increase in total malignant tumors (suggestive increase in F) are reported. Results of statistical evaluations are not reported. l The National Toxicology Program has conducted two-year toxicology and carcinogenesis studies of benzene in F544 rats and B6C3F1 mice which. Male F344 rats were administered benzene in corn oil by gavage at daily doses of 0, 50, 100, or 200 mg/kg (5 days/week, 103 weeks). Female F344 rats, and male and female! B6C3F1 mice were administered benzene in corn oil by gavage at daily doses of 0, 25, 50, cr 100 mg/kg (5 day^/Kesk, 103 weeks). In rats, increased turner incidences were seen for the' Zymbal gland (fl l F>, oral cavity (Ft St F), and skin (fl only). In the benzene-treated mice, increased tumor incidences Nere reported for Zymbal gland (fl k F), lymphoma U1 & F), lung (ft 1 F), Karderian gland SAL 000001167 ^4 ID LJ 9 carcinal in F), m it. .t. a r y clar.d (F), preputial Gland (h?, f ores t c-ma : h (5 r 5 i n s 1 i n M 5r F > , ovary C F) f and liver (marginal in F). haltor.i an M his cell escues have also evalu a ted the carcir,c genic potential of benzene vapor via inhalation. In experiments 574004/4006, 13-week-oi d pregnant female Spr agus-Dawley rats (gestation day 12 at start of study) ware exposed to benzene vapor at a concentration of 200 ppm (4 hours/day, 5 days/week, 7 weeks), then exposed at 200 ppm (7 hours/day, 5 day s/week, 12 weeks), then at 300 ppa (7 hours/day, 5 days/week, B5 weeks), giving a total of 104 weeks of benzene exposure (Group 1). These animals were then observed until spontaneous death. The offspring from the above rats were exposed transplacenta!1y during the prenatal period (note: gestation in the rat is approximately 21 days), by inhalation and probably by ingestion (via milk) during weaning, and then by inhalation as for the parental animals (Group II). One group of offspring was removed fro# further exposure after the 15th week of the above treatsent schedule (5rcup III). The offspring in Broups II and III were also held for observation until spontaneous death. The results in these three treatment groups will be discussed separately. Among the benzene-treated pregnant rats (Group I), a suggestive increases in Zyobal gland carcinoma (3/53=5.71 in treated rats vs. 1/60=1.75) and malignant mammary tumors (6/54=11.1Z vs. 2/60=3.35) were seen. Increases in other types of tumors were seen near the end of the study, but are of unclear significance due to the low number of surviving animals. Among the offspring exposed to benzene vapor for 15 weeks (Group III), an increased incidence of Zymbal gland carcinomas (H 1 F), oral cavity carcinomas (F; suggestive in h), carcinomas of the nasal cavities (F), malignant mammary tumors (suggestive in F), and hepatomas (F) were observed. In the offspring exposed to benzene vapor for 104 weeks (Group II), an increased incidence of Zymbal gland carcinomas (ft & F? , carcinomas of the oral cavity (F; suggestive in M)j nasal cavity carcinomas (reported by the authors, but considered only suggestive by this reviewer), and oalignant mammary tumors (suggestive in F) were reported. Increased incidences of other tumors were seen near the end of the study, but again the low number of surviving animals make difficult the interpretation of the biological significance of such observations. The studies of Kaltoni et al. and the National Toxicology Program, have demonstrated without question that high level benzene exposures can produce-an increased incidence of a wide variety of tumors in ratsanU mice, it is somewhat more complicated, however, to concTuGe tnaz tn's'se* 1 effects are due to a direct carcinogenic effect of benzene on these highly diverse tissues, and that these animal data are appropriate for quantitative risk modelling for extrspolation to environmentally* *' relevant levels of benzene exposure ir. mart. Before current models can be applied three confounding factors must be considered further: 1. As discussed above, recent data from the National Toxicology Program CSabourin et a 1.3 indicated that 2' ** the dosages of SAL oooooaug 10 b e r z 5 r. e utilized in the above cancer tioassays have been at levels where tbs usual ci&tsbolic -pathways cay have been wholly or partially saturated. Ther e-fore, it is possiaie cr.at oerffen e in these animals was forced into metabolic pathways which would not normally be significant in defining the toxic pro-file of this compound. 2. The role o-f murine leukemia virus'in the development of thymic lymphoma in the B6C3F1 mouse Has discussed above. It is not clear whether or not current risk modelling techniques are appropriate for virally mediated neoplasia. 3. Benzene is well known to be immunosuppressive, such that it is possible that ail of the tumors reported by naitoni et al. and by NTP are the secondary result of benzenefinduced inability of the animal to monitor and destroy spontaneously occurring transformed cells. Certainly, this type of mechanism would explain the occurrence of tumors of the oral cavity in the NTP benzene inhalation study, as well as the development of carcinomas of the skin in the benzene gavage studies. 2-J.6 CONCLUSIONS As discussed above the biology of leukemia, bone marrow function, and carcinogenesis as relates to benzene exposure is extremely complex. Application of current models of quantitative risk extrapolation depend on assumptions whTch are wellrecognized as beTng simplistic in the extreme. Nonetheless, such methods are noT, and will continue to tTe used, because more definitive understanding of the mechanisms of benzene-associated toxicity and the relevance of such mechanisms to human health, will not be available in the near future. It becomes imperative, therefore, to recognize the limitations of our biological understanding and to document fully the assumptions and uncertainties of estimating by extrapolation the risks to human health due to environmental benzene exposures. 2-1.7 REFERENCES Aksoy M (19G5). Benzene as a leukemogenic and carcinogenic agent. ftmer. J. Indust. Med. 8: 9-20. Battifora HA, McCreary PA, Hahneaan BM, Laing 6H it Haas EM (1963). Chronic magnesium deficiency in the rat. Studies of chronic myelogenous leukemia. Arch. Pathol. Be: 610 ff. Blank IK it McAuliffe DJ U?S5>. Penetration of benzene through human skin. Invest. Dermatol. G5: 522-526. Dameshek U (1951). Some speculations on the myeloproliferative syndrome (editorial). Blood 6; 372 ff. SAL 000001169 11 Daceshsk W (1966). Certain -forms o-f leukemia as immuncproliferati ve disorders. In Carcinogenesis: A Bread Critique (Baltimore: Williams tt Wilkins Company, 1970), pp 141 ff, Environmental Protection Aoency (1983). Benzene? Occurrence in Drinking Water. Foc-d, end Air. {Prepared by JRB Associates). Fishbein l (1984). An overview of environmental and toxicological aspects of aromatic hydrocarbons. I, Benzene. Science Total Environ. 40: 1B9-219. ttaltcni C, Conti B, Cotti 6 Belpoggi F (1985). Experimental studies on benzene carcinogenicity at the Bologna Institute of Oncology: current results and ongoing research. flmer. J. Indust. Med. 7: 415-446. Hehlman MA, ed. Benzene: Scientific Update. Prodeedinos of the International Conference on Benzene Sponsored bv the Collegium Ramazrini, Hew York Citv. November 5-4. 1983 (New York: Alan R. Li's, 1955). National Research Council. Health Effects of Benzene: A Review (Washington, D.C.: National Academy of Sciences, 1976). National Research Council. Drinking Water and Health (Washington, D.C.: National Acadeay of Sciences, 1980). National Toxicology Program (19B6). Toxicology and Carcinogenesis Studies of Benzene (CAS No. 71--43--2) in F344/N Rats and B6C3F1 Mice (Savage Studies). (Washington, D.C.: National Toxicology Program, galley draft of February 1986). Technical Report No. 2S9. Sinkovics JS, Trujillo JM, Pienta RJ fc Ahearn HJ (1969). Leukeaogenesis stemming from autoimmune disease. In 6enetic Concents and Neoplasia (Baltimore: Williams & Wilkins Company, 1970), pp 138 ff. ff. - Snyder R (1984). The benzene problem in historical perspective. Fund. Aool. Toxicol, 4: 692-699. Wasseraan LR (1954). Polycythemia vera - its course and treatment: relation to myeloid metaplasia and leukemia. Bull. N.Y. Acad. Med. 30: 343 ff. s4l 000ou?0 ittinBt/WXSCtLUMOPS leference Study Effect API, 1981-83 lurm, K. A.. at al., 1883 Skin absorption in minipigs, monkeys and kaau C5711 ales* 10 ppm. 6 hr/day. 5 days/week. 178 days 0.05-0.2X of applied dosa was absorbed. Higher absorption occurred If bencene was la a solvent (l.e., toluene). Progressive depression of erythrold stem cell depression of splenic ideated red cells, circulating HBCs and lymphocytes. i H. C., at al., 1983 las as ahsas --espe exposure was for 8 days and various coacoatratlons (10, 31. 100, or 301 ppn) gapcaaeloa of mitogeninduced blaetogeneels for femoral - and splenic T-lynphocytes. ^ It la difficult to assess the significance of thia research since the experiments suffer froa lack of a dose response, variability of control values. small group site. poor salaal health, etc. 000001171 sal lPtZOTE 'LABORATORY STUDIES FOR REPRODUCTIVE AND TERATOLOGIC EFFECTS Reference Study Design Results API 1977 Green* J. D. et el. 1978 Hudak* A. ud Ungvary, G. 1978 Murray* 7. J.* et al. 1979 API 19*0 Ck/CD rata* 10 or 40 ppn* 8 houra/day, days 6*15. Rats (Sp. Dawley)* 300 or 2200 ppa* 6 hours/day for gestation daya 6*15. CFY rata* 1000 ng/n* (313 ppn)* 24 hours/day* daya 9*14 of gestation. Mice (CF-1)/Rabbits (New Zealand), 500 ppm, 7 hours/ day* during organogenesis (days 6-15 for nice, daya 6-18 for rabbits). CR/CD rata; 1, 10* 30, or 300 ppm, 6 hours/day* 5 days/week for 10 weeks of pre-matlng to 21 daya lactation (only fenalea exposed). No teratogenicity, effects on other parameters were equivocal (reviewed by Du Pont blostatiatlclans). No teratogenicity. Slight teratogenicity (fused etemebrae)* fetal development slowed. No teratogenicity* slight eaferyofetal toxicity. No toxicity seen in 21-4ay old newborn. SAL 000001X72 BEHZEKE/MUTAGENIC STUDIES Reference American Petroleum Institute 1977 Study Ames Assay Mouse Lymph< Cytogenetics In Vivo (Rat bone marrow; 0.006* 0.02v and 0.06 ml/kg* 5 days dosing l.p.) Results negative Negative Positive at 0.02 t 0.06 ml/kg SAL OOOOOII73 KVZEffE/CHKOHOSOHAL EFFECTS lafarence Tough, 1. H. at al. 1970 Kiliaa, D. J. and Daniel, I. C. 1978 API 1980 Study Results Workpiece Study Croup 1: n 20 Croup 2: 12 Chromosomal breakage at 25-150 ppn for 1-25 years; affects correlated with worksite expoeuree end age. Workplace Study; n - 52 Chromosomal abnormality at an estimated TWA of 2-3 ppn (1 month to 26 years) but 15 min. peaks of 25-50 ppn with oc casional peaks of > 100 ppn. Ethyl benzene nmposure also occurrad. Dominant Lethal Assay; CR-CD rats, nsles exposed to 1, 10, 30, or 300 ppn for 10 weeks prior to noting, 6 hours/day, 5 days/weak. No adverse effects. Chromosomal abnormalities may persist far years and perhaps arc the result of prior unquancltated anpoeures. Ransaher that control of btnsene has Improved over the pears aod thus, present-day low-level exposures to bensene nay not produce chconoeonal abnormalities. Variables not controlled in the above workplace studies that nay affact tha results: smoking, intake of nsdlclnals, viral infections, mixed exposures to solvents. SAL 000001174 liftr--ct API 197t :.ItelCMl, C Suruco, i 1979 Snyder, C. A* i at si 1976 Snydsr, C. A., t 1 1960 BOiZEME/CHROWIC STUDIES (fags l) Study Results Exposure: 6 hours/day, 5 days/week for llfetlma. Mice (CD-I); 300 ppm. Tuaors: 2/40 Incidence of ayelogenous leukeala while no cases aver seen In present or past control animals. Rats, gvt| dosing, tlui/vMk, 52 tmki: Group 1: 50 a|/k| day Group 2: 250 ng/kg day (Vt. gala and survlyal vara radacad.) Group 1: Zymbsl gland tuattrs. Croup 2: Zyafcal gland carcinomas; non-atatistical Increase of miaary carcinomas snd leukemias. Lifetime atudlaa (6 hoars/ day, 5 days/vaak). a) AKR mica, exposure to 300 ppa. b) $p. Davlay rats, exposure to 300 ppa. a) High mortality, anemia, lymphocytopenia, neutrocytosla and redculocytosls. b) lymphocytopenia. Lifetime atudlaa (6 hours/ day, 5 days/vaak, 40 aslas/ group. a) MJl Mica, 70 vaaks expoaura to 100 ppa. b) C571L Mice, 66 vaaks exposure to 300 ppa. a) Anemia, lymphocytopenia 4 bone marrov hypoplasia. b) Anemia, lymphocytopenia, neutrocytosla, bone marrov hyparplaaia (332 vs. OZ) and hemopoietic neoplasms (201 vs. 52; 6 of 8 neoplasms were thymic lymphomas). S4L oooo1175 msztm/vmmic studies --------------- TfFiiTll------------------ Rafarapea Haltool, C., at al. * 1*902 (a) * 1962 (b) 1962 (c) Cffoct Pr|Mtc rtci; 200 ypa. 4 br/day. 5 daya/vaak for gttutlot dayo 12 to dallvary sad offiprlni for IS mki or 104 vaaka (200300 ppii 4-7 br/day, 5 day#/ VMk). ZyMbal glad carciaoou vlth aataataala to regional lynph ao4ti, lungs and brain. Laukopanla vaa also obaarvad. Koto. gavaga. S00 ag/kg, dolly for 104 wnnka. Catclaoufl of oral cavity and synbgl gland. Soo 1962 (o) atody. apatonaa. Dottonal Toxicology Progran, 1963 Mica (B(CjFt) and rata (F344); gavaga doalag. S daya/vk, 103 woaka. Mala rata; SO, 100 or 200 ng/kg; Faaalc rata and all alca: 25. SO and 100 ^/kg. MICK BIBb41 W aa Low a Ugb U. Cain Survival Control S4Z SftC a 46X 14 to 36% in 14Z Elavatad baott anacopniatlc, cynMal. atoaach. adraaal. lung. livar Faaalaa: Low Saa Mad. afeava High Control 401 52Z 46Z 36Z Ovary, livar. ardorlan/ propauclal/wawaary gland IATS l^a1gg Law Mad. Blgb OK OK -231 Control 441 5*Z SOZ 32Z Fanalaa: Low Mad. Kick OK OK OK Control 92Z 76Z 66Z 50Z liaatofolctlCr ifMtl, aconach adrenal. oral cavity ZfMtl gland 4 oral cavity SAL 000l176 fteference Aboj M., tt al 1974 Aksoy* M. and Erdia. S.* 1978 Aksoy* M.i 1980 Da Coufla, P.* at al., 1963 Infanta* P.* at al.* 1977 Infanta* P., 1979 wgag/CTiPonoijocY studies (Page 0 Study Moults Shoeaskers; beasene cone. af 150-650 ppa. Shoemakers. Export not reviewed, See coatnt on paper by Aksoy* M. 1980. Saa consent on papar by Aksoy (1960). Shoemakers* n 21*500 Leukemia rata; nornal population* 6/100*000; shoemakers* 13/100*000. o exposure data and ago adjustment not parfornad thee, atatlatlco are ao week aa to 6a rejected by Wblta, H. C-, at al.* (1962) paper. Chemical industry (Conoco Inc. /baitlmore) n - 262 (1947-60); exposures not piMCltatad. Follow up to 1977. Lyaphoretlcular cancers: Observed* 4 Expected* 1.1 tubber Industry* 10-350 ppa lamia of bensene are debatable as documentation Is contradictory; other solvents vara present, n - 746 (1960-49); follow up to 1975. tpdete of 1977 seedy. Exposures claimed to be <15 ppa but realistically ween greater than 100 ppa (Van Eaalte* R.G.5., and Gsaaso, P.* 1982) laakaala: Observed* 7 Expected* 1.25 Sea Infanta* P. (1977) 0000H77 BENZm/EFTDEMIOlOGY STUDIES (?* 2) Reference Study Results McMichael, A. J. et *1., 1975 Ott, H.. et *1., 1978 Rlnsky. I. and Young. R. 1981 White* M.C., Infante* P.F., and Chu, t. C., 1982 Rubber industry, exposure vas to various solvents. Petrochemical Industry, exposures claimed to be 1-30 ppm but probably 0-937 ppm with possible exposure to ocher solvents; m - 594. Re-evaluation of Infante*s 1979 study; n - 748 (194059) follow-up to 1975; second cohort, n 258 (exposures of 1950-59). Review of data in papers by Rimsky and Young (1981) and Ott. et al. (1978) for calculating relative leukemogcnlc hazard of benzene. Standardised Kortallty Ratio. SKR: Leukemia: t3-fold Chronic lymphatic leukemia:^ 7-fold Myeloid leukemia:2-fold Leukemia: Observed. 3 Expected. 0.8 ieoxene is leukemogen at estimated TWA range of 16 ppm to less than 100 ppm. Report submitted for publlestIon. 1982. Excess lifetime risk is calculated using the very conservative One-Hit Probability Model: Exposure 10 ppB 1 ppB 1-4 0.1-0.4 Risk per I.000 $ yrs. 15 yrs. 30 yrs. 5-18 0.5-2 15-54 1.5-5 30-104 3-11 45 yrs. 44-152 5-16 SAL 000001178 bftrnci Du Font study, 1963 CMA, 1963 jqggg/PIDEHIOLOCT STUDIES (P* 3J Study UHubo plant esployees potentially exposed to Itnitot for 1946-77; n 664; ttpomrM worn lover than than TLVs for 19461977 (10-100 ppn). Mortality study of 7 plant/6 companies; n ca 7700 (lacludod 1963 Du Font study of Repauso plant). Exposure data: < 160 pps soothe: 50X* 160-720 ppn soothe: 30t > 720 pps soothe: 20Z Percent of workers Results Slight significant in crease la leukesla (3 observed, 1 expected) and bladder tusors (4 observed, I sspected). Significant Increase In lyphatlc and hesatopoletlc cascer; however, control Incidence was lower than national average. These cancer rates are not sig nificant If cospared to the satlesal control rate. Note that leukesla cases were set acute syelogenous type. Shell Oil, 1963 Mortality study of 3 refinery-petrochemical plants; 1973-1962; statis tical Increase of total leekiMi m and acute and syelagenoue leukesla In emly 1 pleat. Exposure date la weak bet benzene prebebly > 10 pps. Con ciselone as ef March 1964: Review ef cases showed bensese swposeres do net correlate with leukesla. Mo. of Deaths Reviewed ladssto Expected Observations Meed Ml Mfg Deer Mfg. 237 Literecwre: -- *StAtUtlfiftl elaslfIrenes Intel ef 0.05. 6.6 2.6 14* (SNR of 2.13; 3 cases of AML) 6 (SHE of 2.3; AML cases, 3) 3.9, 4.5 SAL OOOoou ?9 KEVlPf or MDIATOLOCICAL EFTTCTS IM WHAMS EXPOSED TO IDCim (VAM EXALTE. lfefr) U"l ittm) 10 IS 20-25 50 100 150 taatolocr Mytloptthy Uubali * At thm vorkfUct total aoac mi thi tiM. SAL 000001180 tfpm of kttltot Cyuttttile*, Imh MlMtd liftl fiiiHit 4u U vMk. Co--nts -ChmoMMl cfftcti ny rifltct high ipewrM In H|( ytari ehen kutot M 1n tightly con trolled. -Significant uriillaa not controlled: seoklng, nixed expo sures, Tirol infec tions, etc. >300 ppn Bo adverse effects in huMu here been reported. Chronic: Mice Bets < > m < M peer Bleed Erecroolo --rm*m-- < 2B0 wm Beet--e ly Ben taelto (MB), M Ben Baelte end Crneeo (1912). SAL 000001181 AUG 3 0 1385 MEDICAL OlV, Shell Development Company A Oivi.iqo of Sh*M Oil Company One Shell Plaza P.O. Do* 4320 Houston. Texas 77210 August 27, 1985 FROM: F.B. THOMAS, ACTING CHAIRMAN, PS-7 TASK FORCE TO: MEMBERS, API MBSD EXECUTIVE COMMITTEE SUBJECT: OVERVIEW OF API BENZENE RESEARCH PROGRAM Appended for your Information and approval is an overview of benzene toxicology prepared by the API PS-7 Task Force. This document is being sent directly to you at the request of Dr. Scala, in order that approval can be solicited from the API MBSD Executive Committee prior to the next meeting of'HESC (September 5, 1985). I understand that a telephone survey of the members of the Executive Committee will be made shortly. As a separate item, I have been asked by Dr* Craig to send to you a copy ofa draft statement which will be sent as a formal communication from Mobil to HESC. This document, which has not yet been reviewed by the PS-7 Task Force, outlines Mobil's position concerning the need for a chronic low dose study of benzene in the rat. No action by the API Executive Committee has been requested by Dr. Craig, and the document is being sent to you at this time for your in fo rmation. cc (w/attachment): Members, PS-7 Task Force C. DiPerna--Mobi1 J, Sul 1ivan--Amoco M. Beauchamp--API N.K. Weaver--API C.E. Holdsworth--API SAL 000001182 OVERVIEW OF BENZENE TOXICOLOGY PROGRAM API PS-7 TASK FORCE Version of 8/26/85 INTRODUCTION: The U.S. Occupational Safety & Health Administration (OSHA) is expected In the near future to issue regulations concerning the use of benzene in the workplace, establishing a not-to-be-exceeded Permissible Exposure Limit (PEL) for this compound of 1 ppm, a Short Term Exposure Limit (STEL, 15 min) of 5 ppm, and an action level of 0.5 ppm. OSHA will justify this regulation on the basis of quantitative estimates of human cancer (e.g., leukemia) risk derived from epidemiological studies of populations exposed to benzene. Data from animal studies are cited by OSHA as further support for the need of such regulation. The California Air Resources Board (CARB) has also developed quantitative estimates of human cancer risk from benzene based on tumor data in laboratory animals seen in a cancer bioassay sponsored by the National Toxicology Program. CARB has concluded that human cancer risks from even ambient benzene levels of 4-5 ppb are not negligible, and may use their estimate in support of California's listing of benzene as a hazardous air pollutant. The present document is not intended to provide a detailed review of the epidemiological and toxicological basis of the OSHA and California regulations. Rather this document identifies those issues surrounding benzene where it is believed that toxicological data may make a contribution. The PS-7 Task Force believes that the major benzene issues of relevance to the occupational use of this compound continues to revolve around hematotoxicity and the development of leukemia. While of concern, other biological endpoints of benzene toxicity (e.g., solid tumors, cytogenetics, micronuclei, etc.) are poorly understood and are of unknown significance to human health. The PS-7 Task Force has identified the following issues where toxicological research programs might be considered by the Industry:1 1. RELEVANCE OF RODENT DATA TO MAN: The major question affecting the development of reasonable workplace exposure limits for benzene is the relevance of findings in rats and mice to human health. It is known from the API/CMA research programs that mice are significantly more sensitive to the hematotoxic effects of benzene than are rats. Lacking, however, are definitive data for the relative sensitivity of man to the toxic effects of benzene on the blood-forming organs. This SAL 000001183 f uyc C issue was in fact recognized previously by the PS-7 Task Force who initiated pilot studies at the Brookhaven National Laboratory (BNL) in 1985. Sammett et al. (J Toxicol Environ Health 5: 785-592, 1979) reported that rats subjected to partial hepatectomy were significantly less sensitive to the hematotoxic effects of benzene, suggesting that the liver may play a key role in metabolizing benzene to a pretoxic derivative which may be subsequently activated in the bone marrow. This program is developing a method of culturing rodent and human bone marrow in chambers implanted into the peritoneal cavity of a host animal which is exposed to benzene. Thus, all marrow samples will be exposed to the same milieu of benzene and benzene metabolites, so that a direct comparison can be made of toxic effects seen in marrows across species. To date, BNL investigators have demonstrated that human marrow can in fact be grown in the body cavity of rodents, and they hope to identify certain cytokinetic parameters (e.g., the growth of specific bone marrow cell populations, etc.) which will allow a measure of the relative sensitivity of mouse, rat and human bone marrows to the tox'c effects of benzene. If useful cytokinetic parameters are not found by BNL, the Task Force anticipates that analysis of covalent benzene-DNA adducts and/or other endpoints may be considered as crude measures of benzene toxicity. In this regard, it should be noted that the Task Force is presently reviewing data from a recent report (submitted for publication) from the Chemical Industry Institute of Toxicology CIIT) finding increases in micronuclei and sister chromatid exchanges in rats and mice exposed in a single 6-hour exposure to benzene vapor. Pharmacokinetic and metabolite identification studies are ongoing by NTP at Lovelace. Interim findins will be available this year: when this information is available, the need for further pharmacokinetic studies can then be better assessed. The PS-7 Task Force recommends examination of prior CIIT work in this area and notes that the current CIIT approach on 1,3-butadiene (i.e., immune response, oncogenes, retrovirus activation) may also be relevant to benzene research. As mentioned earlier, the first phases of this research program are presently on-going at BNL, and it is estimated that the entire program will require approximately 18-24 months more to complete. While it must be stressed that this effort must be characterized as highly experimental, the Task Force believes that a number of important benefits may be derived from this exercise: SAL 000001184 ruyc O a. The data on the relative sensitivities of the bone marrow samples from various species may provide a basis for scaling In risk modelling. b. Such data may also give a basis of selecting the most appropriate test species for further research on benzene. c. Development of the implanted marrow model provides the Industry with a unique tool to evaluate the different degrees of benzene toxicity which might result from gavage vs, inhalation, pulse vs. continuous exposures, gavage in oil vs, gavage in water. d. Such data contribute substantially to our understanding of the mechanisms of benzene hematotoxic1ty. 2. PERCUTANEOUS ABSORPTION: The API Toxicology Committee has been sponsoring a complex program examining the absorption of benzene through the skin. This program is nearing completion and a final report is anticipated by the end of 1985. 3. REPRODUCTIVE TOXICITY: The PS-7 Task Force has been informed that a report of reproductive toxicity associated with benzene was recently presented by investigators at New York University to the 25th Annual Meeting of The Teratology Society. While details of the NYU findings are not available at this time, the Task Force understands that this information is presently under review by one API member company, and further information is being sought. It should be noted that reproductive toxicity was not seen in a previous study of benzene sponsored by API (Report No. 28-31212). 4. CARCINOGENICITY: In 1977, Maltoni and Scarnato (Gli Ospedali della Vita 4: 111-113, 1977) reported that the daily oral administration of benzene in olive oil to Sprague-Dawley rats for 52 weeks resulted in the appearance of a number of highly diverse solid tumors. This was subsequently confirmed in a bioassay sponsored by the National Toxicology Program (NTP) in which benzene in corn oil was administered orally to F344 rats and B6C3F1 mice on a daily basis (NTP, 1983). Maltoni et al. subsequently reported that Zymbal gland carcinomas were seen in rats exposed chronically to benzene vapor. In this latter study pregnant Sprague-Dawley rats were exposed to 200 ppm of benzene vapor, 4 hours/day, 5 days/ week from gestation day 12 to delivery. The offspring were then exposed to 200 or 300 ppm of benzene vapor, 4 or 7 hours/day, 5 days/week for up to 104 weeks. At 104 weeks, 8 of 137 rats had developed Zymbal gland carcinomas compared to none in the concurrent controls. Sal 00Ollgs page 4 Various investigators have found that some strains of mice respond to benzene exposure with increased incidences of thymic lymphoma and related tumors. However, these same strains of mice are known to harbor a virus (Murine Leukemia Virus) which is believed to play a critically important role in their developing such tumors. Consequently, the human health significance of the occurence of thymic lymphoma in these specific strains is not clear. The PS-7 Task Force has considered two proposals for carcinogenesis bioassays on benzene: a. CARCINOGENESIS BIOASSAY IN CBA/Ca MOUSE: Recent data from investigators at BNL indicate the mice of the CBA/Ca strain exposed to 300 ppm of benzene vapor (6 hr/day, 5 day/wk, 16 weeks) appear to develop an increased incidence of Acute Myelogenous Leukemia (AML). This is the histological type of leukemia most commonly associated with benzene exposures in man. Further, according to the BNL investigators, this strain of mouse apparently does not harbor Murine Leukemia Virus, leading BNL to suggest that the CBA/Ca strain may be an appropriate animal model for benzene 1eukemogenesis. The Task Force has conducted a search of the common toxicological databases for Information on the development of AML in this strain of mouse, but did not identify any published information. For this reason, the Task Force does not endorse a cancer bioassay in the CBA/Ca mouse at this time. However, as additional information becomes available on this strain, the Task Force will reevaluate the merits of conducting studies in the CBA/Ca mouse. b. CARCINOGENESIS BIOASSAY IN THE RAT: The API Health, Environment & Safety Committee (HESC) has asked the PS-7 Task Force to review a proposal submitted by Mobil Research and Development Corporation (Letter J.E. Penick to W.J. O'Keefe, 6/19/85) suggesting that the Industry consider sponsoring a low-dose benzene inhalation study in the rat in an effort to define a no-effect level for solid tumor development. Several benefits have been suggested to justify such a study: (1) Mr. Penick's letter notes that the finding of solid tumors in rodents exposed to high oral doses of benzene (diluted with vegetable oil) raises a new basis for concern beyond the workplace--the possibility of unwarranted class action suits claiming damages for all SAL 000001186 rage t> types of cancer allegedly caused by benzene emissions from industrial facilities and operation of vehicles. (2) Mobil notes that California has used the NTP data to conclude that health risks associated with 4-5 ppb ambient levels of benzene are not negligible. The California Air Resources Board is evaluating various strategies for reducing levels, including lowering the benzene and/or aromatics content of gasoline. (3) According to Mr. Penick's letter, OSHA may use the NTP data to justify a further lowering of their proposed benzene standard from 1.0 ppm to even lower levels* Mobil suggests that without animal data showing a no-effect dose level, extrapolation based on studies at high doses will continue to be used to calculate worst-case human risks, and almost any exposure level could be alleged to cause cancer in man. (NOTE: The draft OSHA benzene standard reviewed by the PS-7 Task Force bases its regulation of benzene on risk assessments using epidemiological data, not animal data). (4) The PS-7 Task Force believes that the development of additional tumor data via the inhalation route may shift regulatory modelling of human risk from ambient and workplace exposures to benzene vapor (e.g., CARB) away from the gavage data reported by NTP and Maltoni. (NOTE: Questions about benzene as a groundwater/drinking water contaminant are still impacted by the gavage data.) The benefits suggested above (i.e., regulatory risk assessment and litigation) are the purview of other groups within API. For this reason, the PS-7 Task Force will not address these issues, except where specific technical comments are believed to be appropriate However, the PS-7 Task Force has identified a number of technical concerns which should be considered fully by the Industry before sponsoring a low-dose benzene inhalation study as proposed by Mobil . (1) It is understood that the CARB risk estimate is based on the incidence of preputial gland tumors in the B6C3F1 mouse and not in the F344 rat. Thus, if there is concern about solid tumor data being used in risk calculations, the API may want to consider a study using both rats and mice. Similarly, the Task Force believes that defining a no-effect level only in the rat (i.e., the less sensitive of the rodent species would be subjected to SAL 000001187 Hage t> technical criticisms. (2) The Task Force reviewed an analysis of the likely effect of various assumed no-effect levels upon risk estimates derived from the "Global 82" model which was performed by Bob Sielken on behalf of Mobil. Although Sielken concludes that such data can have significant impact on the maximum likelihood estimates of risk, he notes that the data would have little effect on the 95% confidence limits; these limits are presently used by regulatory agencies as their basis for decision-making. It should be noted that Sielken's analysis makes no allowance for error and also presupposes that only one tumor type is identified as a basis rather than total tumors. In addition, his analysis shows that if the no-effect level is determined to be 30 ppm instead of 50 ppm, even the maximum likelihood estimate would be little affected. (3) The study design as proposed includes 200 to 1000 rats per dose to improve the statistical significance of the results. PS-7 had hoped to utilize Dr. Sielken as a consultant to determine the statistical power to be derived from the size of the experimental groups, as well as other statistical design considerations. Unfortunately, Dr. Sielken is not available until early September. However, based on discussions with statisticians from within the Industry, the Task Force believes that conducting a "mega-rat" study using 1000 animals/group would not yield significantly better data than a study using 300 animals/group. (4) Related to the question of group size above, the Task Force notes that large numbers of animals could necessitate that as many as 10 exposure chambers be employed for each treatment group, greatly increasing the complexity of the statistical evaluation of this experiment. (5) It was suggested that API consider sponsoring the proposed low-dose study at Dr. Cesare Maltoni's laboratory in Bologna, Italy. However, Dr. Maltoni uses Sprague-Dawley rat in his studies, so that data from such an experiment would do little to refute the observations of NTP in the F344 rat and B6C3F1 mouse. In addition, Mobil has noted that Dr. Maltoni lacks the computer facilities to analyze the volumes of animal observations which would accumulate from such a study. Thus a third-party would have to be involved for data analysis . SAL OOOOOHaa page 7 (6) The proposed study design involves exposures to benzene vapor for 6 hr/day, 5 day/week, for approximately two years. This exposure schedule is considered by the Task Force as being more appropriate for mimicking occupational exposures, than for the consumer exposures which are of litigious concern (see Penick letter). (7) Similarly, if the intent of the proposed study is to refute the tumor observations of the NTP bioassay, the route of exposure should be the same as that used by NTP (i.e., gavage in corn oi1 , not inhalation ). (8) As noted above, previous data developed by API and CMA indicate that the mouse is substantially more sensitive to the hematotoxic effects of benzene vapor than is the rat. The Task Force is concerned, therefore, that in a low-dose study involving rats and mice, that the no-effect level determined in mouse may be substantially lower than the 25 to 50-ppm no-effect level predicted by Mobil in the rat. This outcome would, of course, raise once again the basic question of the relevance of rodent data to human hea1th . The PS-7 Task Force hopes this discussion, in combination with the inputs of API's regulatory and legal experts, will provide an adequate basis for putting into perspective the overall direction and content of the Industry's research program on benzene. sal 0oOliB9 APIDPOs:CRAIG APIDPOs:THOMAS BENZENE DRAFT AUG-1985 15:15 H0TE-- A will L>c of ^ -b Hesc Vj Mobil. Ti^ mT m API P5-7 w-t THE CARCINOGENICITY OF BENZENE Mobil believes that carcinogenicity has been and will continue to be, the primary -factor which drives benzene regulation. Further, Mobil believes that -future regulations will be based upon a -formal process o-f evaluation, i.e. , quantitative assessment o-f risk. Industry has the responsibility to conduct its own assessments, including particularly the development o-f valid and credible scientific data upon which an unbiased evaluation of e::posurs/r i sk can be founded. Although many other aspects are significant, cl ear1ydefined dose response curve is the central requirement of a risk assessment. For assessments which use animal data to predict human risk, other important requirements include appropriate experimental design, and other factors for minimizing the significance of species differences. As a generality, the latter factors are derived from metabolic and kinetic studies. Without a well-defined dose response curve based on an applicable experimental design, be no valid risk assessment can be made. SAL 000001190 It is recognized that in-formation may come from a variety of sources, but Mobil believes that the most significant data in the -future will come -from animal models of benzene carcinogenesis, i.e., the rat and the mouse. Both sexes of both species predict a carcinogenic response in man and therefore must be regarded, in a general sense, as applicable models. No currently available data provide a satisfactory basis for risk assessment of benzene carcinogenesis. Recent epidemiology studies of workers exposed to benzene several decades ago have been flawed by speculative (probably highly underestimated) exposure values. The several inhalation carcinogenicity studies in rats and mice conducted in the last two decades have been of the screening type, designed to reveal whether a carcinogenic hazard exists, and conducted at levels of 100 ppm and above. An oral carcinogenicity study in rats and mice conducted by the- National Toxicology Program (NTP) used high rates of administration (25 mg/kg/dsy and greater). Every dosed greup of both sexes of both species experienced a significant carcinogenic response; SAL 000001191 there were no no-effect levels. The California Air Resources Board recently used the NTP data derived from long-term oral administration to predict the effects of benzene in the atmosphere, concluding that there is significant inhalation risk in the low ppb range. This is a misapplication of the risk assessment process. Mobil has proposed a long-term study of benzene in the rat, to be conducted by inhalation at concentrations between zero and 300 pom. The purpose of this study is to provide a dose response curve suitable for risk assessment. The study should demonstrate experimental no--effect levels, which establish the degree of sublinearity cf the dGse response curve. Mobil has further proposed that the final experimental design be statistically optimized for the purpose, and that metabolic and kinetic studies generate information applicable to the interspecies extrapolation. The final design of. the various studies is the responsibility of the Technical Task Force. Mobil believes that the work of design and conduct of these investigations in the rat should proceed forthwith. SAL 000001192 Mobil has not proposed the conduct o-f parallel studies in the mouse because o-f recent developments concerning that species at Brookhaven Laboratory. In screening studies at 100 ppm and above, the CBA/ca strain o-f mouse has been shown to develop myeloid leukemia, a type o-f cancer observed in workers exposed to high concentrations o-f benzene in the air. The Benzene Toxicology Task Force has the responsibility of determining whether the CBA/ca mouse should be regarded as a speci-fic model o-f human benzene 1 eukemoaenesi s. I-f it is concluded that i+ the model appears applicable, studies in the CBA/ca mouse should be considered. sal 00001193 SAL 000001194 William D. Broddle S: To J* R. Bender, M.D 1 For your information. wo&Jm $ WDB/lel i i (conoco) Date 09/03/85 3 f :x i- ii i XT r >*$ ... *<' ..-/-ji''. ' SAL 000001195 iVft-.V.* ' V. American Petroleum Institute 1220 L Street. Northwest Washington, D.C. 20005 Committee Correspondence Reply to: To: From: Re: Date: The HESC Planning and Budget Subcommittee Steven M. Swanson _______________ Proposed Study to Collect Refinery Worker Exposure Data on Benzene and Gasoline-Range Hydrocarbons June 13, 1985 API is preparing to participate in the OSHA hearings on benzene which are likely to be held later this year. As part of that effort, counsel and consultants have recom mended that new exposure monitoring data be collected to bolster API's defenses against potential PEL's of 1.0 ppm or 0.5 ppm. This memorandum discusses the reasons why such new data are needed and describes a study to respond to those needs. If appropriate, the study can be expanded, at small additional cost, to simultaneously collect data on worker exposure to gasoline-range hydrocarbons. THE NEED FOR SUPPLEMENTAL BENZENE EXPOSURE DATA OSHA's draft proposed benzene standard, which is pre sently undergoing final CMB review and is expected to be published later this year, contains two broad findings of concern from a regulatory standpoint. First, OSHA's draft proposal concludes that workers would face a "significant" health risk even under revised benzene FEL's of 1.0 and 0.5 ppm. Second, the Agency finds that a 1.0 ppm PEL is tech nologically and economically "feasible" and appears ready to conclude that a 0.5 ppm PEL is also feasible in most set tings. In the petroleum refining industry, for example, OSHA claims that a 1.0 ppm PEL is already being uniformly achieved and thus would impose no capital costs, and comes very close to finding that a 0.5 ppm PEL is feasible.^/ */ In fact, OSHA's feasibility contractor purports to have identified three refineries that are consistently achieving 0.1 ppm. SAL 000001196 2 OSHA is also going to propose a 5.0 ppm short-term (15 min ute) exposure limit (STEL), which is claimed to be feasible without respirator use. API's approach to preparing for the upcoming OSHA hearings is to collect data that will support the most effective challenge that can be mounted against these conclusions on medical, technical and cost grounds. Exposure data are critical for all these purposes. To date, API's efforts to develop such a data base have included (i) an extensive survey in 1983 of historical monitoring data collected by member companies, and (ii) a statistical analysis of data supplied by four of the companies having the most extensive monitoring programs. The preliminary results of these efforts underscore the importance of exposure data for the upcoming OSHA hearings. In particular, the data in hand suggest that occupational benzene exposures, while quite low on average, are highly variable from day to day. As a result, employers may find it necessary to reduce average exposures to levels well below any never-to-be-exceeded PEL (perhaps by a factor of four or five) to achieve reasonably consistent (e.g., 95%) compliance. This fact, if it could be adequately documented, would raise the following concerns: o It is far from certain that average exposures in the petroleum industry can be maintained at levels low enough to ensure reasonably consistent compliance with a never-to-be-exceeded PEL of 1.0 ppm, much less 0.5 ppm. If the preliminary conclusions of the previous efforts are confirmed by new data, CSHA's feasibility findings will be subject to serious question. o Even if it is technically feasible to attain a reasonable degree of compliance with a never-to-bc-exceeded 1.0 ppm PEL, the tentative conclusions arising from the data in hand suggest that a potentially large number of refinery operations would be required to install engineering controls to maintain average exposures at sufficiently low levels. If substanti ;ted, this conclusion would undercut OSHA's finding that refineries are already fully in compliance with a 1.0 ppm PEL. In addition, it would raise serious questions about the cost-effectiveness of 1.0 ppm or lower PEL's, part.icu] arly given the marginal health benefits of further reductions. sal 000001197 3 Unfortunately, our efforts to date have also shown that even the companies with the most extensive and sophisticated monitoring programs have not developed exposure data which are sufficiently coherent and systematic in collection and analysis, for their combined use to definitively support or refute conclusions like those just described. The underlying problem is that company programs have been designed to serve purposes (such as OSHA compliance) that are fundamentally different from the regulatory issues we now face. Hence, a defensible statistical analysis of the current data base is frustrated by a variety of factors, such as: o the use of different sampling strategies by different companies; o the absence of sufficient detail to relate individual measurements to engineering controls, the particular tasks being performed and the work practices used that affect analysis of the data; o the paucity of data sets involving multiple measurements of similarly-situated workers over a reasonable period of time; and o the absence of data suitable for aggregation for analysis. Moreover, the available data base does not provide a suf ficient basis for evaluating a 5.0 ppm STEL, even though that provision could well prove to have the greatest practical impact on the refining industry. For these and other reasons, outside counsel and con sultants have cautioned that our tentative conclusions doubt variability, feasibility, and compliance costs and benefits may not withstand the rigorous scrutiny that is likely to occur during the upcoming hearings. Our data must support analysis that is not only convincing but sufficient to over power analyses of data that lead to other conclusions. Additional data confirming or refuting these tentative con clusions would therefore provide an essential supplement to the data and analysis already collected and prepared. Apart from facilitating a more defensible statistical analysis than that already completed, the collection of new data by an additional independent expert witness is likely to produce a more credible and influential submission. The additional capability to address general questions concer ning the effectiveness of particular exposure controls will be of great importance in any OSHA proceeding. SAL 000001198 - 4- SUMMARY OF THE PROPOSED STUDY Because of the obvious importance of API's tentative conclusions about the effects of a 1.0 ppm not-to-exceed PEL to the presentation of an effective case in the upcoming hearings, a field study designed to explore and further develop these conclusions has been developed in consultation with the group of statisticians from the University of California at Berkeley who analyzed the historical data, counsel. Radian Corporation and member-company industrial hygienists. The field study would involve about a month of field time by teams of approximately five industrial hygienists working simultaneously at each of three refineries selected to span the range of current exposure conditions. The hygienists would examine three or four units in each refinery, documenting benzene exposure con trols, work practices and other parameters relevant to expo sure such as weather and operating conditions. The focus of the study would be exposure monitoring, primarily through full-shift sampling. In addition to these TWA measurements, some fifteen-minute sampling to assess the feasibility and cost of alternative possible short-term exposure limits and to aid in apportioning total worker ex posure among various possible sources would be undertaken. The hygienists would follow one or two workers on each unit through their shift rotations, assembling for each of these workers the most extensive series of repeat measurements possible within the 30-day period of observation. The hygienists would also collect several five-day series of exposure measurements on other workers on the unit. As time permits, the hygienists would take selective fifteen-minute samples on workers being monitored for a full shift and collect additional full-shift samples on other workers on the unit. Preliminary plant visits will allow this general plan to be tailored to each unit to be observed. Oversight for the project would rest with the Benzene Issue Group, staff and counsel. Responsibility for actual conduct of the project would be shared by company hygiensts, and the Radian and Eerkeley groups. Radian would develope the final study designs, perform the field work and coordi nate sample analysis. The Eerkeley group would have respon sibility for analysis of the data. The final project report would be a joint Radian/Berkeley effort with provision for review by API, counsel, and the Benzene Issue Group and other company participants. In addition to the normal con tract provisions for confidentiality exposure measurements and all other information would be blinded for anonymity and coded. IJo identification of individual companies, refineries, units, or workers would appear in the final report. SAL OOOOOII99 -5Radian estimates that the project can be completed by November 1, 1965 if the field work is started in early August. We anticipate that the project will cost between $550,000 and $650,000, including the expense of additional data analysis by the Berkeley group and the time of a process-engineer who may be necessary to supplement the results of the project with additional data needed to project industry-wide costs for the installation and operation of particular exposure controls. This proposed work has application beyond the benzene case. The cost above anticipates additional exposure analysis for a full boiling range of gasoline components, including the gasoline fractions under test in PS-53, as well as the components being considered for testing under Section 4 of TSCA. SAL 000001200 COtftgHTS OH THE FS-7 TASK FORCES PROPOSED BEHZEKE LIFETIME STUDIES 1. H HSRC/SEHL reviewed the proposal to Mie9 its risks vs. its benefits? 2. The June 19 Penlck letter correctly assesses the current state of affairs both as to events in California and OSHA: data which have been in hand for more than two years, together with never, suggestive dsta (e.g., the CIlT*s findings on 8CE and other effects at very low doses) provide information which, if used by OSHA, &PA, or state authorities, coupled with the significant latitude snd siandate to exercise prudence agencies have, could veil drive health-based proposals on standards to very lov levels. If the proposed study were to identify a NOEL in the 25-50 ppm range then, based either on tbe usual Methods of extrapolation or on safety margins (1,000 - 5,000 times below tbe NOEL for carcinogens has been suggested) the health-related driving force toward lov standards would be enhanced vitbin OSHA, EPA, and state agencies. Doing tbe study thus does entail risk, over snd above that which already exists, with respect to regulation. Vith respect to regulatory agencies, therefore, 1 propose that a study to establish the engineering snd operational feasibility of controlling exposures and emissions at different levels be launched; the exposure studies now being defined could, if appropriately directed, provide Invaluable data on levels, frequencies and sources of exposure and of emissions as inputs to feasibility studies. This effort needs to go forward whether the proposed Inhalation studies do ot not; aoreover, if tbe Inhalation studies are carried out, this study will serve to reduce the extra risk in doing the inhalation studies. 3. The area in which the inhalation studies might be most valuable is in countering extravagant adverse health effects claims. Here, a clearly established, large-study K0EI may veil be important, outweighing possibly enhanced risks in the regulatory arena. This is not a sure-fire proposi tion, even here, since claimants can and will argoe on tbe basis of their preferred extrapolations and/or interpretations. At the moment, however, embers of the industry have too little with which to counter claims. It must be remeabered, though, that even large studies entail some degree of risk of obtaining false positives at lov levels. Clearly, the relative risks snd benefits need to be assessed for snd by the HESC before deciding whether or not to do the inhalation studies, considering both the regulatory and the litigative factors. 4. Where in all this do tbe Brookhaven CBA^ mice fit? Have all the pros and cons of this approach been explored? For example, Is a arouse such as this a unique creature, or does leukemogenesis in it signify anything vith respect to leukeirogenesis in humans? CK&51$90) FROM SHELL 0IL-HS*E 07/08/85 15:36 P. 2 SAL 000001201 t 2 5. At tbe Hircb HE8C meeting, the HASP wab ebx|d vith denlopiat * program of ial studies of benzene; ate the proposals now before os a complete and balanced response to that charge? Is there more to coae? 6. I would suggest that the nechaniatic studies mentioned night well be funded st CUT where such benzene research is already underway. FFDtean 7/OB/$5 /nMIC SAL 000001202 AMERICAN PETROLEUM INSTITUTE Medicine and Biological Science Department Benzene Toxicology (PS-7) Task Force The API Benzene Toxicology Task Force (PS-7) met on July 2, 1965, to consider the issues raised in Mr. Penick's letter (Penick to O'Keefe, June 19, 1985), attached. At that meeting, it was recommended that API sponsor a lifetime study of benzene in the rat, at concentrations between 0 and 300 ppm, for the purpose of defining the relationship between concentration and carcinogenic response. The Task Force believes that the study should be initiated in 1965. It was further recommended that, in parallel with this study, mechan istic/pharmacokinetic investigations be conducted. The Task Force will survey laboratories capable of perform ing this work, and will present further recommendations in September 1985. Also, a model of leukemogenesis in the CBA/Ca mouse recently proposed by the Brookhaven Laboratory, is being actively inves-tigated as a potential surrogate for benzene leukemogenesis in man. PCraig/TKeenan/7/2/85 SAL 000001203 Mobil Research and Development Corporation RECEIVEC PRODUCT SAFE1 4 IRcO. SYSTEMS po ton '0> JJjf PMNCCTON. NCW Mmcr Nr. William J. O'Kbefe American Petroleum Institute 1220 L Street, Northwest Washington, DC 20037 Jura 19, 1985 -yy^lY jotcPD.01 CJ DIPGRNA _____ JPMc _____ RC JCH CCF enl PAN FMC _____ PAL KBIL PROPOSED BENZENE HEALTH EFFECTS sraw ___________ Dear BUlx API has been unable to reach a consensus on research programs to iuprove our understanding of turnon risks frcn low level exposures to benzene. Mobil believes that recent benzene findings make it imperative to initiate a rodent earner study via the inhalation route without further delay. Other necessary research should be planned and contacted during the three years needed to cocapiete the cancer study. Recent studies by the National Toxicology Program (NIP) and Professor Cesare Maltoni show that high oral doses of benzene cause solid bmors in rodents. The findings of solid txzoors raise a new basis for concern beyond the work place -- the possibility of unwarranted class action suits claiming damages for all types of cancer allegedly caused by benzene emissions frcn industrial facilities and from fueling and operation of vehicles. California already has used the NIP data to conclude that health risks asso ciated with 4-5 ppb anfcient levels of benzene are not negligible. The California Air Resources Board is evaluating various strategies for reducing anfeient levels, including lowering the benzene and/or aromatics content of gasoline. In addition, OSHA may use the NIP data to justify a further lower ing of their proposed benzene standard from 1.0 to 0.5 ppn. Without animal data showing a no-effect dose level, extrapolation based on studies at high doses trill continue to be used to calculate worst-case huaan risks, and almost any exposure level could be alleged to cause cancer in man. SAL 000001201 -2- 3h bast rtsporM to possible damage suits and writ*ein regulatory findings will require high quality data from aniaal atudiaa using tha inhalation routs# rwith appropriate mechanistic information. Iha animal studies should cover a range of exposures from 300 ppm to 1 ppm and uaa 200 to 1#000 rats per does to isprove tha statistical significance of ths rsaults. Vis believe that the study will demonstrate a no-effect doee in the range of 25-50 fib. It is essential that oosplsmantary pharaoooklnatic and metabolic atudiaa be carried cut to permit rational extrapolation of tha results from animals to tuxaane. In rscont months# API has learnad that ths Brookhaven Laboratory has developed an animal Iwikamta Bxlel in mica. It probably is dasirabla for API to sponsor m leukosis study with associated mechanistic studies# but we believe the solid tutor study has higher priority because risk asseasnsnts based on the NIP results predict a greater risk to man than those based on earlier epidemiology assessments. For the foregoing reasons# I move as follows! API-HE9C directs the *BSD to initiate during 1985 a cancer study in rata over a range of doses fron about 1 p(B to 300 ppn, with the understanding that appropriate mechanistic research is to be done concurrently. Sincerely# /El 0580Q oc: B. G. Bissormet FL J. Canpion R. H. Compton J. E. Crawford E. T. DiCbrcia M. L. Hanson C. Renfrew R. Scale C. B. Scott R. J. Vblz bocs R. Adams J. M. Cannella J. P. McCullough O. E. Miller P. J. Wolfe SAL 000001205 American Petroleum Institute 1220 L Street. Northwest Washington, D C. 20005 202-682-8000 TH- r.mmeee. Pk.fi. Toxtcologtst 202/682-8*42 J TO: FROM: DATE: SUBJECT: PS-7/TRTG Task Forces Thomas H. Keenan July 24, 1985 Meeting Minutes The Minutes of the June 13, 1985 Meeting are enclosed for your information. Please review the minutes and inform me of any additions/corrections. xc: C.E. Holdsworth An ecus! ODDoMLiniT> employe' SAL 000001206 American Petroleum Institute Medicine and Biological Science Department PS-7/TRTG Task Force Meetng Minutes API Offices, Room 1273 Thursday, June 13, 1965 1-4 p.m. Attendees p. Craig (Mobil) M. Lakin (Chevron) S. Cragg (ARCO) R. Nair (Monsanto) Others J. Amsel (API) M. Bird (Exxon) C. Blank (API ) PS-7 Task Force P. Garvin (AMOCO) B. Thomas (Shell) TRTG R. Kociba (Dow) C. Stack (CMA) T. Slone (DuPont) K. Bristol (API) E. Cronkite (Brookhaven) J. Rodricks (Environ) T. Keenan (API) I. Dr. Cronkite1 s Benzene Research. Dr. Cronkite presented evidence for his purported benzene leukemogenesis model. The experimental design consisted of exposing animals via inhalation to 100 or 300 ppm benzene 6 hr/d, Sd/vk for 16 weeks. Two strains of mice were used (i.e.f C57B6 and CBA/Ca). The lymphomas/leukemias observed with the C57B6 strain are roughly analogous to human acute lymphoblastic leukemia; however, the lymphomas produced are associated with a retrovirus. Acute myelogenous leukemia (AML) is induced in CBA/Ca. The spontaneous incidence of AML is low; there is no evidence for the existence of a retrovirus (Personal communication to Dr. Cronkite: Ester Hays (UCLA) and Robin Mole). The results as of April 4, 1985 are summarized in the attached tables and the data is presented in the figures. General conclusions as presented by Dr. Cronkite are: C57B6: a shortened latent period and a more rapid increase in tumors is observed with animals exposed to benzene or radiation. SAL 000001207 CBA/Ca: benzene or radiation induces an increased incidence of leukemia. This strain is more responsive than the C57B6 strain. II. CUT Manuscripts. A preprint of a manuscript released by CUT concerning SCE and micronucleus formation in mice and rats was discussed. The results indicated that a single 6 hr exposure of benzene induced statistically significant increases in SCE in peripherial blood lymphocytes and micronuclei in polychromatic erythrocytes in mice (10 ppm SCE and MN) and rats (3 ppm - SCE; 1 ppm - MN). III. Developmental Project (Dr. Cronkite). The feasibility of growing bone marrow cells in Plasma Clot Diffusion Chambers in mice and rats is being determined. The data (table attached) indicate that human bone marrow cells grow better in mice than in rats. The PS-7 Task Force will review this information and deter mine if the second phase of the project will be funded. The experiments of the second phase will compare the eryth ropoietic responses of human, rat, and mouse bone marrow cells following benzene exposures. IV. TRTG Meeting. Dr. Snyder's review of the recent benzene literature used by OSHA has been distributed. Task Force members are requested to review the manuscript and be prepared to comment by the next meeting. SAL 000001208 (*1 f tCl STRAIN SEX C57B6 M M M M F F F F F F CBA/Ca M M M M M M F F F F MORTALITY, LEUKEMIA, AND TOTAL TUMOR INCIDENCE IN TWO STRAINS (C57B6 AND CBA/Ca) IN A BENZENE INHALATION EXPERIMENT EXPOSURE BENZENE CONC. EXPOSURE1 TIME DURATION ON STUDY Z x2 MORTALITY LEUKEMIA 300 ppm sham 300 ppm sham 300 ppm sham 300 ppm sham 300 ppm sham 16v 450d 450d 8v 430d 430d 16v 1023d 1025d 8w 230d 230d 16v l 340d Intermittent 540d 43 35 0-- 55 0-- 95 50 35 55 2 NA, 8 NA3 0-- 300 ppm 8 ham 300 ppm sham 100 ppm sham 300 ppm sham 100 ppm sham 16v 16v 16w 16w 16v 503d 505d 520d 520d 480d 480d 505d 505d 480d 480d 50 17 0 48 NA3 0-- 0-- 0-- 35 10 0-- 0-- 0-- Z TOTAL TUMORS NA -- NA -- 7 NA NA NA NA 20 -- NA -- -- -- 25 -- -- -- Exposures were 6 br/d, 5d/vk. Thymic and nonthymic lymphomas Id C57B6* Acute myelogenous leukemia in CBA/Ca. NA, not available. 4 Exposure vere for 2 weeks on, then 2 weeks off for a total of 16 weeks exposure. 00001209 MORTALITY, LEUKEMIA, AND TOTAL TUMOR INCIDENCE IN TWO STRAINS (C57B6 AND CBA/Ca) IN A RADIATION EXPERIMENT STRAIN C57B6 CBA/Ca TIME ON SEX TREATMENT STUDY M Bonlrraddlated M 525r-single dose M 175r-3 times &d Intervals M 5.25r/d,5d/vk to total 525r lOOOd lOOOd lOOOd 720d M Nonlrradiated 300r 250r 200r lOOr 50r 1050d 1050d 1050d 1050 X MORTALITY 80 80 90 20 X LEUKEMIA 26 38 50 NA2 X1 TOTAL TUMORS 35 45 65 NA2 85 3 95 27 100 28 35 10 6 NA2 35 48 Total tumors in the CBA/Ca excludes hepatomas. This strain has a high spontaneous Incidence of hepatomas. KA, not available. SAL 000001210 Treatment Croup 550 Rads HUMAN BONE HARKOV CROVN IN DIFFUSION CHAMBERS WITH RICE AMD MTS AS HOSTS Host Experiment Day 7 cru-E* ________ _ P*T 14 cpu-e* BFD-E0 BNLC mice 1 2 $4.7*14.9 55,7*14.7 61.3*24.8 22.5* 6.7 4.0*1.8 1.0*0.6 550 Rads and PHZd PHZd Hypoxia^ 550 Rads and Hypoxia^ 550 Rads and Hypoxia* 600 Rads 600 Rads and Hypoxia* BNLC mice BNLC mice BNLe mice C57B1/6J mice SpragueDawley Rats SpragueDawley Rats 1 2 1 2 1 2 3 1 2 3 1 1 47.7*2lll 57.5*14.7 $1.8*19.3 26.2*11.0 44.3* 9.6 22.2* 6.2 97.8* 41.9 7.2* 2.2 22.3* 7.8 80.0*13.6 22.5*11.0 56.5*20.6 e 36.0* 4.7 9.3* 2.9 94.3*18.9 114.0*14.7 49.3* 9.8 54.0* 3.5 2.3* 1.4 9.5*4.9 e 0 0 9.5*3.0 17.7*4.0 8.2*3.3 6.5*1.2 0 0.8* 0.5 57.8*14.4 11.2*3.6 Inoculum ** 2.5 x 10^ separated bone marrow cells (LSMmethod) per chamber. * Colony forming unit* - erythroid (CFU-E). Mean colonies (8 to 64 erythroid cells) * standard error. fe Burst forming units - erythroid (BFU-E). Hean bursts (64 erythroid cells or cluster of 3 colonies) * standard error. c Randomly bred white mice of the Brookhaven (Hale/Stoner) strain. d Phenylhydraiine Hydrochloride (PHZ) 50 mg/kg body weight I.P. 2 hours prior to inplant c chambers. e Host mice in this treatment group died before day 14. f Hypobaric chamber 6 hours a day, 7 days a week (starting 24 hours post implant of chambers) . t SAL 000001211 CO' tO'C: 00 DC`0t 0w?'v0h "i k 00`CS t -iui. 00`09 00'01 co da 00`06 00*001 T ).0n ( SAL 000001212 u- ~o CO CD tO w CL / v 1 0 .0 0 2 0 ,0 0 3 0 .0 0 *10.00 5 0 .0 0 5 0 .0 0 7 0 . OP 0 0 .0 0 , D'l.OQ FICE IN 0HY5 H io ' 1 0 0 .0 0 1 1 0 .0 0 JOO.OD l? 0 .0 0 1 1 0 .0 0 1 5 0 .0 0 H (B8) C57 F, 1SWK BENZENE (300 PPM 6HR/D 50/WK) AS OF 4 RPR 85 c SAL 0000012I3 01''OM CC`06 oo*de oc`dzmJi ore's ocro;-. Gbiu STbiilNO DO*OE t0'02 Cu'CI 00 V co t- 100.00 t'lO.OO 120.00 tl'0 .0 0 149.00 150.01 c BO. 00 , BO.00 f . b . 0 0 70.00 (B9) C57 F. 8WK BENZENE 1300 PPM GHR/D 50/WK) AS OF 4 APR 85 50.00 40.00 a cr X o XO a. o m X 1-^ n >- cc to LJ cr N C>- __ in G_ a Ui O --i cr -J LU X ID cr Z iu in t-- 5CT o cc __r S Cl o _j Ui X a: a _J UJ 0< * ( SAL 000001215 o 00`OCil DO *C5 DCT6 dot: OO'ds oFoi 00 'dll U&3G SMOrilNb /. oo*oc ocoe 03*01 DO <f 30.00 to .00 20.00 IpQ.OO r* (Bim C57 M, 16WK BENZENE (300 PPM 6HR/D SO/WK) H5 OF l) RPR 05 (NO DEATHS IN SHAM GROUT5) o MORTALITY A ALL NEOPLASMS + LEUKEMIAS/LYMPHOMPTR * EXPOSURE PERIOD 9p.gQ 7 0 .CO 60.00 6p.G0 Hf.QQ ` SO.03 30.00 jQ.OO 10.00 1>,oo lo.do ?o.oo 3o.oo 'to.oo r.o.oo bo.no zo.oo oo.oo oboo RGE IN OATS h!0` 100.00 10.00 130.00 170.00 I0.00 |<.00 c 7 M, 8WK BENZENE (300 PPM SHR/D 5D/WK) hce in RPR 85 no deaths in sham group)( cz LO o =r u. CO O CD CO -- CL o ,r< oc yov oo oo c. .o oc> .co o * o O oo .(oS c o .o . .o oo*c:7 tr*C5 Cl Cu 'Oi D-'C-I ..D.VW rO'Ci') OdBG 5 loNlnb /. OC'OE SAL 000001217 00'0? Bj-01 (B12) CS7 F, 16WK BENZENE (300 PPM 2WK ar'r,2WK"0FF") R3 OF 4 RPR 85 (NO DEATHS IN SHAM GROUP) O MORTALITY A ALL NEOPLASMS + LEUKEMinS/LTMPHOMRTn * EXPOSURE PERIOD SAL 000001218 b .On ?0.C0 30.00 10.00 50.00 to.OP 70.00 80.00 . 00.00 OGE IN DRYS m]0* 100.00 110.00 120.00 f0.00 110.OO T\o.oo (B131 CBR F, 1GWK BENZENE (300 PPM 6HR/0 50/WK) OS OF 4 RPR 85 (NO DEATHS IN SHAM GROUP) 0 MORTALITY A rll neoplasms -f RLL NEOPLASMS OTHER THRN HEPPTOMR X LEUKEMIRS/LYMPHOMRTR * EXPOSURE PERIOD ~vnr SAL 000001219 10.00 ?o,oo 30.00 >10.oo 50.00 00.00 70.00 00.00 . 00.00 PGE ]N OPTS h i rj* 100.00 I 10.00 i?o.oo 1^0.00 ivo.oo (B13) CBR M, 16WK BENZENE (300 PPM 6HR/D 50/WK) RS OP 'i RPR 85 (NO DEATHS IN sham group) SAL 000001220 SAL 000001221 r> (515) CBfl M, 1BWK BENZENE (300 PPM 6HR/D 5D/WK) AS OF y RPR 85 (no deaths in sham gf.oup) oo o mortality A pll neoplasms + ALL NEOPLRSMS OTHER THRN HEPRT0MR o x leukemias/lymphomrtr * EXPOSURE PERIOD O o. Ci' a: uJ co V'**. _ i-a. O z c. c (B21) CBR F, 1GWK BENZENE (100 PPM GHR/D 5D/WK) R5 OF ^ RPR 85 no DEATHS IN MALE GROUP)( cc 2= D I-- cr c_ UJ X z cr X *- cc tr f-- Ui X XX i-- o DX o tn to cl X o 21 X >- OC CO to UJ cr cr V. 0. _j cn n_ CL X UJ oD cc UJ LU X z Z UJ in o i _J r> L _J UJ X s (X UJ < + X* o_ ce..> cn >c g ,z LJ O oc e c J.. fg .a SAL 000001222 tMTOcft co*cs oircfa DO ` OZ 00*09 00 *05 00 *0h oo*o; oo *d? ccci cT L ._ ENV&OHS OCT 31 1988 DECEIVED REVIEW AND EVALUATION OF LEUKEMIA RISKS POTENTIALLY ASSOCIATED WITH ENVIRONMENTAL EXPOSURE TO BENZENE Prepared for: Western Oil and Gas Association Prepared by: Joseph V. Rodricks, Ph.D. Susan M. Brett, M.P.H. ENVIRON Corporation Washington, D.C. 20007 May 1986 SAL 000001223 The authors acknowledge with gratitude the contributions of the following ENVIRON scientists who were consulted or otherwise participated in the development of this report: Julia M. Dady, M.S., Maureen Kane, Robert H. Ku, Ph.D., and Duncan Turnbull, D.Phil. SAl 000001224 CONTENTS Page I. INTRODUCTION......................................................................................................... 1 II. GENERAL REVIEW OF DATA AVAILABLE FOR BENZENE RISK ASSESSMENT................................................................................................. 2 III. HUMAN STUDIES AVAILABLE FOR RISKASSESSMENT............................. 11 A. Description of Studies and theirLimitations.... 11 1. Infante et al. 1977/Rinsky et al. 1981/ Rinsky et al. 1985................................................................... 11 2. Ott et al. 1978/Bond et al. 1985............................... 20 3. Aksoy 1980....................................................................................... 23 4. Wong 1983 .......................................................................................... 26 B. Conclusion............................................................................................... 28 III. REVIEW OF AVAILABLE BENZENE RISK ASSESSMENTS....................... 29 A. Earlier Risk Assessments Employing the Linear Model................................................................................ 29 B. White, Infante and Chu 1982..................................................... 32 C. Crump and Allen 1984..................................................................... 35 D. USEPA/CAG 1985..................................................................................... 45 E. Rinsky et al. 1985.......................................................................... 46 F. Chinchilli 1986 .................................................................................. 48 IV. ADDITIONAL FACTORS SUGGESTING THAT THE ACTUAL RISK OF BENZENE EXPOSURE IS LOWER THAN PROJECTED IN THE AVAILABLE RISK ASSESSMENTS OF THE RINSKY ET AL. COHORT...................................................................................................... 55 V. CONCLUSIONS ABOUT LEUKEMIARISK ON THEBASIS OF THE AVAILABLE BENZENERISKASSESSMENTS.................................... 59 Appendix A - Dermal Absorption of Benzene (ENVIRON 1986) Appendix B - A Preliminary Review of Literature Pertaining to Non-Pliofilm Rubber Worker Benzene Exposure before 1970 (American Petroleum Institute 1986) Appendix C - Case Control Analysis of Ott et al. Cohort (American Petroleum Institute 1986) Appendix D - A Statistical Analysis of the Rinsky Data Set on Benzene Exposure (Chinchilli 1986) -l- SAL 000001225 I. INTRODUCTION In preparation for hearings before the California Air Resources Board, the Western Oil and Gas Association requested that ENVIRON review the available scientific data for the assessment of the leukemogenic risk of human exposure to benzene in the environment and to render a judgment on the most appropriate data and methodology for assessing such risks. The following report incorporates the results of an analysis prepared by ENVIRON for the American Petroleum Institute (API) of the leukemia risks potentially associated with occupational exposure to benzene (Rodricks and Brett 1986). In addition, it contains results of analyses performed and information obtained subsequent to the preparation of that report. Furthermore, in the discussion which follows, an attempt will be made to express risks in terms of lifetime exposure to benzene concentrations in ambient air, as opposed to working lifetime exposure to benzene in the occupational setting. The report will begin with a discussion of the general nature of risk assessment and the data upon which benzene risk assessments have been based to date. The reasons for our preference for the use of human epidemiologic data in the case of benzene risk assessment will be detailed. In the following section, the epidemiologic studies will be reviewed and their strengths and limitations for benzene risk assessment will be described. This will be followed by a review of the available benzene risk assessments, including their strengths and weaknesses. Additional factors suggesting that the actual risk of benzene exposure is lower than that projected in the available assessments of the Rinsky et al. cohort will be described in the following section. The final section presents our conclusions about leukemia risk at low exposure levels on the basis of the available risk assessments and recently acquired data related to the total benzene exposure of the primary human cohort upon which these assessments have been based. -1- SAL 000001226 II. GENERAL REVIEW OF DATA AVAILABLE FOR BENZENE RISK ASSESSMENT Before proceeding further, it seems appropriate to describe briefly our understanding of what constitutes an adequate risk assessment. The National Research Council recently issued a report which includes a description of what it considered the necessary elements of a risk assessment (NRC, 1983) and we concur with their view. An adequate risk assessment consists of the following four steps: o Hazard identification: The determination of whether a particular chemical is or is not causally linked to particular health effects. o Dose-response assessment: The determination of the relation between the magnitude of exposure and the probability of occurrence of the health effects in question. o Exposure assessment: The determination of the extent of human exposure before or after application of regulatory controls. o Risk characterization: The description of the nature and often the magnitude of human risk, including attendant uncertainty. The first step, hazard identification, typically includes a review of all data pertinent to the determination that a particular chemical causes a specific adverse health effect. In general, the greater the quantity and quality of data (preferably in several species) indicating that exposure to a particular chemical results in development of the adverse effect(s) of concern, the more sure we are that there is a causative relationship between exposure to the chemical and the adverse effect; moreover, our certainty that the most important effect of the substance has been identified is also increased. The second step, dose-response assessment, involves analysis of the relationship between dose of a chemical and the incidence and severity of an adverse health effect in an exposed population. Since experimental and epidemiologic data often -2- SAL 000001227 involve dose levels higher than those to which humans are likely to be exposed, this step generally requires extrapolation from observed effects at high dose levels to predicted effects at lower dose levels and may also involve extrapolation from animals to humans. When available, this step should include consideration of information on comparative metabolic processes and rates in experimental animals and humans. For a risk assessment to be scientifically credible, it must include a description of and justification for the methods for both these forms of extrapolation, and should characterize the statistical and biological uncertainties in these methods. Where appropriate, for toxic effects believed to display a threshold, the no-observed-effect level (NOEL) may be identified and appropriate safety factors applied to estimate the likely human exposure level below which exposure is not expected to be associated with increased risk. The third step, exposure assessment, involves the measurement or estimation of the amount, frequency, and duration of human exposure to a chemical. It may also include identification of the numbers and classes (e.g., adult males, children, pregnant women, etc.) of humans exposed, and should also include a description of the uncertainties associated with all estimates. The fourth step, risk characterization, involves combining the results of the earlier steps to produce an estimate (or estimates) of risk (the incidence of an adverse health effect) in the population(s) described in step 3. Alternatively, for threshold effects, this step may include a comparison of the estimated human doses and experimental NOEL to determine if the human dose is sufficiently below the NOEL to be considered acceptable. This step should also summarize the uncertainties inherent in each of the foregoing steps and their influence on the identification of risk or the magnitude of margins of safety. Hazard Identification The hazards of benzene exposure are well documented both in humans and experimental animals (IARC 1982; Goldstein 1977, -3- SAL 000001228 1983). In the following we will only briefly summarize the available data pertinent to the assessment of the risk of human exposure to benzene. The reader should refer to review documents such as those cited above for additional information on benzene toxicity. Effects in Humans In humans, exposure to high levels of benzene has caused a variety of disorders of the hematopoietic system, particularly leukemia, especially of the acute myelogenous type, and aplastic anemia (Goldstein 1977; IARC 1982). Evidence of the leukemogenic properties of benzene has come both from collections of case reports (e.g., Vigliani 1976; Aksoy 1980; Goldstein 1977) and from epidemiologic studies (Infante et al. 1977; Ott et al. 1978; Rinsky et al. 1981). There is no substantial disagreement in the scientific community that benzene exposure can cause leukemia in highly exposed humans. What does remain uncertain, however, is the relationship between a particular level of benzene exposure and the resulting probability of developing leukemia. This uncertainty results from uncertainties regarding the levels of benzene to which individuals in the epidemiologic studies were exposed and a number of other factors that affect the dose-response relationship. A number of studies have also demonstrated elevated frequencies of chromosome aberrations in bone marrow cells and peripheral leukocytes of individuals exposed to benzene (IARC 1982). It is not clear whether these are significant indicators of health damage. Effects in Animals Studies of the effects of benzene exposure in animals have shown some similarities to, and also some significant differences from the effects observed in exposed humans. As with humans, the hematopoietic system in the bone marrow is a critical target of benzene exposure, with anemia, lymphocytopenia and bone marrow hypoplasia as common responses to repeated inhalation of benzene -4- SAL 000001229 in the 100-300 ppm range (IARC 1982). Also, mice and rabbits exposed to benzene show increased numbers of chromosome aberrations in their bone marrow. The major difference in response between humans and the species and strains of experimental animals that have been tested is that*, although one or two cases of leukemia have been attributed to benzene exposure by some researchers, no animal model for benzene-induced leukemia has been well-established. Several other forms of neoplasms have been found at elevated incidence in rats and mice exposed to benzene by inhalation or ingestion, however. This information is summarized in Table 1. The reasons for the differences in response between species are not known, though interspecies differences in metabolism and pharmacokinetics of benzene via different routes of exposure may contribute. Selection of Data for Use in Risk Assessment The findings in experimental animals confirm qualitatively the carcinogenic potential of benzene. However, it would be inappropriate to rely on such data to estimate quantitatively the risks of exposure of humans to benzene. As it has been noted by the U.S. Occupational Safety and Health Administration in the preamble to its 1980 cancer policy <45 FR 5200): Extrapolation from animal data to predict risks in humans introduces many additional uncertainties. These include selection of appropriate scaling factors for size, lifespan, and metabolic rate; differences in routes of exposure, duration and schedule of exposure, absorption, metabolism, and pharmacokinetics; differences in intrinsic susceptibility and repair capabilities; intra-population variation in susceptibility; and exposure to other carcinogens and intrinsic and extrinsic modifying factors. At least theoretically, these factors can affect the relative response of humans and animals by many orders of magnitude. Most other expert groups, including EPA (1984) and the Office of Science, Technology, and Policy (OSTP) agree that where epidemiologic data of reasonably good quality are available, they should be used for risk assessment. The pros -5- SAL 00000*230 Soecies. strain, sex Table 1 Observed Neoplastic Responses to Benzene Exposure in Humans and Animals Response Jypp nf Study Reference Human, Hale Human, male Human, male Human, male Human, male Leukemia Leukemia Leukemia Leukemia Lymphatic and hematopoietic neoplasms Occupational epidemiology Occupational epidemiology Occupational epidemiology Occupational epidemiology Occupational epidemiology Rinsky et al. (1981) Aksoy (1980) Ott et al. (1978) Wong et al. (1983) Wong et al. (1983) Rat. Sprague-Dawley, female Rat, Sprague-Dawley, male Rat. Sprague-Dawley, female Rat, Sprague-Dawley, male Rat, Sprague-Dawley, female Rat, Sprague-Dawley, male Rat, Sprague-Dawley, female Rat, Sprague-Oawley, male Zymbal gland carcinoma Leukemia Zymbal gland carcinoma Zymbal gland carcinoma Oral cavity carcinoma Oral cavity carcinoma Zymbal gland carcinoma Zymbal gland carcinoma Chronic gavage Chronic gavage Chronic gavage Chronic gavage Chronic gavage Chronic gavage Chronic inhalation Chronic inhalation Haltoni and Scarnato (1979) Maltoni and Scarnato (1979) Haltoni et al. (1983) Haltoni et al. (1983) Haltoni et al. (1983) Maltoni et al. (1983) Maltoni et al. (1982) Maltoni et al. (1982) SAL 000001231 Table 1 (continued) Observed Neoplastic Responses to Benzene Exposure in Humans and Animals Sneries, strain, sex Response Type of Study Mouse, CD-I, male Mnuse, C57BI/J6. male leukemia Lymphoma/Hematopoietic neoplasms Chronic inhalation Chronic inhalation Goldstein et al. (1982) Synder et al . (I960) Rat, Sprague-Dawley, male Zymbal gland carcinoma Chronic inhalation Snyder et al . (In Press) Rat, F344/N, male Rat, F344/N, male Rat, F344/N, male Rat, F344/N, female Rat, F344/N, female Mouse, B6C3F1, male Mouse, B6C3F1, male Zymbal gland carcinoma Oral cavity carcinoma Skin carcinoma Zymbal gland carcinoma Oral cavity carcinoma Zymbal gland carcinoma Preputial gland carcinoma Chronic gavage Chronic gavage Chronic gavage Chronic gavage Chronic gavage Chronic gavage Chronic gavage NTP (1984) NTP {1984) NTP (1984) NTP (1984) NTP (1984) NTP (1984) NTP (1984) SAL 000001232 Table 1 (continued) Observed Nenolastic Resoonses to Benzene Exooxure in Humans and Animals Soecies. strain, sex Hiuse. B6C3F1, male House, B6C3F1, male House, B6C3F1, male House. B6C3F1, female Mouse, B6C3F1, female Mouse, B6C3F1, female Response Harderian gland carcinoma Lung carcinoma lymphoma Zymbal gland carcinoma Ovarian tumors Mammary carcinoma and carcinosarcoma Type of Studv Chronic gavage Chronic gavage Chronic gavage Chronic gavage Chronic gavage Chronic gavage NTP (1984) NTP (1984) NTP (1984) NTP (1984) NTP (1984) NTP (1984) Mouse, B6C3FI, female Mouse, B6C3F1, female tn >r Lung carcinoma and adenoma Lymphoma Chronic gavage Chronic gavage NTP (1984) NTP (1984) tCETOOOOO and cons of using human versus animal data for risk assessment have been discussed in an earlier document (ENVIRON 1985) which points out the added uncertainty that is introduced to benzene risk assessment by the use of animal data. It should further be noted that the Carcinogen Assessment Group (CAG) of the U.S. Environmental Protection Agency recently made the judgment that benzene risk estimates should be based upon epidemiologic studies only (USEPA 1985). CAG specifically indicated that: "In general, the studies in which the species and route of exposure most closely correspond to the environmentally exposed population are given the most weight in developing unit risk estimates. Also, the route of exposure in the epidemiologic studies and the environment are both by inhalation. As a result, we would place most of our emphasis on the unit risk estimates developed from the epidemiologic studies. Even so, animal studies can supply valuable confirmatory information. However, a number of factors strongly suggest that animal studies are less reliable than those based upon human response. Among the more important factors for benzene are the following: o Equivalent exposures were higher in the animal than in the epidemiologic studies, resulting in a greater extrapolation distance to the unit risk. o The possibility always exists that some unknown qualitative difference between man and rodent could result in a major difference in sensitivity to benzene. o The risks estimates are upper-bound in nature, and could be considerably above the true risks. When estimating inhalation risks from gavage studies, the following important considerations also arise: -9- SAL 000001234 o An implicit assumption is made that the fraction of benzene delivered to the target organ via gavage in rodents is equal to the fraction of the benzene delivered to the target organ from the tidal volume of air by man. Such an assumption is highly speculative. o The approximate surface area correction is employed -- a usage which, although standard, is somewhat controversial. '* Further, during the March 1986 OSHA benzene hearings Dr. J.E. Huff, principal investigator of the National Toxicology Program (NTP) rodent bioassay on benzene, concurred with the opinion that while comparisons between estimates of humans and animal data are instructive, in the case of benzene, estimates made from human data should take precedence over those from animal data. Thus, although it may be of interest for the purposes of comparison to use the animal data, greatest reliance for any regulatory action should be placed on the more relevant human data. The balance of this document discusses selection among the various epidemiologic data sets that might be used for risk assessment, how risk assessments of benzene have been conducted in the past, the strengths and weaknesses of these various risk assessments, and our preferred estimates of leukemia risk in man. -10- 0ooooi235 sM- III. HUMAN STUDIES AVAILABLE FOR RISK ASSESSMENT A number of epidemiologic studies have been used to assess the risk of leukemia mortality to persons exposed to benzene. In the following discussion, we will describe the four studies which have be'en most frequently used for this purpose, and their associated limitations. A. Description of Studies and their Limitations 1. Infante et al. 1977/Rinsky et al. 1981/Rinsky et al. 1985 Infante et al. 1977, Rinsky et al. 1981, and Rinsky et al. 1985 are three reports representing continued follow-up of the leukemia mortality experience of a group of Goodyear workers who had been exposed to benzene in the manufacture of rubber hydrochloride (also known as pliofilm) at three facilities at two locations in Ohio. We shall limit our discussion to the methodology and results obtained in the two latter reports, as these have been the primary basis for the more recent risk assessments. Rinsky et al. (1981) divided the pliofilm cohort from the three facilities into two groups, according to the time period worked in the pliofilm department. Group 1 consisted of 748 workers who worked at least one day between January 1, 1940, and December 31, 1949; group 2 consisted of 258 workers whose first pliofilm exposure occurred between January 1, 1950, and December 31, 1959. Vital status was ascertained to June 30, 1975, for 98% of the cohort. The investigators obtained death certificates for all known deaths that were coded by a nosologist according to the rules of the International Classification of Disease Adapted for Use in the United States (ICDA) that were in effect at the time of death. For each group, the number of workers who died from leukemia between January 1, 1950, and June 30, 1975, was compared to the expected number based on U.S. white male mortality, using a modified life table approach. -11- SAL 000001236 Among the 748 workers in the first group, seven deaths from leukemia occurred. From United States death rates standardized for sex, age, and calendar time period, only 1.25 leukemia deaths would have been expected. This resulted in a standardized mortality ratio (SMR) of 560 (p < 0.001). It'was noted that the mean duration of benzene exposure was relatively brief, with 437 persons (58%) of the cohort exposed for less than 1 year. Upon data analysis by length of employment, a significant excess in leukemia was observed among workers employed 5 or more years, but not among workers employed for less than 5 years. Five deaths from leukemia were observed among workers employed for more than 5 years, compared to 0.23 expected, resulting in an SMR of 2100. In Group 1 workers employed less than 5 years, two deaths from leukemia were observed, compared to 1.02 expected, resulting in an excess which was not statistically significant. Among the 258 workers in the second group, only 1 case of leukemia was observed vs. 0.46 expected, representing an increase which was not statistically significant. Rinsky et al. 1985 (unpublished), expanded the pliofilm cohort by including all non-salaried white males employed in a pliofilm department at the two locations for at least one day between January 1, 1940 and December 31, 1965 (i.e., 6 additional exposure years). Vital status was ascertained through December 31, 1981 (6.5 additional years of follow-up). Rinsky produced a total cohort of 1196 white males with at least one ppm-day (one day of employment in a pliofilm department with at least one ppm average benzene concentration) of cumulative benzene exposure. As in the Rinsky et al. 1981 study, a life-table analysis was used to generate expected numbers of deaths from leukemia. A total of 9 leukemia deaths was observed versus 2.7 expected, resulting in an SMR of 328, 95% C.I. = 150-623. Thus, during the additional 6.5 years of follow-up, one additional leukemia death was observed in the overall cohort. -12- SAL 000001237 Rinsky et al. 1985 further refined their analysis by stratifying the cohort by cumulative benzene exposure. To develop estimates of cumulative benzene exposure they created 10 broad exposure classes, each associated with a specific job title in the pliofilm operation. They then constructed job-exposure matrices, which associated an average annual benzene exposure level with each exposure class. Actual industrial hygiene data, where available, were used for Locations 1 and 2. When no data for a particular exposure class and year were available, Rinsky et al. interpolated between available previous and subsequent values. When no measured value existed for a period to be used for interpolation, the investigators projected the available values backward or forward. In the many instances in which no monitoring data were available for Location 2, benzene levels from Location 1 were substituted. This was based on the assumption that as the processes and job assignments were essentially identical at the two locations, benzene concentrations measured at Location 1 would be natural simulations of the benzene concentrations at Location 2. Rinsky calculated cumulative benzene exposure over a working lifetime for each individual based upon estimated benzene concentration in a pliofilm job category during the particular year(s) of exposure and the duration of exposure in particular jobs. The cohort was then divided into four cumulative exposure categories: less than 40 ppm-years; 40-199.99 ppm-years; 200-399.99 ppm-years; and more than 400 ppm-years. The SMRs for leukemia over the four cumulative exposure categories were as follows: Cumulative Benzene Exposure (ppm-years) less than 40 40-199.99 200-399.99 more than 400 Leukemia SMR 105 314 1757 4535 -13- SAL 000001238 During the March 1986 OSHA benzene hearings, Rinsky was questioned by API's counsel about certain apparent coding errors in the Rinsky et al. 1985 study. As a result of this questioning, a subsequent draft of the study was prepared and submitted to the OSHA record (Rinsky et al. 1986), in which such coding errors were reported to be corrected. In this version of the study, the leukemia SMR was 337 (95% C.l. = 154-641) and again an increase in the SMR for leukemia was associated with increased cumulative benzene exposure. In addition, Rinsky et al. 1985 performed a matched case-control analysis using conditional logistic regression. This aspect of the Rinsky et al. 1985 report will be discussed below, under Section III, in which the available risk assessments on benzene are reviewed. There are number of limitations to this study, many of which relate to the characterization of exposure. First, environmental monitoring data for the two locations were significantly less than complete for the years under consideration. For Location 1, the location on which the majority of data were available for the years under consideration, there were no data available for the years prior to 1946. The data on Location l for the years 1946-1976 were derived from a number of sources. These included: 1) two letters written in 1946 and 1955 by the Industrial Commission of Ohio that briefly characterize company monitoring data for the corresponding periods; 2) one report by the Ohio Department of Health of an engineering investigation that presented ranges of benzene concentrations for 3 work stations and single measurements for 3 additional work stations within Location 1; 3) industrial hygiene survey data obtained by the University of North Carolina during 1973-1974. These data characterized benzene concentrations in 5 work areas with a range of 1-10 samples per work area (mean - 4.4 samples per work area); -14- ooo1239 4) results of a NIOSH "walk-through" survey in 1976 in which benzene concentrations were determined in a total of 20 breathing-zone air samples, for 6 occupational titles; 5) company measurements from 1946-1976. It should be noted that no company data were available for the years 1951-1963. Further, for the years 1946-1950, only 15 benzene determinations from 4 different days were available. In 1963, the company began to record benzene concentrations on a .standard form. The frequency of company surveys for atmospheric benzene for the years 1963-1971, however, was quite low, with an average of only 2.3 surveys/year during this time interval, and an average of only 2.3 samples/year collected for each of the 12 work areas considered. Thus, even for the plant location at which monitoring data were more readily available, the body of evidence is limited, and certainly not optimal to serve as the basis for the making of judgments about year-specific benzene concentrations. Environmental monitoring results for Location 2 were extremely limited. For Plant 1 (of Location 2), only three sample points, determined in an industrial hygiene survey on one day in 1948 were available. These samples were taken in three different locations. Similarly, for Plant 2 (of Location 2), the only environmental data available were believed to have been taken "around 1957". Thus, apparently no sampling data were available for 27 of the 29 years during which pliofilm was manufactured at this location. Rinsky et al., for lack of better monitoring data, made the assumption that benzene exposures at Location 2 were similar to those at Location 1. This assumption has not been verified. It should be considered, however, that it is very possibly in error. This may be particularly significant because it suggests that for greater than 40% of the overall cohort and two-thirds of the leukemia cases, no directly -15- SAL 000001240 applicable monitoring data were available upon which to base worker exposure. Data on the average number of hours spent by individual workers in specific work areas were apparently not available. This, consequently, is another area of uncertainty in the assessment of the exposure experienced by this cohort. These significant gaps in the available benzene monitoring data for Location 2 in general, and for many of the years under consideration for Location 1, necessitated the making of a large number of assumptions in the investigators' attempts to estimate individual cumulative benzene exposure. Clearly, this is an issue of great importance if one relies on this study to assess benzene-leukemia dose-response relations and risk. Rinsky et al. also appeared to make selective use of the available industrial hygiene data in estimating individual worker exposure. For example, they failed to incorporate approximately 130 company charcoal tube measurements taken between 1973 and 1976. In addition, they did not include the three sample points of high benzene concentrations reported at Location 2 (Plant 1) in 1948. No explanation was provided for the exclusion of these data. Another area of uncertainty relates to the fact that Rinsky et al. failed to consider all routes of benzene exposure in this cohort of plio'film workers. During the 1977 OSHA hearings on benzene, testimony was presented suggesting that dermal exposure in certain work areas in the pliofilm plants was significant. According to the testimony of certain pliofilm workers, environmental conditions were often poor and unhygienic. Dr. Sakol, an Akron physician whose practice included many of these workers, testified to having treated several who had been drenched or soaked with benzene. He further testified that the wife of one of the workers indicated that she had to wash the benzene off her husband's uniforms each night because he would come home with -16- SAL 000001241 them in a wet condition. The Rinsky et al. study, however, did not report on these conditions, nor did it consider that the dermal route might have contributed significantly to total benzene exposure of certain workers in the cohort. It should be considered that the contribution of dermal benzene exposure can be very significant. The rate of undiluted benzene absorption through the arm in man has been estimated to be 0.2 to 0.4 mg/cm2/hr (Hanke et al., 1961; Franz, 1984). If we assume that 50% of the body surface area of a worker (9000 cm ) is immersed in benzene for 8 hours, and that undiluted benzene is absorbed at a uniform rate of 0.4 mg/cm /hr throughout the body, then that worker would absorb 28.8 g of benzene during an 8-hr workday. If we assume a more reasonable scenario of a worker ''drenched" with undiluted benzene for 30 minutes to half of his body, then he would absorb 1.8 g of benzene. If we assume that 50% of the body surface area is drenched for 30 minutes with a solvent containing 0.5% benzene, then the worker would absorb 9 mg of benzene. It should be noted, however, that the amount of benzene absorbed under this latter scenario is likely less than 9 mg, because some experimental results suggest that diluted benzene is less readily absorbed than undiluted benzene (Maibach, 1980a and 1980b, Maibach and Anjo, 1981; Blank and McAuliffe, 1985). It should further be considered that the rate of dermal absorption of benzene is unlikely to be uniform throughout the body and that these estimates are consequently crude. Nevertheless, they demonstrate the very high potential contribution from dermal exposure, particularly when compared to the 15 mg/day absorption by inhalation of 1 ppm benzene over an 8-hour workday. (See ENVIRON 1986, Appendix A for further discussion of the available benzene dermal absorption data). Rinsky et al. did not consider the extent of benzene exposure that members of the pliofilm cohort may have had in non-pliofilm jobs in the Goodyear plants themselves. Through a Freedom of Information Act request, we have been able to -17- SAL 000001242 review the Goodyear job history records of the Rinsky cohort workers who have died. This review indicates that most members of the cohort worked in a variety of non-pliofilm jobss throughout the Goodyear plants. Many of the job histories show employment as early as 1910. Review of some early published reports by medical personnel of Goodyear suggests that pure benzene or solvents with high benzene concentrations were used by the company in several non-pliofilm operations. For example, Wilson <1942) described the blood examinations and symptomatology of 1104 workers at Goodyear who had used benzol. He indicated that the concentration of benzol to which these workers were exposed varied between 50 and 50Q ppm, with an average concentration of 100 ppm; occasional sharp exposures of 500-1000 ppm benzol were also cited. Davis (1929), who was assistant medical director of Goodyear, wrote of examining about 7000 workers who had used various substances containing benzol over a 12-year period. These two reports suggest that Goodyear used benzol in various jobs at least as early as 1917 to 1942 or later. Further, a survey conducted in 1926 by the Committee on Benzol of the Chemical and Rubber Sections of the National Safety Council reported benzene concentrations in the rubber industry during this period between 100 and 900 ppm (National Safety Council 1926). These reports suggest that the total benzene exposure of the pliofilm cohort may have been seriously underestimated by the failure to consider exposure, both by the inhalation and dermal routes, to benzene in non-pliofilm jobs throughout the Goodyear plants involved in the study. A review of the literature pertaining to non-pliofilm rubber worker benzene exposure before 1970 prepared by the American Petroleum Institute contains additional data related to this issue (American Petroleum Institute 1986, Appendix B). Rinsky et al. did not consider the possible contribution of other (non-benzene) exposures to the leukemia mortality of the cohort. There was no control for factors such as smoking -18- SAL 000001243 (which may increase benzene exposure) and drug history or for substances used in activities outside of the workplace or in previous or subsequent employment. Particularly for the leukemia cases, it would have been informative to have explored these possible alternative factors to assess whether thfe cohort may have differed from the general population to which it was compared in ways other than benzene exposure alone. Another area of uncertainty involves a possible selection bias on the part of the investigators. During the 1977 OSHA benzene hearings, data were introduced suggesting that exposure to benzene existed in an area of the pliofilm plants known as the "dry side", which was not included in the study. Results of an environmental study, conducted in 1974 by the University of North Carolina Occupational Health Study Group, showed that levels of up to 20 ppm benzene were present in the area. According to Infante, the "dry side" workers were excluded because at the time of selection of the study cohort, data on these workers were requested of industry, but never supplied. Infante, however, later dismissed the data presented at the 1977 OSHA Benzene hearings because no details (i.e., sampling location, duration, analytical procedure, or definition of department) were given to permit a valid interpretation of the only data points in the University of North Carolina Occupational Health Studies Group report (Infante 1977). The interpretation by Infante of the quality of these data can certainly be questioned, in light of the paucity of environmental monitoring results available for the cohort in general and for Location 2 in particular. Thus, it appears that the investigators were inconsistent in their treatment of the lack of environmental data. Certainly, once the investigators became aware (in 1977) that benzene exposure existed in the "dry side" of the plant, it would have been appropriate to add these workers in subsequent follow-up of the pliofilm cohort. -19- sal 000001244 Of the 9 leukemias observed in the overall cohort, 6 had worked in Location 2. This may be important because Location 2 is that for which almost no environmental monitoring data were available. The higher rate of leukemia mortality in Location 2 than Location 1 suggests that benzene exposure at the former may have been greater; the investigators made the assumption, however, that exposures at the two locations were very similar; this assumption may have been in error. 2. Ott et al. 1978/Bond et al 1985 Ott et al. (1978) studied the mortality experience of 594 white males who were exposed to benzene in three production areas of Dow Chemical Company in Michigan. The workers had been employed at the plant between 1940 and 1973, with no apparent minimum length of employment required for inclusion in the cohort. Benzene concentrations in the three production areas (i.e., chlorobenzol, alkyl benzene, and ethyl cellulose) were characterized based upon environmental monitoring data from 1944 to 1973. Overall, benzene levels ranged from 0 to 937 ppm, although the estimated time weighted average benzene concentrations ranged from 0.1 to 35.5 ppm in the various job categories. Exposures were further categorized for specific jobs in the production areas based upon time weighted average benzene exposure. A total of 3 leukemia cases was observed from 1940 to 1973 versus 0.8 expected, based upon incidence data from the Third National Cancer Survey. This resulted in an SMR of 375 (p < 0.047). There are a number of factors which limit the usefulness of this study for the purpose of leukemia risk assessment. First, it must be considered that workers at the Michigan Dow plant were exposed to a large number of chemicals in addition to benzene, some of which have been associated with carcinogenic effects. The chemicals listed in the report included vinyl chloride, vinylidene chloride, -20" SAL 000001245 arsenicals, asbestos, nitrobenzene, bromine, monochloro benzene, dichlorobenzene, trichlorobenzene, and tetrachlorobenzene. This lack of specificity of exposure may have had a significant influence on the study results. In fact, Ott et al. were more likely studying the effect of exposure to mixtures of chemicals, rather than pure benzene exposure. This concern is magnified upon examination of the work exposure histories of the three leukemia cases. The first had a history of potential exposure to vinyl chloride, vinylidene chloride and alkyl benzene. The second case had a history of employment in a saw mill which manufactured veneer; increased myelocytic leukemia has been observed in workers in the wood and pulp industry (Milham 1976). The third case had p-chlorophenol, ethyl chloride, phenetidine, acetic anhydride, and phenacetin dust listed as other exposures. Another limitation of the study, in terms of its utility for establishing causal associations, was the lack of an observed dose-response relationship. The estimated timeweighted average exposures of the three leukemia cases were 4.3 ppm ("low exposure"), 1 ppm ("very low exposure"), and 3.6 ppm ("low exposure"), respectively. This is in contrast to other members of the cohort who were categorized into the moderate (10-24 ppm TWA) or high (25+ ppm TWA) exposure categories, who did not develop leukemia. When duration of benzene exposure was accounted for, cumulative dosage for the three cases was estimated to be 545, 18, and 305 ppm-months, respectively. Thus, two out of the three leukemia cases were in the low cumulative benzene exposure group, one was in the mid-range cumulative benzene exposure group, while there were no leukemias in the high benzene exposure group, which included approximately 29% of the cohort. Thus, the occurrence of leukemia in the lower exposure categories, but not in the higher exposure category, is inconsistent with the existence of a positive dose response relationship. -21- 000012*6 SAL 0 suggesting that benzene exposure may not have been of causal importance. It is also questionable whether one of the cases of leukemia should have been included in the analysis. According to the death certificate of this worker, the cause of* death was listed as bronchopneumonia bilateral, with myeloblastic leukemia listed under "other significant conditions." The investigators apparently attempted to correct for this discrepancy by comparing the leukemia rate observed to incidence (as opposed to mortality) data. If this case were excluded, a significant increase in leukemia mortality would not have been observed. Finally, the small size of the Ott et al. (1978) study makes it of somewhat limited use for the purpose of risk assessment. Due to the small study size, the standardized morbidity ratio of 375 which was observed for leukemia had a 95% confidence interval which ranged from 75 to 1100. The width of this interval would generally be considered to be too wide to provide confidence in the use of the SMR of 375 as the basis for quantitative risk estimates. This investigation has been recently updated in an unpublished report by Bond et al. (1985). In this analysis, 956 Dow Michigan division employees potentially exposed to benzene were studied (594 workers from Ott et al. 1978 plus 362 additional workers). The period of observation was 1940-1982, representing nine additional years of follow-up from the earlier investigation. Four deaths coded to leukemia were observed versus 2.1 expected based upon U.S. white male mortality rates; this increase was not statistically significant. It was noted, however, that all four leukemias were of the myelogenous type. When the mortality for myelogenous leukemia was compared with that which would be expected based upon National Cancer Institute Surveillance, Epidemiology End Results (SEER) data, a statistically significant excess was observed (4 observed vs. 0.9 expected; p=0.0ll). The investigators noted a fifth -22- SAL 000001247 leukemia case, who was the same individual whose death certificate was classified to pneumonia in the Ott et al. (1978) study. Thus, this update identified 2 additional leukemia deaths among benzene-exposed Dow Chemical workers. The Bond et al. (1985) update suffers from the same limitations for use in risk assessment as the earlier study of the cohort. Once again, the analysis failed to show a positive dose response relationship. The number of leukemias observed remains small and consequently the confidence interval around the risk estimate remains extremely wide. The possible influence of additional exposures remains an important issue for consideration. The American Petroleum Institute performed a conditional logistic regression case-control analysis of the Ott et al./Bond et al. studies in order to investigate whether they represented evidence of a relationship between increasing cumulative benzene exposure and increasing risk of leukemia. The method of analysis was consistent with that employed in the Rinsky et al. (1985) case-control study (see Section III). Each leukemia case was matched to ten controls on date of birth and date of first employment in a benzene exposure job. On the basis of these analyses, there was not a statistically significant relationship observed between increasing cumulative benzene exposure and increased risk of leukemia (American Petroleum Institute 1986c, Appendix C). 3. Aksoy (1980) Aksoy (1980) reported that during 1967-1975, a total of 34 workers at shoe manufacturing facilities where benzene was used were admitted to the hematology departments of a medical school in Istanbul, Turkey. The total number of shoe workers in Istanbul was estimated to be 28,500. The crude annual incidence of leukemia in this population was estimated to be 13/100,000 person-years of observation. The annual incidence rate of leukemia in the general population was reported by the investigators to be 6/100,000. The observed incidence -23- SAL 000001248 was reported to be significantly higher <p < 0.01) than the incidence in the general population. The Aksoy study reportedly evaluates the incidence of leukemia among 28/500 shoeworkers in Istanbul. In fact, a study of 28,500 shoeworkers was never performed. Aksoy's study population was actually a case series of 34 shoeworkers who were admitted to the hematology departments of Istanbul Medical School with a diagnosis of leukemia between 1967 and 1975. The figure of 28,500 was taken from "official records" of Istanbul which indicate that there are 28,500 workers involved in the shoe, slipper, and handbag industry in which benzene is used as a solvent. Thus, the leukemia incidence in only a small percentage of the Istanbul shoeworker population was actually directly examined. For a standard population, Aksoy reportedly used data on the incidence of leukemia in the general population of western nations, which he obtained from a paper by Gunz (1970). Dr. Aksoy indicated during the 1977 OSHA hearings that the leukemia incidence rate of 2.5-3/100,000 for the general population of Turkey was not used in the analysis because vital statistics reporting in Turkey could not be relied upon to draw scientific conclusions. Questions had been raised about the use of the Gunz rate as a standard, however, because it actually estimated the leukemia mortality rate in Western nations, as opposed to the leukemia incidence rate which was being estimated in Aksoy's population. Furthermore, leukemia incidence rates in Europe have been reported to be higher than leukemia mortality rates, thereby suggesting that the standard rate applied was inappropriate. An additional question in the interpretation of Aksoy1s results was the fact that his calculation used crude rates, without adjustment for variations in age or leukemia cell-types. Leukemia rates are known to vary widely with age, thereby requiring that comparisons be made between populations with reasonably similar age distributions, or -24- SAL 000001249 that age adjustment be performed prior to relative risk ascertainment. Perhaps the area of greatest uncertainty in the Aksoy study was that of characterization of exposure. One must assume that these shoeworkers were exposed to a mixture of volatile hydrocarbons, including benzene. In addition, workers may have been exposed to curing agents, dyes and other chemicals commonly used in the shoe industry. The leukemic effect observed may therefore have been related to these other chemicals exposures, or to benzene activity in combination with these materials. In the Aksoy studies, however, it was merely indicated that the working conditions in the shoeworking industry were not good; the shops were usually small, not hygienic, and poorly ventilated. In Aksoy (1974), it was indicated that the concentration of benzene was found to reach a maximum of 210-650 ppm when adhesives containing benzene were in use. During the OSHA benzene hearings in 1977, Dr. Aksoy indicated that the concentration of benzene ranged between 15-30 ppm outside working hours and between 150 and 210 ppm during working hours. The number of measurements upon which these ranges of benzene concentrations were based was not specified in any of the reports. It is most likely, however, that only a very small percentage of the workplaces under consideration were actually sampled. Applying these environmental data to the entire cohort, therefore, results in a very high degree of uncertainty in any projected exposure-related leukemia risks. In addition, the Aksoy studies did not consider the issue of dermal exposure to benzene. One can assume, however, that dermal exposure in this occupational setting may have been substantial. In light of recent experimental evidence which suggests that dermal exposure to benzene can result in a high degree of absorption, it would be best advised that this matter be further investigated to assess whether dermal exposure was in fact involved, and if so, to -25- SAL 000001250 attempt to estimate its contribution to total benzene exposure in this cohort. 4 Wong (1983) Wong (1983) conducted a historical prospective mortality- study of a group of 4602 male chemical workers from seven plants who were occupationally exposed to benzene for at least six months between 1946 and 1976. They were compared to a group of 3,074 male chemical workers from the same plants, but with no occupational exposure to benzene. The vital status of the workers was followed through December 1977, and underlying causes of death coded to the 8th Revision of the International Classification of Diseases. Cause-specific mortality was assessed using 1) the comparison group to obtain relative risks and the corresponding Mantel-Haenszel chi-square with one degree of freedom, and 2) the U.S. male population as a comparison for obtaining standardized mortality ratios (SMRs). For leukemia, the SMR for the exposed group was 117.4 (7 deaths observed vs. 5.96 expected). This increase was not statistically significant. The relative risk of leukemia could not be determined in the exposed group as compared to the non- exposed group, however, as no deaths from leukemia were observed in the internal control population. The reason for this deficit in leukemia in the unexposed group remains unknown. The exposed cohort was divided into categories, based upon an exposure classification of jobs. The continuous category consisted of jobs in which workers were assigned to a discrete area in which benzene was produced, separated, recovered, processed or loaded/unloaded and in which potential benzene exposure occurred at least three days/week. The intermittent category involved more casual exposure to benzene, encompassing jobs in which workers were not assigned to discrete areas of benzene production, separation, recovery, processing or loading/unloading; the -26- 5A.U 000001251 c, ` particular jobs, however, required periodic work in these areas, the pattern of which could not be considered continuous. In the continuous exposure group a total of 6 deaths from leukemia were observed, vs. 4.43 expected yielding an SMR of 135, which was not significant at the 0.05 level. In the intermittent category, a deficit in leukemia occurred with only one leukemia death observed vs. 1.49 expected. It should be noted that none of the leukemia deaths in the exposed cohort were of the acute myelogenous type, the cell type which has been most commonly associated with benzene exposure in other occupational studies (Ott et al. 1978, Rinsky et al. 1981, 1985). Rather, four of the leukemias were lymphatic, two were chronic myeloid, and one was an acute leukemia (type unspecified). The study has a number of limitations, some of which were acknowledged by the investigators. First, it should be noted that each plant collected data on its own workers. Consequently, it is likely that there was a lack of uniformity in data collection procedures which may have biased the results. Second, data on benzene exposures during the early part of the study were reported to be limited for some of the plants, necessitating estimation of exposures on the basis of uniform tasks in the majority of plants studied. Two of the plants, however, did not use this approach, and estimates of exposures were derived by supervisors or industrial hygienists. This lack of consistency in the methodology for exposure estimation may have further biased the study results, the direction of such bias, being impossible to determine. Third, workers in the study were probably exposed to a large variety of additional chemicals in their studied jobs (and in past employment). This factor was not accounted for in the analysis. Fourth, relative risk of leukemia could not be determined between exposed and non-exposed workers, as there were no leukemias observed in the unexposed group. Fifth, the number of -27- SAL 000001252 leukemia deaths was quite small, limiting the confidence that can be placed in any assessment of dose-response relationships. Sixth, two of the nine plants which originally participated in the early stages of the study reportedly withdrew from the study, due to difficulties in data collection and in participation in the study as designed. This occurred after the collection of death certificates, raising the suspicion that the data contained in the death certificates themselves may have been related to the decision to no longer participate in the study. It should further be noted that during the OSHA benzene hearings held in March of 1986, Wong indicated that in his judgment the inadequacies in the benzene exposure estimates made the Wong (1983) study an inadequate basis for quantitative risk assessment. B. Conclusion This brief review has emphasized data from epidemiology studies that might be suitable for use in assessing risk. Other available studies, some of which do not reveal an effect of benzene exposure, are clearly not suitable for risk assessment, primarily because of a complete lack of quantitative exposure information. Although there are significant limitations in the epidemiology data base regarding the magnitude of exposures of the cohorts studied, it nevertheless appears possible to estimate a dose-response curve (or range of curves) from these data with the degree of reliability usually considered appropriate for such studies. We note, however, that some additional information on the exposures experienced by the cohort studied by Rinsky et al. appears to be available (see Section IV), and additional efforts to collect and organize this information will be made in the coming months. -28- SAL 000001253 III. REVIEW OF AVAILABLE BENZENE RISK ASSESSMENTS A large number of assessments of the risk of leukemia associated with benzene exposure have been published since OSHA first proposed its occupational benzene standard in 1978. In the following discussion, these risk assessments will be considered, beginning with the earlier assessments, all of which employ similar methodology, followed by the more recent assessments which have attempted to make some distinct improvements in exposure characterization and consequent estimates of risk. A. Earlier Risk Assessments Employing the Linear Model EPA 1979 (CAG/EPA) presented the first major risk assessment following the OSHA hearings. It considered three sets of occupational epidemiology data, namely Infante et al. (1977), Aksoy <1974, 1976, 1977), and Ott et al. (1978). EPA assumed that for low exposures, the lifetime probability of death from leukemia may be represented by the linear equation: P = A + ftx where A is the rate of leukemia mortality in the absence of benzene exposure and X is the average lifetime exposure to benzene in parts-per-million (ppm). The term ft represents the increase in the leukemia mortality rate due to each increase of one ppm average lifetime exposure to benzene; this term may also be referred to as the slope of the dose-response relation. EPA assumed that the relative risk of leukemia is independent of the duration of exposure or the age at which exposure occurs in the worker population. Given this assumption, through several algebraic transformations, ft can be derived as follows: ft - Px (R - 1)/X2 where P1 is the lifetime probability of dying of leukemia with no or negligible benzene exposure, R * the relative risk of -29- SAL 000001254 leukemia for a benzene-exposed worker cohort compared to the general population, and X2 = the cumulative occupational exposure to benzene, averaged over a lifetime. EPA documents their methodology for deriving P^ from available U.S. mortality data. EPA derived separate values of P1 for total, myelogenous, and non-lymphatic leukemia, corresponding to the pattern of leukemia types observed in the three epidemiologic studies considered. At least six additional risk assessments were subsequently developed by other groups, all accepting EPA's general model (API/Lamm (1980), Hattis and Mendez (1980), IARC (1981), Luken and Miller (1981), A.D. Little (1982), and Environmental Law Institute (1983)). These risk assessments differed primarily in their judgment of the adequacy for risk assessment of the three studies originally considered by EPA, and in their choice of values to be used for P^, R and X2 in deriving 13; several of the assessments rejected the Aksoy and Ott data sets entirely. This resulted in these assessments producing a wide range of estimates for the slope G of the linear dose-response function at low doses. In our judgment, of the three epidemiologic data sets considered in these risk assessments, the Infante et al. 1977/Rinsky et al. 1981 data are most suited for quantitative risk assessment. Consequently, for the remainder of this discussion of these seven risk assessments based on the linear model, the results presented will be limited to those derived from the Infante et al. 1977/Rinsky et al. 1981 study. Table 2 presents the additional lifetime risk of leukemia death predicted due to continual lifetime exposure to 1 ppm benzene in these seven risk assessments based upon the Infante et al. 1977/Rinsky et al. 1981 data. Due to variations in these assessments in assumptions about Pj, R and X2, the resultant predictions of risk at l ppm varied by a factor of approximately 9. Variations in assumptions about exposure of the Infante/Rinsky cohort (X2> had the greatest influence upon the range of predicted leukemias in -30- SAL 000001255 ? rOon w_, - t e - to tv > i In os Table 2 Comparison of Risk Assessments Using Linear Model Based on Epidemiological Data of Infante et al. (1977) or Follow-up Reported by Rinsky et al. (1981) , 1. CAG/EPA (1979) 2. API/lamm (1980) 3. Hattis & Mendez (1980) 4. IARC (1981) 5. Luken & Miller (1981) 6. A.D. Little (1982) 7. ELI (1983) Relative Risk IR) Average Lifetime Exoosure in DDm (xol 9/1.25 = 7.2 2.81 7/1.25 = 5.6 2.81 9/0.84 = 10. T* 0.84 7/1.25 = 5.6 N.A.""* 7/1.25 = 5.6 1.30 9/0.84 = 10.7** 3.27 7/1.25 = 5.6 Low 0.37 High 0.88 Assumed Background Prnhabi1it v (Pj) 0,006732 0.006732 0.004517 0.007 0.006732 0.00452 0.006732 Additional Lifetime Risk for an Average Lifetime Exposure of One (11 DDm" fBI 0.015 0.011 0.052 0.009-0.037 0.024 0.013 0.084 0.035 * All based on a linear model of the dose- response relation. Note that IARC did not project the estimated slopes beyond the range of observed dose-response relations. ** These authors use backgoond rates for non-lymphatic leukemias Onl y. IARC did not estimate average lifetime exposure. benzene-exposed populations. Differences in assumptions about background probabilities and relative risks in the Infante/Rinsky cohort had a far less significant influence. In our opinion, all seven of these risk assessments suffer from very poor characterization of the benzene exposure history of this cohort and, consequently, little faith can be placed in the risk estimates derived therefrom. Subsequent risk assessments have attempted to make improvements in the characterization of exposure in the Infante/Rinsky cohort. They will be discussed below. B. White, infante and Chu (1982) White, Infante, and Chu (1982) performed a risk assessment based upon the data presented in Rinsky et al. (1981) and Ott et al. (1978). It is this assessment that OSHA has proposed to rely upon as the principal basis for the benzene rule. For the Rinsky et al. cohort, the risk assessment was based solely on the experience of workers who had been employed for five years or more. It was further assumed that the upper limit on duration of employment was 30 years, because workers who had been employed for more than 30 years contributed less than 0.01 to the number of leukemia deaths expected. White, Infante, and Chu made the general assumption that during the years 1941-1975, workers were exposed to benzene at the environmental concentrations recom mended during these years. They further assumed that benzene concentrations before 1941 were 50% higher than a recommended level for 1941. On this basis, the range of cumulative benzene concentrations for workers in the cohort with 5-30 years of experience was estimated to be 415 ppm-years (83 ppm x 5 years) to 1,500 ppm-years (50 ppm x 30 years). The one-hit model was then selected for low-dose extrapola tion, primarily because of its simplicity. This model states that excess cancer risk (P^) is related to the dose (d) by the equation pd " ^ ~ exP('fi x d)3(l - PQ> -32- SAL 000001257 where G represents the rate at which the excess probability of leukemia increases with each increment in dose, d represents dose, and Po the background risk of cancer. Thus, the total risk of leukemia (P^) to an individual exposed to benzene is the sum of the background risk (PQ) and the risk associated with benzene: Pt - P0Cl - exp(-G x d)](l - PQ) The relative risk of leukemia death in the Rinsky et al. study was approximated by the standardized mortality ratio (SMR). It was assumed, for the purpose of this risk assessment, that: Pt - SMR <P0) 100 On the basis of the above two equations, it was shown that G, the slope of the dose-response relation, can be determined as foilows: G = -ln[(1 - <SMR/100)Po/(l - P )]/d B values were determined for the upper and lower range of estimated exposure of the cohort. The excess leukemia risk was thereby estimated to be 44 to 152 per 1,000 workers exposed for 45 years at 10 ppm benzene, and 5 to 16 per 1,000 workers exposed for 45 years at 1 ppm benzene. (On the basis of the Ott et al. study, which we consider less suitable for risk assessment, the excess leukemia risk was estimated to be 48-136 per 1000 workers exposed for 45 years at 10 ppm benzene, and 5-15 per 1000 workers exposed for 45 years at 1 ppm benzene) . If these data were extrapolated to lifetime continuous exposure (as was done in the seven earlier assessments using the linear model), the additional risk at 1 ppm would be 0.03-0.11 based upon the Infante/Rinsky data. (On the basis of the Ott et al. study the risk at continual lifetime exposure to 1 ppm would be 0.04-0.10.) -33- SAL 00000X258 In our judgment, one of the primary deficiencies in the risk assessment was its bias in its elimination from consideration workers in the Rinsky et al. study who were exposed for less than 5 years. It appears the 5 year period was chosen arbitrarily. Clearly, it is inappropriate to exclude the observed mortality data on' workers who were actually subject to the lower range of exposure to which the model will actually apply. Rather, the entire exposed cohort, and its corresponding SMR, should have been used in the assessment of risk of this worker cohort. Further, it should be realized that the range of risks estimated by White, Infante, and Chu on the basis of these data is highly unlikely to represent the true range of risks. The SMR selected (2,100) represented the average SMR for the subsets of workers with five or more years of exposure. White, Infante, and Chu, however, applied their range of cumulative exposure estimates to this average cohort SMR. Thus, this average risk estimate does not correspond to the risk at either the upper or lower estimates of exposure. It would have been more appropriate to have applied this average SMR to an estimate of the average cumulative exposure of the cohort. It is not apparent why an estimate of the average cumulative benzene exposure of the cohort was not derived for this assessment. Employing their general assumptions about exposure. White, Infante, and Chu could have better estimated average cumulative exposure by obtaining the sum of the products of the prevailing recommended benzene concentrations of each year and the number of men working during each year and dividing by the overall total number of person-years worked. Review of the environmental monitoring data in the Rinsky et al. 1981 study calls into question White, Infante and Chu's assumption that workers were exposed to benzene at the environmental concentrations recommended during the time periods under consideration. The data indicated that in certain areas of Location 1 (on which the large majority of data were available), environmental benzene concentrations well exceeded the recommended -34t SAL 000001259 concentrations for the respective time period. Table 3/ based entirely upon data published in the Rinsky et al. 1981 study, presents the data which illustrate this point. Thus, it is suggested that White, Infante, and Chu may have underestimated the exposure of the Rinsky et al. (1981) cohort. It* should be noted that the one-hit model utilized by White, Infante, and Chu produces risk estimates very similar to those predicted by the more simple linear model applied in the earlier benzene risk assessments. This is because the one-hit model is a close approximation of the simple linear model at low rates of disease. The use of either the simple linear model or the one-hit model in the risk assessments described thus far seems appropriate, as in no case were more than two data points considered. Overall, it is our view that the White, Infante, and Chu risk assessment, like the earlier risk assessments described above, was deficient primarily in its characterization of exposure of the cohort. The method of exposure estimation applied was extremely crude in its lack of consideration of actual duration of exposure of individuals in the cohort or of exposure measurement data available for specific work operations during the years under consideration. Consequently, the risk estimates derived by White, Infante, and Chu must be considered crude and unreliable for these and for the other reasons raised above. The general methodologies employed in the subsequent risk assessments of benzene and leukemia, namely those by Crump and Allen (1984), Rinsky et al. (1985) and Chinchilli (1985) are, in our view, superior to those employed in all of the earlier risk assessments considered above. A description of these latter assessments, and their strengths and limitations, is contained below. C. Crump and Allen (1984) Crump and Allen (1984) made a significant improvement over earlier assessments of the Rinsky et al. cohort in their characterization of its benzene exposure history. In their -35- SAL 000001260 Table 3 BENZENE CONCENTRATIONS REPORTED IN RINSKY ET AL, 1981 WHICH SUGGEST THAT RECOMMENOED BENZENE STANDARDS MAY HAVE BEEN EXCEEDED Year 1956 Area of Plant Spreader Case Banzane Concentration room) 200 1956 1973-1974 1973-1974 Dryer Case Recovery Rooms Spreader-Dryer Units 160 at least 30 193-355 1976 1946 1947 1949 1950 1950 1963 1971 1972 1965 1965 1964 1963 1967 1971 1972 1973 1974 1963 1972 1973 1974 1972 1972 1975 1973-1976 Entire Plant Storage Room Stripper Rolls Stripper Rolls Stripper Rolls Inside Drier Quencher Quencher Still house Spreader-DryerBetween Units Spreader-Dryer Platform Mixers Stripper Stripper Stnppe r Stripper Str.pper Stripper Storage Storage Storage Storage D Unit Cement Press Visual check of storage tank while emptying during stock change Spreader-Drier Platform Spreader-Drier Platform 7.2*24.9 TVA 250 66-125 660 350 250 34 26 (mean) 17 (mean) 35 (mean) 60 (mean) 33 (mean) 60 (mean) 150 (mean) 40 (mean) 112 (mean) 37 (mean) 35 (mean) 23 Cmean) 15 (mean) 12 (mean) 14 (mean) >200 200 41.9 (mean) 166.9 (maximum) Sourca Recommended Siar.da Ohio Health Dap't. University of North Carolina NI0SH Company Data t* II It tl tl tl M 35 ;5 ;_2 w ^ 5: 35 35 25 *n V 23 II 25 It If t t M f M M >9 rr rr NX OSH NI0SH 25 25 25 L2 i: 1^ 1J '* - lJ - '3 Company Data Company Data ** * 36- 0000012^1 SAt analysis, an exposure profile was constructed for each worker in the Rinsky et al. (1981) cohort. In order to accomplish this, they used the benzene measurement data provided in the Rinsky et al. (1981) study, an updated data tape on the cohort, and data provided by Mr. Rinsky, permitting the association of work areas with occupational codes. Estimates of benzene exposure were based on available measurements in eight major areas and were derived for seven time periods, which corresponded to the years at which recommended occupational benzene concentrations were changed. Time periods were so categorized based upon the assumption that the companies' procedures with respect to benzene concentrations would be approximately the same unless revisions in the recommendations or standards had occurred. Available measurements within time periods were averaged, based upon the assumption that roughly equivalent measurement procedures would have been used within a given time period. In calculating exposure period estimates. Crump and Allen also assumed that the concentrations within a work area would not increase with time. Thus, if an average exposure estimate for an area during a time period was less than that of the period which followed, both period estimates were recalculated using all available measurements in the two periods, and the estimates applied for the two periods were equal. In the event there were no measurements for a given area in a given period. Crump and Allen multiplied the estimate from the following period by the ratio of the recommended occupational concentration for the period to that of the recommended concentration of the following period. The general assumption was made that monitoring data from one plant location were applicable to the other. In the few instances where actual data were available from Location 2, they were generally treated no differently from data from Location 1 (on which the majority of monitoring data were available), and were averaged together as if they represented one location. On the basis of these assumptions about exposure in specific work areas during specific time intervals, estimates of cumulative -37- SAL oooi262 benzene exposure in ppm-years were determined for each worker. Crump and Allen recalculated the standardized mortality ratios for the cohort, both for all workers combined and for six subgroups categorized by cumulative exposure. Their calculations were also different from those in the White, Infante, and Chu assessment (based bn Rinsky et al. 1981) because they included follow-up between 1940 and 1950, and between 1975 and 1978. For the overall cohort, 8 leukemias were observed versus 2.98 expected, resulting in an SMR of 268 (p = 0.01). Mortality from leukemia was dose-related, with six of the eight leukemias occurring in the two highest cumulative dose categories. Crump and Allen also used the data on leukemia mortality from the Ott et al. (1978) study for deriving their risk estimates. The data tape from the study was furnished to Crump and Allen so they could perform some additional calculations beyond those in the published study. Their estimation of an SMR for the cohort differed from that in the published study in its elimination from consideration of the third leukemia case whose cause of death was listed as bronchopneumonia on the death certificate, with myeloplastic leukemia listed under "other significant conditions." In addition, the expected number of leukemia deaths in the cohort estimated by Crump and Allen (expected * 0.96) was slightly higher than that reported by Ott et al. (expected = 0.8), due to the increase in years of cohort follow-up. Thus, the SMR for leukemia was estimated to be 208 (two leukemia deaths observed/ 0.96 expected) versus the SMR of 375 estimated in the Ott et al, analysis. Crump and Allen distributed each worker's person-years into cumulative dose groups on the basis of the exposure assumptions provided in the Ott et al. (1978) paper. As in the Ott et al. analysis, no dose-response association was observed for leukemia, with one of the two leukemia deaths occurring in the lowest dose group (0-5 ppm-years) and the other occurring in the intermediate dose group (20-80 ppm-years); no leukemia deaths were observed in the two highest cumulative dose groups. -38- SAL ooo1263 Crump and Allen made the judgment that the Ott et al. study, involving only two deaths from leukemia, would not be used independently to make risk estimates, but only in conjunction with data from other studies. Crump and Allen also used the data set of Wong et al. (1983) in deriving some of their risk estimates. They used the cumulative exposures as estimated by Wong et al. directly in their analysis. They focused on the unexposed comparison group and the "continuous exposure" group (consisting of those with jobs in which benzene was produced, separated, recovered, processed, or loaded/unloaded and in which potential benzene exposure occurred at least three days/week) in their assessment of risk for this cohort. Thus, on the basis of cumulative exposure, and using the unexposed comparison group to represent no exposure (0 ppm-months), the dose-response likelihood ratio test indicated a significant dose-response relationship between cumulative benzene exposure and leukemia (p = 0.007). It should be noted, however, that without inclusion of the unexposed comparison group, the dose-response likelihood ratio test yielded a non-significant result for leukemia (p = 0.13). Thus, as indicated by Crump and Allen, without some explanation for the leukemia deficit in the unexposed group, the Wong et al. study does not provide strong evidence of a relationship between occupational exposure to benzene and leukemia. Crump and Allen, however, proceeded to use the Wong et al. data set to estimate excess leukemia risk on the basis of cumulative dose ..only. Because they did not have access to the Wong et al. data tapes, they were unable to use this data set in their remaining risk estimations, which involved other measures of dose (described below). Crump and Allen fit the available Rinsky dose-response response data to both the relative risk and the absolute risk linear dose-response models. The relative risk model assumes that the increased age-specific mortality from an agent is proportional to the background mortality. The absolute risk model, on the other hand, assumes that the added benzene mortality is the same 0000012^ -39- $M- for all ages, given equal doses. The relative risk model applied was as follows: E(Oi) = aEi(l + bdi) and the absolute risk model: E(Oi) * Ei + (a + bdi)Yi Where: E(Oi> is the expected number of leukemia deaths in the ith dose category; a is a parameter which allows for the possibility that the background leukemia rates in the cohort differ from those of the reference population; Ei is the expected number of leukemia deaths in the ^th group based upon mortality rates in a comparison population; b is the potency of benzene for causing leukemia mortality; di is the average benzene dose in the ^th group; and, Yi is the total number of person-years in the ith group. Next, Crump and Allen described the four different measures of dose which they selected to be fit to these dose-response models. The first was "cumulative dose," which, in this analysis, represented cumulative dose in ppm-years up to the beginning of the 5-year age interval under consideration. The second measure was "weighted cumulative dose," in which all exposures occurring in the last 2.5 years before the beginning of the five years of observation are assumed not to affect leukemia mortality; exposures in the next earlier five years are given full weight; those in the next earlier five years are given 1/3 weight; and all earlier exposures are given 1/6 weight. The weighted cumulative dose methodology was based upon data on the latency pattern of leukemia in Japanese atomic bomb survivors. -40- SAL 000001265 The third measure was termed "window dose," in which full weight is given to exposures during the 10-year period between 2.5 and 12.5 years prior to the 5-year age interval of interest, while exposures outside of this 10-year "window" are ignored. This "window dose" measure assumes that doses further than 15 years in the past have no effect on mortality from leukemia. Finally, "peak exposure dose" calculations were defined as cumulative exposure in ppm-years in work areas with concentra tions above 100 ppm. As there were no areas with exposures between 76 and 100 ppm, it was noted that, in effect, the peak exposure measure assumed that only levels above 76 ppm contributed to leukemia risk. The peak exposure measure was not subsequently used to develop risk estimates. This was because an analysis comparing leukemia dose-response in workers in the Rinsky et al. study exposed to levels of benzene in excess of 100 ppm to those exposed to less than 100 ppm did not support the hypothesis that peak exposure has any effect upon risk over that which can be explained by the contribution of these exposures to cumulative dose. No attempt was made to determine whether levels other than 100 ppm (to represent peak exposure) had a significant effect. Table 4 compares Crump and Allen's estimates of extra leukemia deaths per 1,000 workers using both the relative and absolute risk models and three different measures of dose. Projections were based upon maximum likelihood estimates and the most comprehensive data set available under each model. Crump and Allen also presented the estimates of extra leukemia deaths per 1000 workers based upon the Rinsky et al. cumulative exposure data alone, to which the relative risk model was applied. For 40 years of exposure beginning at age 20, the estimated extra leukemia deaths were 6.6/1000 workers exposed at 1 ppm and 63/1000 workers exposed at 10 ppm. Estimates based upon the Rinsky et al. data alone using the alternative dose measures and the absolute risk model were not presented in the Crump and Allen paper. -41- SAL 000001266 Table 4 Estimates of Extra Leukemia Deaths Per 1,000 Workers Exposed to Benzene Using Relative Risk and Absolute Risk Models and Three Exposure Measures 40 Years Exposure Beginning at Age 20 1 ppm 10 ppm 1. Relative Risk Model a. Cumulative Exposure1 (b * 0.033) 9.5 88 b. Weighted Cumulative Exposure2 (b = 0.048) 3.0 29 c. Window Exposure2 (b 0.035) 1.2 12 2. Absolute Risk Model a. Cumulative Exposure2 (b = 1.6 X 10-6) 2.0 19 b. Weighted Cumulative Exposure2 (b = 4.1 x 10-6) 1.5 15 c. Window Exposure2 (b - 3.1 x 10*6) 1. 1 11 All Estimates based upon maximum Likelihood Estimates of Dose-Response Slopes. Based upon Rinsky et al. 1981, Ott et al. 1978, and Wong 1983 Based upon Rinsky et al. 1981, and Ott et al. 1978 -42- sal 000l267 Crump and Allen received comments on their report which suggested that some of their exposure estimates may have been too high, as levels above 200 ppm, as a time-weighted average, were believed by the reviewer to be associated with an increased rate of anemia in as little as four months, and such an effect was not documented. Crump and Allen developed an alternative exposure matrix to account for this observation, which in effect instituted a ceiling of 131 ppm for certain job categories. Crump and Allen indicate that use of this alternate exposure matrix will increase risks by about 25%. (This would result in an excess of approximately 8 leukemia deaths/1000 workers exposed at 1 ppm for 40 years, and of 79 leukemia deaths/1000 workers exposed at 10 ppm for 40 years.) In our judgment, the Crump and Allen estimates based upon cumulative dose should be given the most weight. The window exposure assumption that benzene exposures further than 15 years in the past have no effect on leukemia mortality seems improbable, and at variance with data on leukemia mortality of Japanese survivors of the atomic bomb. Further, examination of the data upon which the weighted cumulative dose measure was reportedly based (leukemia mortality in Japanese atomic bomb survivors, BEIR (1980)), do not support the development of the weighted cumulative dose measure for leukemia. There is little available basis upon which to form an opinion whether the absolute or relative risk model applied by Crump and Allen is most appropriate. Crump and Allen indicate a preference for the relative risk model because if seems most probable that the effect of benzene should be larger when the background occurrences of leukemia are larger. We tend to concur with this preference. In order to ascertain whether there is a basis for a perference for the Crump and Allen original or revised exposure estimates, the American Petroleum Institute sought the expert opinions of Dr. Bernard Goldstein and Dr. John Bennett. On the basis of clinical experience and knowledge of benzene's toxicity, both Dr. Goldstein and Dr. Bennett indicated that the apparent -43- S*L Ooo0l?6a absence of deaths related to bone marrow toxicity among workers in pliofilm areas (i.e., casting) with estimated benzene concentrations in excess of 130 ppm did not indicate that such estimated concentrations were higher than actual concentrations. Dr. Goldstein indicated that the literature reveals that even in the worst of situations (with regard to high exposure to benzene) in the past, there were relatively few individuals with clinically overt pancytopenia; similarly, acute myelogenous leukemia has not been observed in more than 1-2% of such highly exposed workers (Goldstein 1986). Dr. Bennett further indicated that the literature on benzene-induced aplasias and cytopenias, although extensive, does not permit reliable prediction of a specific number of such cases at any given exposure level. Further, he points out that the number of pliofilm workers who experienced these benzene concentrations during the study period was only approximately 50. On the basis of Jandl (1977), which reviewed the most reliable clinical studies of a total of 7,174 benzene-exposed workers in the U.S. during this century, only about 4% of individuals exposed to from 100-1000 ppm benzene developed aplastic anemia. This incidence rate would predict two cases in the Rinsky et al. group of 50 workers, a population size small enough to make the apparent absence of aplastic anemias in this group unexceptional. Bennett further indicated that the Goodyear monthly blood-testing program, which involved worker removal from the pliofilm operation if peripheral blood counts fell outside of normal ranges, could have been highly effective in reversing the acute marrow effects of exposures in the range of 250 ppm benzene. Furthermore, because we do not have medical records on these workers we do not know whether or not marrow suppressions occurred nor whether in such cases the affected workers were removed and the acute marrow suppression reversed (Bennett 1986). Thus, the opinions these hematology experts suggest that the Crump and Allen original exposure estimates, derived from industrial hygiene data, are preferable to the Crump and Allen revised estimates. Thus, in our judgment, application of the relative 000001269 -44- SAL risk model and original Crump and Allen cumulative dose measure to the Rinsky et al. data, provides the risk estimates which are most plausible in the Crump and Allen assessment. D. USEPA Carcinogen Assessment Group (1985) The Carcinogen Assessment Group (CAG) of the USEPA in 1985 (USEPA 1985) calculated interim quantitative cancer unit risk estimates due to inhalation of benzene which were based upon the Crump and Allen (1984) assessment. To determine unit risks of benzene exposure, CAG translated the slope parameters "b" determined by Crump and Allen by mathematical manipulations based upon Gail (1975). They presented the following table of risks associated with 1 ppm continuous lifetime exposure to benzene which was based upon the Crump and Allen (1984) assessment. Risks (Maximum Likelihood Estimates) Due to Lifetime 1 ppm Benzene Exposure Based Upon Combined Ott et al. and Rinsky et al. Cohorts, Followed from 1940 to 1978 Exposure Model form Relative Absolute Cumulative Weighted cumulative 2.89 X 10"2 2.49 x 10"2 1.96 X 10-2 1.40 x 1Q--2 Geometric mean * (2.89 x 2.49 x 1 .96 x 1.4)1/4 x 10*2 = 2.11 x 10~2 CAG calculated the geometric mean of the maximum likelihood estimates of unit risk (2.11 x 10 _2/ppm continuous lifetime exposure) as reported in the above table. It was noted that this estimate did not take into account the results of the Wong et al. study. In order to adjust for the fact that data were not available for the Wong (1983) data set to assess risk for all dose -45- SAL 000001270 measures and risk models applied, it was assumed that the ratio of the Rinsky-Ott-Wong studies to the Rinsky-Ott study for the relative risk cumulative dose model was the same as for the other models. Using this assumption, the computed ratio was multiplied by the pooled model geometric mean to obtain a single preferred composite estimate. This adjustment resulted in a preferred "corrected" joint unit risk estimate of 2.6 x 10__o /ppm continuous lifetime exposure. In addition, EPA calculated the risks associated with continuous lifetime exposure to 1 ppm benzene based upon the Rinsky et al. study alone (follow-up from 1940 to 1978): Risks Due to 1 ppm Lifetime Benzene Exposure Based Upon Rinsky et al. Cohort, Follow-up from 1940 to 1978 Exposure parameter Cumulative Weighted cumulative Window ______ Model form Relative Absolute RiskRisk * 10 5.10 x 10~2 2.20 x 10"2 4.40 x 10-2 1.76 x 10"2 1.67 x 10"2 1.10 x 10"2 E. Rinsky et al. (1985) In addition to the cohort analysis of 1196 white male pliofilm workers described in Section Ila above, Rinsky et al. (1985) performed a matched case-control analysis on a subset of this pliofilm worker cohort. In this analysis, each of the 9 leukemia cases was matched to 10 controls by year of birth and year first employed. This analysis was performed in an attempt to evaluate the effect of certain indicators of exposure on the relationship between risk of death from leukemia and exposure to benzene; to evaluate the effect of potential confounders and effect modifiers on this -4 6- SAL 000001271 relationship; and to identify the functional form of the exposure-response relationship. The investigators considered initially the following exposure variables separately and fit a separate model for each variable: cumulative exposure, duration of exposure, and average exposure rate. Cumulative exposure, expressed in ppm-years, was reported to be the strongest predictor of death from leukemia (B = 0.0135, 95% C.I. = 0.0039 - 0.0230; X2 = 7.6; p * 0.006). (The results for duration of exposure and average exposure rate were not provided in the report.) An additional model was constructed in which all three exposure variables were entered simultaneously. Cumulative exposure was the only variable found to contribute significantly to risk of death from leukemia. An evaluation of the shape of the exposure response function was performed in which several models for cumulative exposure were applied. The finding indicated that a log linear model best represented the observed exposure-response relationship. On the basis of this model the equation describing the odds ratio for leukemia in relation to cumulative benzene exposure was reported to be: OR * exp (0.0135 x ppm-years). This equation predicted an odds ratio of 2.6 (95% C.I. = 1.3 - 5.0) at the 70 ppm-years average cumulative exposure level estimated in exposed workers as compared to unexposed workers in the case-control analysis. The Rinsky et al. (1985) method of conditional logistic regression is a valuable approach to analyzing dose-response information, as it makes maximal use of the information available on individual exposure. In its inclusion of individual exposure levels in the statistical analysis, it avoids the loss of information and resultant imprecision which may occur in analyses which dichotomize (e.g., the earlier linear and one-hit model risk assessments) or categorize (Crump and Allen 1984) exposure. It should be noted, however, that this methodology will only result in truly improved risk estimates if it is based upon sound estimates of individual exposure. As was the case in the Crump and Allen assessment involving individual exposure estimation, numerous assumptions were necessarily made about past benzene -47- SAL 000001272 exposure. Further, complex decision rules were developed to estimate exposures for individual years. We are currently closely reviewing the validity of the assumptions and decision rules applied by both Rinsky et al. and by Crump and Allen to ascertain whether either is adequate, or whether an additional methodology should be developed. F. Chinchilli (1986) 1. Occupational Risk Chinchilli (1986, Appendix D) performed several additional analyses of the Rinsky et al. (1985) data set, in which the case-control, conditional logistic approach was applied. Because there is currently uncertainty regarding actual past levels of benzene concentration in the pliofilm plants, Chinchilli performed separate analyses in which the Rinsky et al. (1985) and the Crump and Allen (1984) assumptions about exposure were applied. Chinchilli also examined the Rinsky et al. data tapes and noted several inconsistencies in the case-control data. Specifically, upon examination of the work histories of the controls selected by Rinsky et al. (1985) (control set 1) it was noted that 15 of the 90 controls had 0 ppm-day cumulative exposure; according to the Rinsky et al. (1985) study criteria, individuals with less than l ppm-day of benzene exposure in pliofilm should have been excluded from the cohort. Upon examination of the Rinsky et al. data tapes, Chinchilli noted that the investigators had used inconsistent cohort definition criteria for the case-control and the cohort studies. In the cohort study, Rinsky et al. apparently considered only a smaller group of 1196 "wet-side1' workers, while in the case-control study, a larger group involving 1868 "wet-side" and "dry-side" workers was included. Chinchilli felt it was more appropriate to -48- SAL 000001273 consider workers from both the wet and dry side in the analysis, as there is evidence of benzene exposure in both of these pliofilm work areas. In his reanalysis of the data tapes he consequently considered all 1868 workers in his subsequent selection of controls. Chinchilli proceeded to select another group of 90 controls from the cohort, applying the Rinsky et al. matching criteria (control set 2). In addition, Chinchilli selected a third control group, matched according to the criteria of Rinsky et al. (date of birth and date of first employment), but applying the additional criterion of matching according to plant (control set 3). He elected to match by plant because the two plant locations were located more than 100 miles apart, which consequently may have influenced plant-specific mortality patterns. Chinchilli also selected a fourth control group (control set 4) in which he matched according to the criteria of Rinsky et al., plus by plant and by date of last employment. Table 5 presents the additional lifetime leukemia mortality risks estimated by Chinchilli, (assuming a background leukemia mortality risk of 0.00707), for workers exposed to benzene at 1 ppm for 45 years (45 ppm-years) and 10 ppm for 45 years (450 ppm-years), using the various exposure assumptions and control sets described above. The Crump and Allen I exposure assumptions are those originally derived by these investigators. The Crump and Allen II exposure assumptions are their alternate estimates in which a ceiling of 131 ppm for each job category was enforced. The Chinchilli analyses demonstrate that use of the Crump and Allen I (1984) exposure assumptions instead of those of Rinsky et al. (1985) will reduce the leukemia mortality risks projected substantially. Further, use of control groups in which more stringent and alternative matching criteria are applied will also affect the estimates of risk. -49- SAL 000001274- Table 5 Summary of Chinchilli Analysis of Rinsky et al. (1985) Data Using Conditional Logistic Regression and Alternative Exposure Assumptions and Control Groups Exposure Assumptions Control Set Rinsky et al. 1 1985 Rinsky et al. controls matched on: - date of birth - date of entering pliofilm Additional Lifetime Leukemia Deaths Per 1000 Workers Due to Benzene Exposure 45 ppm-years 450 ppm-years 5.1 (0.83-11.7)* 635 (15.6-986) Rinsky et al. 2 1985 Chinchilli controls matched on: - date of birth - date of entering pliofilm 6.4 (1.2-14.7) 819 (26.4-991) Rinsky et al. 3 1985 Chinchi11i controls matched on: - date of birth - date of entering pliofilm - plant 4.2 (1.0-8.7) 449 (21.3-953) Rinsky et al. 4 1985 Chinchilli controls matched on - date of birth - date of entering pliofilm - plant - date of last employment 2.6 (0.63-5.1) 137 (8.3-638) Crump and Allen 1984 I 1 0.5 (0.13-1.0) 8.3 (1.4-20.4) -50- SAL 000001275 Table 5 (continued) Exposure Assumptions Crump and Allen 1984 I Control Set 2 Additional Lifetime Leukemia Death Per 1000 Workers Due to Benzene Exposure 45 ppm-years 450 ppm-years 0.7 (0.1-1.3) 11.0 (1.4-30.9) Crump and Allen 1984 I 3 0.5 (0.1-1.0) 7.9 (1.1-20.4) Crump and Allen 1984 I 4 0.4 (0.-0.8) 5.2 (0-14.8) Crump and Allen 1984 II I Crump and Allen 1984 II 2 Crump and Allen 1984 II 3 Crump and Allen 1984 II 4 * 95% Confidence Interval 1.3 (0.3-2.3) 29.8 (4.2-106) 1.6 (0.3-3.1) 47.0 (4.0-218) 1.2 (0.3-2.3) 27.8 (3.3-103) 0.9 (0.1-1.7) 15.9 (1.1-56.1) -51- SAL 000001276 In our judgment/ Chinchilli's selection of controls from the larger cohort which included both the so-called "wet" and "dry" side workers was appropriate (Rinsky et al., however, should have applied consistent cohort selection criteria in their case-control and cohort analyses). His additional criterion of matching by plant is also appropriate, as it eliminates potential location bias. His addition, in control set 4, of the matching criterion of date of last employment is, in our judgment, not most appropriate, as this constitutes matching by duration of employment, which is an indicator of exposure. It should be noted, however, that there is some disagreement in the epidemiologic community on this point, with some support for matching on this variable. For the above reasons, we have a preference for the risk estimates based upon the Chinchilli control set 3. (See Section V for a discussion of our preference of exposure assumptions). 2. Low-Dose Environmental Risk To extrapolate risks due to low-dose exposure to benzene, as would be experienced in ambient air, Dr. Chinchilli applied two approaches. The first approach involved the assumption that the dose-response relationships in the low-dose ambient exposure region would be the same as those which were observed at the levels of exposure experienced by workers in the Rinsky et al. study. The excess risk per million persons exposed for a 70-year lifetimed to 1 ppb benzene in ambient air and the benzene concentrations which would be associated with a one in one million risk were then determined. These values were determined using the Rinsky et al., the Crump and Allen original, and the Crump and Allen revised exposure assumptions, and the Chinchilli control set 3 (for which we have a preference). The second approach involved the application of the Gaylor and Kodell (1980) model to the Rinsky et al. 1985 -52- SAL 000001277 data. In this analysis 4.5 ppm-years cumulative benzene exposure was considered the lower end of the observed occupational exposure range. The conditional logistic regression model was fit to the observed data and the 95% upper confidence limit on the excess leukemia rate at 4.5 ppm-years was determined. A straight line was drawn from the upper confidence limit at 4.5 ppm-years to the origin. On the basis of this analysis ambient benzene concentrations were determined which would be associated with an one in one million risk, again using the Rinsky et al., the Crump and Allen original, and the Crump and Allen revised exposure assumptions and the Chinchilli control set 3. The excess lifetime leukemia risk per million exposed to 1 ppb benzene in ambient air for a lifetime was also determined. The following table presents the results of the above Chinchilli low-dose extrapolations: Exposure Matrix Control Set Model Additional Lifetime Risk/Million at One ppb Benzene ___ in Ambient Air ppb Benzene in Ambient Air Assoc. with 10"6 Risk of Leukemia Rinsky 3 (Chinchilli, Match on Date of Birth, Date enter Pliofilm Plant) Gaylor-Kodell/ Cond. Log. Reg 39 0 . o; Crump I 3 Gaylor-Kodell/ Cond. Log. Reg. 6.6 0.15 Crump II 3 Gaylor-Kodell/ Cond. Log. Reg. 14 0.07 Rinsky 3 Cond. Log. Reg. 23 0.05 Crump I 3 Cond. Log. Reg. 3.6 0.26 Crump II 3 Cond. Log. Reg. 7.7 0 . 13 Of the low-dose environmental risk estimates presented by Chinchilli, we have a preference for that based upon the Crump and -53- SAL 000001278 Allen original (I) exposure matrix (for the reasons detailed above in the section on Crump and Allen). We also prefer the use of the Gaylor-Kodell model as it projects an upper bound on risk in the low-dose region, and is therefore conservative. In addition, there is precedent for the use of this model for estimating low-dose risks. -54- SAL 000001279 IV. ADDITIONAL FACTORS SUGGESTING THAT THE ACTUAL RISK OF BENZENE EXPOSURE IS LOWER THAN PROTECTED IN THE AVAILABLE RISK ASSESSMENTS OF THE RINSKY ET AL. STUDY COHORT As indicated in the above analysis, there are a number of additional factors which were not accounted for in the assessment of the total benzene exposure of the Rinsky et al. pliofilm cohort, which may significantly affect the estimates of risk projected on its basis. First, employment of members of the cohort in non-pliofilm jobs involving benzene exposure was not accounted for in any of the exposure assessments of the Rinsky et al. cohort. Preliminary review of a subset of the job histories of the cohort (within the Goodyear plant) indicates that a large percentage of the workers also worked in non-pliofilm jobs in other areas of the plant. These jobs dated back to the early 1900's and involved areas of the plant (e.g., tire building, cement mixing) for which there is evidence that pure- or high-benzene concentration solvents were used up to at least 1942. A review of the literature performed by the American Petroleum Institute indicated that in the early decades of the 20th century rubber workers appeared to be highly exposed to benzene-containing solvents and rubber cements (American Petroleum Institute 1986a). These substances were often applied by hand or in relatively poorly ventilated environments. Based upon a 1924 survey of the industry (National Safety Council 1926), benzene vapor exposures of rubber workers ranged between approximately 100 and 900 ppm. A survey of four rubber plants in 1942 reported benzene levels ranging from 10-350 ppm (Thomas, 1943). According to Pagnotto (1979), as late at 1964, benzene exposures of workers involved in rubber fabric coating were as high as 140 ppm due to the use of petroleum naptha solvents containing 3-7.5% benzene. A preliminary analysis of the work histories of the leukemia cases and controls selected by Rinsky et al. (1985) incidated that the 9 cases had substantially more potential exposure to benzene than did the 90 matched controls, both within the pliofilm SAL 000001280 -55- operation and in other Goodyear operations. Overall/ it was observed that the cases worked, on average, nearly three times as long as controls in solvent-related non-pliofilm jobs, in which benzene exposure was likely. When the analysis was broken down by time periods, this distinction between cases and controls was greatest during the years prior to 1942, when the use of high-benzene content solvents was most prevalent. (American Petroleum Institute 1986b). Another factor not considered in the available risk assessments was the contribution of dermal exposure to benzene, both within pliofilm and non-pliofilm jobs at the Goodyear plants. There was testimony presented during the 1977 OSHA hearings that certain workers in pliofilm were sometimes drenched in benzene. Further in a study recently conducted by NIOSH (Susten et al. 1985), it was estimated that workers in tire-building (a non-pliofilm job in which some of the pliofilm workers had spent some of their years at Goodyear) have 150 contacts of the palmar surface per workday involving exposure to benzene in solution. 2 Assuming a 0.5% benzene content in the solvent, 150 cm of exposed palmar surface, 6.25 ul solvent/cm2 , 0.88 g/ml benzene density, and 1% dermal absorption, Susten et al. estimated that 6.19 mg benzene would be absorbed per workday. Additional studies by Maibach (1980a and 1980b), Franz (1984) and Hanke et al. (1961), however, suggest that the dermal absorption value of Susten was possibly too high by a factor of approximately 3. This would lower the amount of benzene absorbed in tire building in which 0.5% benzene in solvent is used to approximately 2 mg/day (vs approximately 15 mg/workday absorbed from inhalation of 1 ppm for 8 hours). If 100% benzene were used, as was likely the case in certain jobs prior to 1942, the amount absorbed by the dermal route would increase by a factor of at least 200, to a level of at least 400 mg/workday (see Appendix A). Dr. Chinchilli has made some preliminary calculations of the potential effect upon the leukemia risk estimates of the addition of non-pliofilm airborne and dermal benzene exposures to the pliofilm-specific benzene exposure estimates applied in the case- -56- SAL 000001281 control analyses (Chinchilli 1986). For these analyses, API developed three different sets of exposure assumptions for the non-pliofilm jobs of the workers, representing low, moderate, or high benzene exposure. At the time when these calculations were performed, NIOSH had only made available a subset of the work histories of the Rinsky et al. cohort. Consequently, to perform these calculations it was necessary for API to develop a procedure in which non-pliofilm exposure of workers on whom no work history was available was estimated from the experience of workers on whom a work history was available (American Petroleum Institute I986d). These analyses suggested that the additional consideration of non-pliofilm airborne and dermal exposure of the Rinsky et al. cohort could result in a substantial lowering of the excess leukemia risk associated with benzene exposure. For example, on the basis of the high exposure assumptions about non-pliofilm exposure, excess risk associated with continual lifetime exposure to 1 ppb would decrease by a factor of 14 assuming the Rinsky et al. (1985) exposure matrix, and by a factor of 4 assuming the revised Crump and Allen exposure matrix. It should be noted that these estimates were by necessity crude because we do not currently have substantial industrial hygiene data available for non-pliofilm work areas and because complete work histories were not available on all members of the cohort at the time of the analysis. Nevertheless, these estimates suggest that the lack of consideration of inhalation and dermal absorption of benzene in non-pliofilm areas in calculating cumulative exposure of the Rinsky et al. cohort resulted in an underestimation of total exposure and possibly an overestimation of risk. In the future months API intends to investigate additional sources of information on airborne benzene levels in non-pliofilm areas and on the extent of dermal exposure in pliofilm and non-pliofilm jobs. Such data will be incorporated into future estimates of benzene-associated leukemia risk. SAL 000001282 -57- Consideration of non-pliofilm benzene exposure and of the dermal route of absorption will clearly influence the risk estimates available to date. Consequently, every attempt should be made to document fully the magnitude of exposure resulting from these factors. -58- SAL 000001283 V. CONCLUSIONS ABOUT LEUKEMIA RISK ON THE BASIS OF THE AVAILABLE BENZENE RISK ASSESSMENTS In our judgment, and in that of most expert scientific groups, when epidemiologic data of reasonably good quality are available, they should be used for risk assessment. In the case of benzene leukemogenesis, the Rinsky et al. (1981/1985) study of benzene-exposed pliofilm workers, in spite of its limitations, is best suited for assessing quantitatively the leukemia risk of benzene. The risk assessments which have made use of the Rinsky et al. data therefore form the basis of our conclusions about the risk of leukemia associated with environmental benzene exposure. We have reviewed seven earlier benzene risk assessments of the Rinsky et al. cohort which employed the linear model; the assessment of White, Infante and Chu (1982) which employed the one-hit model; the Crump and Allen (1984) assessment which used both the relative and absolute risk linear models; the USEPA/CAG (1985) assessment which transformed the Crump and Allen (1984) occupational risk estimates into ambient risk estimates; the Rinsky et al. (1985) assessment which used conditional logistic regression for a case-control subset of the cohort; and the Chinchilli assessment (1985) which utilized conditional logistic regression and the Gaylor-Kodell model, with various modifications to the Rinsky et al. (1985) case-control analysis. The earlier assessments, and that of White, Infante and Chu (1982), in our judgment, all inadequately characterized the benzene exposure history.of the cohort, and consequently, estimates of risk derived from these assessments should be considered less reliable than those of Rinsky et al.. Crump and Allen, and Chinchilli. Our conclusions about benzene-associated leukemia risk will therefore be based upon these three latter analyses. The Crump and Allen (1984) (and USEPA/CAG 1985) and the Rinsky et al. (1985) assessments should be considered preferable to the earlier assessments as they both attempted to characterize the benzene exposure histories of individual members of the -59- 00000128* SAL cohort, as opposed to making generalizations about benzene exposure of the cohort as a whole. The manner in which exposure in individual work areas of the pliofilm plants was assessed appears to be the factor of greatest influence on the excess leukemia deaths projected in these various assessm'ents. The Crump and Allen (1984) methodology of exposure assessment differed from that of Rinsky et al. (1985) in a number of respects. Crump and Allen calculated time-weighted average benzene levels over seven multi-year time periods while Rinsky et al. derived single year values on the basis of actual values or by linear interpolation. In cases where there were no data available for earlier time periods, Rinsky et al. extrapolated the benzene concentrations for the earliest year back to the plant opening. In fact, for three of the ten exposure classes considered levels from the 1960's were extrapolated back into the 1930*s. Crump and Allen, in the event that there were no measurements for a given area for a given period, multiplied the estimate from the following period by the ratio of the occupational standard or recommendation for the period to that of the occupational standard or recommendation of the following period. Both groups used data from Location 1 as a surrogate for Location 2. Crump and Allen used data from the two locations interchangeably, while Rinsky et al. applied data from Location 2 only to this location. Rinsky et al. also excluded from their estimates data documenting high benzene levels in the storage area of the plant; these were included by Crump and Allen in their "average" exposure category. These various differences resulted in the exposure estimates of Crump and Allen being generally higher than those of Rinsky et al. for the majority of the job titles and time periods covered. This is illustrated in Table 6. In the absence of additional monitoring data, it is not possible to render a judgment as to which methodology best estimates the absolute exposures experienced by the cohort. As described above, a major difference between Rinsky et al. and Crump and Allen was in their methodologies for estimating exposures in the earlier years, when no industrial hygiene data -60- SAL 000001285 - i . -<># 2_ 3*?45 4? U b le 6. iOCAllOM I - B tA itn e li* H (ppa) <w n4trlint4 itia b trt s i g (B in n ify s hi dv .u i (l ! M . i t ulBr t8wb .A Cl trw. opPitr t 1. A lb dI9f Mt ) i * 4 i c i t Cruap v iW t.l i1_ ___________C ld li__ -- ________ ___ ___ _____ftrifld-- L___--------- ----------- Cldld__ I ________ __ ftriad 48 4* M 51 52___53___51 55___55___5Z------50____53___50___51___52 53 H 55 55 51 M 5 t ? i 71 table 6 (cool.) lOCA!ION 2 - BENZENE LEVELS (ppm) (Rmsly et at. 198b - Cruap et t. 19641 (underlined numbers signify idual measurements. Parentheses indicate Crump values.) 1-- Ifl 19 40 41 Miner 45 45 45 45 45 45 (63) 2_ 1 4? 41 44 46 4b 47 3_ 1 48 49 45 45 45 45 45 45 45 (61) III) 45 Pecind 1 11 50 61 6? 53 54 56 6ft 6? 6A 61 ftO ftl 1 6? ftl 54 ft6 40 35 30 25 20 15 10 lb 10 10 9 9 9 8 34 26 (22) (16) (18) keat tor 10 10 10 10 10 10 (60) 10 10 10 10 10 10 10 (601 ( 10) 10 Neut ral i i*r n zi 23 23 23 23 (61) 23 23 23 23 23 21 23 (51) (2b) 2* Presses 4b 4b 45 45 45 45 (43) 45 45 45 45 45 45 45 (43) (21) 45 Quen< her 10 30 30 30 30 30 30 30 30 30 30 30 10 1 (Ml) (Mil (56) <Ti ro Belee Units 30 1 20 20 20 20 20 20 20 20 20 20 20 20 20 20 (259) (240) (120) Still 10 10 10 10 10 10 (31) 10 10 10 10 10 10 10 1 ID 1 16) 10 Lastmq Unit 34 34 34 34 34 34 34 34 34 34 34 28 34 50 Hi n imum 111, 1 1 1111 l 1 1 10 10 10 10 10 10 10 U (21) 8 76S6 (2) 5S5 (2) 23 23 23 23 23 23 23 lb 22 21 21 20 20 19 28 7 (16) (18) (HI 45 45 45 45 45 45 45 45 45 45 45 45 45 60 25 5 (15) (IS) (3) 30 30 30 30 30 30 30 33 30 30 30 30 30 34 25 16 (39) (34) (18) 20 20 20 20 20 20 20 11 20 20 20 20 20 20 20 35 (36) (20) (20) 10 10 10 10 10 10 to 10 10 10 10 10 10 ( ID (8) 7 10 12 (8) 42 34 34 34 34 34 33 39 34 34 34 34 34 23 39 59 1 1 1 1 111l111 1 1 11 1 t&dtlAf___ Neutrali<er 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 19 15 14 14 13 13 12 17 6 Storage . i ,i ',) r 1, |I. r IS) r- o o o o o M fg CD -j (250) 4 .10 | (ZS9| ( It.) 1 16) UB) 1 1.0. { 120) (42) t.'4Uj 1 I/O) (96) Nil i te. et al,. 1982 (26) (31) (69) (20) 1 11) (69) were available. The result of this methodologic difference is that the Crump and Allen estimates for the early years generally exceeded those of more recent years, while the Rinsky et al. estimates for early years were often the same as for more recent years. We have a preference for the Crump and Allen methodology for estimating relative benzene exposures during the earlier years, as it seems more plausible that exposures in the early years were higher than those measured more recently. A recent review in which an attempt was made to correlate hematology data of the pliofilm cohort with both the Rinsky et al. and the Crump and Allen exposure assumptions, tends to further support the methodology applied by Crump and Allen (i.e., the Crump and Allen exposure estimates correlated more strongly than the Rinsky et al. estimates with fluctuations in the white and red blood cell counts of the cohort) (Kipen et al. 1986). Of the two exposure matrices, presented by Crump and Allen, we prefer the original matrix. As detailed in Section IVC, the available data on human benzene toxicity provide more support for this exposure matrix, which was derived from existing industrial hygiene data. The Carcinogen Assessment Group of the USEPA (USEPA 1985) performed an analysis in which the occupational estimates of Crump and Allen (1984) were transformed to estimates of risks associated with continual lifetime exposure to benzene. No additional methodologic approaches were applied in this USEPA assessment. Chinchilli (1986) adopted the exposure methodologies developed by both Crump and Allen and Rinsky et al. in his estimations of risk based on the Rinsky et al. cohort. His analyses utilized the matched case-control conditional logistic regression approach. Chinchilli assessed the effect of applying the Crump and Allen exposure methodology to the Rinsky et al. case-control data set. Chinchilli selected three additional sets of controls: the first applying Rinsky's criteria of matching by date of birth and date of first employment in pliofilm; the second in which the controls were matched by plant in addition to the Rinsky matching criteria of date of birth and date of first -63- SAL 000001289 employment in pliofilm; and the third in which controls were matched by the Rinsky criteria, plant, and date of last employment. To assess risk associated with low-dose ambient benzene exposure, Chinchilli applied the conditional logistic model alone, and the Gaylor-Kodell model to the upper 95% confidence bound on excess risk in the observed exposure range in the Rinsky et al. case-control study. Table 7 presents the range of additional leukemias per million persons associated with continual lifetime (70-year) exposure to 1 ppb benzene which were projected in the various assessments in which the Crump and Allen (1984) and the Rinsky et al. (1985) exposure methodologies were applied. In all cases, risk was associated with cumulative benzene exposure. Also included, for comparison purposes, are the risks projected by the California Department of Health Services. We have a preference for the conditional logistic regression approach adopted by Rinsky et al. (1985) and subsequently by Chinchilli (1986) as it makes maximal use of the data points available. We also prefer the strict criteria for matching employed by Chinchilli, in which the cases were matched by date of birth, date of first employment in pliofilm, and plant (control set 3). As indicated above, we prefer the use of Crump and Allen exposure matrices as they, in effect, assume exposures in earlier years exceeded those in later years. Available data on benzene toxicity in humans provide greater support for Crump and Allen's original exposure matrix. Because we do not have available epidemiologic data in the low-dose range applicable to benzene in ambient air, we have a preference for the use of the Gaylor-Kodell model, as it presents an upper-bound on low-dose risk (and is therefore conservative) and it is a model for which there are precedents in regulatory decision-making. Thus, at the present time, our overall preferred risk estimate, based upon benzene exposure in pliofilm only (and the Gaylor-Kodell model applied to Chinchilli Control Set 3 and the Crump and Allen Exposure Matrix I), predicts an excess leukemia risk of 6.6 x 10-6 at 1 ppb -64- SAL OOOOOI289 benzene in ambient air (or an additional leukemia mortality risk of one in one million at 0.15 ppb benzene in ambient air). It should be noted, however, that this estimate does not take into account the influence of benzene exposure of workers via inhalation and dermal absorption in non-pliofilm areas of the Goodyear plant studied by Rinsky et al. Accounting for such exposures will likely result in a substantial lowering of the leukemia risks associated with lifetime low-level benzene exposure which were estimated on the basis of this study (by a factor as great as 14 as suggested by preliminary analyses). The American Petroleum Institute is currently analyzing Goodyear worker history records recently made available by NIOSH and investigating additional sources of data on the total inhalation and dermal benzene exposures of the Rinsky et al. cohort. Risk analyses incorporating such data will be available in the coming months. Clearly such further investigation of the actual extent of such additional benzene exposures of the cohort is warranted in order to improve subsequent estimates of the leukemia risk associated with human exposure to benzene. -65- SAL 000001290 table 7 Comparison of Available ..izene Risk Assessments in which Crump and Allen (1984) or Rinsky et al. (1985) Exposure Assumptions were Applied Risk Data Set Used Exposure Assumotions Model Aoolied Additional lifetime Leukemia Risk Per Million Persons Associated with 1 ppb Continual Ambient Exposure to Benzene ppb Benzene in Ambient Air Associated With IQ-6 Risk Rinsky et al. 1985 Rinsky et al. 1985 casecontrol analysis Rinsky et al. 1985 cumula tive exposure estimated on an individual basis conditional logistic regression 29 0.04 Chinchill i 1 Rinsky et al. 1985 alternate casecontrol analysis; control set 3 Rinsky et al. 1985 cumu lative exposure estimated on an individual basis conditional logistic regression 23 0.05 Chinchilli II Rinsky et al. 1985 alternate casecontrol analysis; control set 3 Crump and Allen 1984-1' cumulative exposure esti mated on an individual basi s conditional logistic regression 3.6 0.26 Chinchilli III Rinsky et al. 1985 alternate casecontrol analysis; control set 3 Crump and Allen 1984-11 cumulative exposure esti mated on an individual basis conditional logistic regression 7.7 0.13 Chinchilli IV Rinsky et al. 1985 alternate casecontrol analysis; control set 3 Rinsky et al. 1985 cumu lative exposure estimated on an individual basis conditional logistic regression; Gaylor-Kodel1 39 0.03 SAL 000001291 Table 7 (continued) Comparison of Available Benzene Risk Assessments in which Crump and Allen (1984) or Rinsky et al. (1985) Exposure Assumptions were Applied I oi Oi ooO o rvj Aj Risk Data Set Exposure Model Applied Additional Lifetime Leukemia Risk Per Million Persons Associated with 1 ppb Continual Ambient Exposure U Bentene ppb Benzene in Ambient Air Associated With 10~6 Risk Chinchilli V Rinsky et al. 1985 alternate casecontrol analysis; control set 3 Crump and Allen 1984-1 cumulative exposure esti mated on an individual basis conditional logistic regression; Gaylor-Kodell 6.6 0.15 Chinchilli VI Rinsky et al. 1985 alternate casecontrol analysis; control set 3 Crump and Allen 1984-11 cumulative exposure esti mated on an individual basis conditional logistic regression; Gaylor-Kodel 1 14 0.07 Crump and Allen 1984/ USEPA 1985 Rinsky et al. 1981 -Cohort study <8 leukemias) Crump and Allen 1984-1 Cumulative exposure esti mated on an individual basis relative r i sk (1 i near) 51 0.02 California/ DOHS a. NTP Bioassay; Mouse Preputial Gland b. Infante Ott, Wong multistage model; 95% Upper confidence limit 1inear 170 24 0.006 0.04 References Aksoy, M. 1980, Different Types of Malignancies Due to Occupational Exposure to Benzene: A Review of Recent Observations in Turkey. Environ. Research 23:181-190. American Petroleum Institute (API). 1980. Supplemental Post-Hearing Evidence of API. Before the U.S. Environmental Protection Agency, November 6, 1980. EPA Docket No. OAQPD 79--3, Part II, Section 3 (Assessment of Lamm, S.). American Petroleum Institute (API). 1986a. A Preliminary Review of Literature Pertaining to Non-Pliofilm Rubber Worker Benzene Exposure before 1970. OSHA Docket H-059C, Exhibit 201-5. American Petroleum Institute (API). 1986b. Benzene Exposure Potential of NIOSH's Pliofilm Cases and Controls. OSHA Docket H-059C, Exhibit 247. American Petroleum Institute (API). Analysis of Ott et al. Cohort. Exhibit 247. 1986c. Case-Control OSHA Docket H-059C, American Petroleum Institute (API). 1986d. Non-Pliofilm Benzene Exposures of Deceased Akron Workers: Preliminary Estimates for Sensitivity Analysis. OSHA Docket H-059C Exhibit 218D. Bennett, J.M. 1986. Post-Hearing Submission of John M. Bennett, M.D. on medical surveillance issues of OSHA's proposed standard for occupational exposure to benzene. OSHA Docket H-059C, Exhibit 247. Blank, I.H., and McAuliffe, D.J. Benzene through Human Skin. 85:522-526. 1985. Penetration of J. Invest. Dermatol. Bond, G.G., McLaren, E.A., Baldwin, C., and Cook, R.R. 1985. Executive Summary of Report: An update of Mortality Among Chemical Workers Exposed to Benzene. Dow Chemical U.S.A. October 29, 1985. Chemical and Rubber Sections of the National Safety Council. 1926. Final Report of the Committee on Benzol. National Bureau of Casuality and Surety Underwriters. Chinchilli, V.M. 1986. A Statistical Analysis of the Rinsky Data Set on Benzene Exposure. Prepared for the American Petroleum Institute. -68- SAL 000001293 Committee on the Biological Effects of Ionizing Radiation (BEIR). 1980. National Academy of Sciences. The Effects on Population of Exposure to Low Levels of Ionizing Radiation. National Academy of Sciences, Washington, D.C. Crump, K.C. , and Allen, B.C. 1984. Quantitative Estimates of the Risk of Leukemia from Occupational Exposure to Benzene. Prepared for the Occupational Safety and Health Administration. May, 1984. Davis, P.A. 1929. Toxic Substances in the Rubber Industry. Part 1: Benzol. The Rubber Age. 367-368. ENVIRON Corporation. 1985. Sensitivity Analysis of the California Department of Health Services Risk Assessment of Benzene. Prepared for American Petroleum Institute, January 11, 1985. ENVIRON Corporation. 1986. Dermal Absorption of Benzene. Prepared for American Petroleum Institute. OSHA Docket H-059C, Exhibit 201-5. Environmental Law Institute. 1983. Benzene Health Effects in Humans and Risk Assessment. Prepared for U.S. Occupational Safety and Health Administration. June, 1983. Franz, T.J. 1984. Percutaneous absorption of benzene, in*. Applied Toxicology of Petroleum Hydrocarbons (H.N. MacFarland, C.E. Holdsworth, J.A. MacGregor, R.W. Call, and M.L. Kane, eds.) Princeton Scientific Publishers, pp. 61-70. Gail, M. 1975. Measuring the benefit of reduced exposure to environmental carcinogens. J. Chronic Dis. 28:135-147. Gaylor, D.W., and Kodell, R.L. 1980. Linear Interpolation Algorithm for Low Dose Risk Assessment of Toxic Substances. J. Environ. Pathol, and Toxicol. 4:305-312. Gilbert, D. 1982. An Exposure and Risk Assessment for Benzene. A.D. Little. 1982. (EPA Contract 68-01-5949, Final Report). Goldstein, B.D. 1977. Hematotoxicity in Humans. J. Toxicol. Environ. Health Suppl. 2:69-105. Goldstein, B.D. 1977. Clinical Hematotoxicity of Benzene. In Mehlman, M.A., ed. Advances in Modern. Environmental Toxicology. Volume IV. Carcinogenicity and Toxicity of Benzene. Princeton Scientific Publishers, Princeton. Pp 51-61. -69- SAL 00000X294 Goldstein, B.D. 1986. Letter to H. Derrick Peterson. OSHA Docket H-059C, Exhibit 247. Goldstein, B.D., Synder, C.A., Laskin, S., Bromberg, I., Albert, R.E., and Nelson, N. 1982. Myelogenous Leukemia in Rodents Inhaling Benzene. Toxicology Letters. 13:169-173. Hanke, 3., Dutkiewicz, T.f and Piotrowski, J. 1961. The absorption of benzene through the skin in man. Med. Pracy 12:413-426. (OSHA translation). Hattis, D,, and Mendez, W, 1980. Discussion and Critique of the Carcinogen Assessment Group's Report on Population Risk due to Atmospheric Exposure to Benzene, Center for Policy Alternatives, Mass. Inst. Tech: Cambridge, MA. Infante, P.F., Rinsky, R.A., Wagoner, J.K., and Young, R.J. 1977. Leukemia in Benzene Workers. Lancet ii:76-78. Interagency Regulatory Liaison Group (IRLG). 1979. Scientific Bases for Identification of Potential Carcinogens and Estimation of Risks. JNCI 63:244-268. International Association for Research on Cancer (IARC). 1981. Risk Assessment of Benzene and Some Aspects of Quantitative Risk Estimation. Lyon, France. October 3, 1981 (Final) draft. International Agency for Research on Cancer (IARC). 1982. Benzene, IARC Monographs 29:93-148. Jandl, J.H. 1977. A Proposal for Medical Surveillance to Detect Early and Reversible Changes Caused by Occupational Exposure to Benzene, Recommendations Based Upon a Critical Analysis of Published Case Reports of the Hematologic Effects of Benzene. August 1977. (OSHA Docket H-059, Exhibit 217.26 B). Kipen, H.M., Cody, R.P., Lioy, P.J., and Goldstein, B.D. 1986. Preliminary Report of Pliofilm Cohort Hematology. Prepared for American Petroleum Institute. Luken, R.H., and Miller, S.G. 1981. The Benefits and Costs of Regulating Benzene. Journal of the Air Pollution Control Association 31:1255-1259. Maibach, H.I. 1980a. Percutaneous Penetration of Benzene: Man. (Submitted to OSHA, Ex. No. 231-6). Maibach, H.I. 1980b. Percutaneous Penetration of Benzene: Man. II (Submitted to OSHA, Ex. No. 231-7). -70- SAL 000001295 Maibach, H.I., and Anjo, D.M. 1981. Percutaneous Penetration of Benzene and Benzene Contained in Solvents Used in the Rubber Industry. Arch. Environ. Health 36:256-260. Maltoni, C. and Scarnato, C. 1979. First Experimental Demonstration of the Carcinogenic Effects of Benzene. Long-Term Bioassays on Sprague-Dawley Rats by Oral Administration. Med. Lav. 70:352-357. Maltoni, C., Cotti, G. , Valgimigli, L., and Mandrioli, A. 1982. Zymbal Gland Carcinomas in Rats Following Exposure to Benzene by Inhaltion. Am. J. Ind. Med. 3:11-16. Maltoni, C., Conti, B., and Cotti, G. 1983. Benzene: A Multipotential Carcinogen. Results of Long-Term Bioassays Performed at the Bologna Institure of Oncology. Am. J. Ind. Med. 4:589-630. Milham, S. 1976. Neoplasia in the wood and pulp industry. Ann N.Y. Acad, of Sci. 271:294-300. National Research Council (NRC). 1983. Risk Assessment in the Federal Government: Managing the Process. National Academy Press, Washington, D.C. National Safety Council. 1926. Final Report of the Committee on Benzol, Chemical and Rubber Sections, National Bureau of Casualty and Surety Underwriters, May 1926. National Toxicology Program (NTP). 1984. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Benzene (CAS No. 71-43-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies) NTP-TR 289. NIH Publication No. 84-2545. Board Drft, 7/84. Occupational Safety and Health Administration (OSHA). 1980. Identification, Classification and Regulation of Potential Occupational Carcinogens. Fed., Reg. 45:5001-5296. Ott, M.G., Townsend, J.C., Fishbeck, W.A., and Langner, R.A. 1978. Mortality Among Individuals Occupationally Exposed to Benzene. Arch. Environ. Health 33:3-10. Pagnotto, L.D., Elkins, H.B., and Brugsch, H.G. 1979. Benzene Exposure in the Rubber Coating Industry - a follow-up. Amer. Ind. Hyg. J, 40:137. -71- SAL 000001296 Rinsky, R.A., Smith, A.B., Hornung, R., Filloon, T.G., Young, R.J., Okun, A.H., and Landrigan, P.J. 1985. Benzene and Leukemia: An Epidemiologic Risk Assessment. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health, Division of Surveillance, Hazard Evaluations and Field Studies, Cincinnatti, OH. August 9, 1985. Rinsky, R.A., Smith, A.B., Hornung, R., Filloon, T.G., Young, R.J., Okun, A.H., and Landrigan, P.J. 1986. Benzene and Leukemia: An Epidemiologic Risk Assessment. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health, Division of Surveillance, Hazard Evaluations and Field Studies, Cincinnatti, OH. April 22, 1986. Rinsky, R.A.,- Young, R.J., and Smith, A.B. 1981. Leukemia in Benzene Workers. Am. J. Ind. Med. 2:217-245. Rodricks, J.V. and Brett, S.M. 1986. Review and Evaluation of Leukemia Risks Associated with Occupational Exposure to Benzene. Prepared for American Petroleum Institute. March 5, 1986. OSHA Docket H-059C, Exhibit 201-5. Snyder, C.A., Goldstein, B. D., Sellakumar, A.R., Bromberg, I., Laskin, S., and Albert, R.E. 1980. The Inhalation Toxicology of Benzene: Incidence of Hematopoietic Neoplasms and Hematotoxicity in AKR/J and C57BL/6J Mice. Toxicol. Appl. Pharmacol. 54:323-331. Snyder, C.A., Goldstein, B.D., Sellakumar, A.R.., and Albert, R.E. In press. Evidence for Hematotoxicity and Tumorigenesis in Rats Exposed to 100 ppm Benzene. Susten, A.S., Dames, B.L., Burg, J.R., and Niemeier, R.W. 1985. Percutaneous Penetration of Benzene in Hairless Mice: An Estimate of Dermal Absorption During Tire-Building Operations. Am. J. Ind. Med. 7:323-335. Thomas, T.R. and Tebbens, B.D. 1943. Control of Solvent Exposures in the Rubber Industry. Ind. Med 12:255. U.S. Environmental Protection Agency (USEPA). 1979. Final Report on Population Risk due to Ambient Benzene Exposure Environmental Protection Agency. Washington, D.C. U.S. Environmental Protection Agency (USEPA). 1984. Proposed Guidelines for Carcinogen Risk Assessment. Fed. Reg. 49:46294-46303. -72- SAL 000001297 U.S. Environmental Protection Agency (USEPA). 1985. Interim Quantitative Cancer Unit Risk Estimates Due to Inhalation of Benzene. Prepared for Office of Air Quality Planning and Standards. Prepared by Carcinogen Assessment Group. EPA-6Q0/X-85--022. February 15, 1985. Vigliani, E.C. 1976. Leukemia Associated with Benzene Exposure. Ann. N.Y. Acad. Sci. 271:143-151. White, M., Infante, P., and Chu, K. 1982. A Quantitative Estimate of Leukemia Mortality Associated with Occupational Exposure to Benzene. Risk Analysis 2:195-204. Wilson, R. 1942. Benzene Poisoning in Industry. J. Lab. Clin. Med. 27:1517-1521. Wong, 0., Morgan, R.W., and Whorton, M.D. 1983. Comments on the NIOSH Study of Leukemia in Benzene Workers. Technical Report Submitted to Gulf Canada, Ltd. (Environmental Health Associates, 31, August). Wong, 0. 1983. An industry-wide study of chemical workers occupationally exposed to benzene. Report to the Chemical Manufacturers Association, Environmental Health Associates, Berkely, CA. -73- SAL 000001298 APPENDIX a SAL 000001299 for American Petroleum Institute DERMAL ABSORPTION OF BENZENE In OSHA's preliminary assessment of worker exposure to benzene via the dermal route, they estimated that 6 mg of benzene could be absorbed per day by workers in the tire manufacturing industry. Their estimate was based primarily on the work of Maibach and Anjo (1981) and Susten et al. (1985). Susten et al. (1985) found that 1% of the benzene applied to the back of hairless mice was absorbed. Using some assumptions pertaining to probable exposure to benzene by a worker in the tire manufacturing industry, they calculated the amount of benzene absorbed per workday was 6.19 mg. The assumptions and calculations are listed below: 2 1. 6.25 HL solvent/cm of exposed surface - the actual experimental value used, presumably selected to be comparable to the experimentally derived value of 6.82 ML/cm2 by Maibach (Johnson, 1979). 2. 0.88 g/mL; density of benzene - an overestimate, because the density of rubber solvent is 0.722 g/mL and a 0.5% benzene solution would have a density of 0.723 g/mL. 3. 0.5% benzene in solvent - presumably the maximum amount of benzene found as a contaminant in rubber solvent. 2 4. 150 cm of exposed palmar surface - assuming 1/3 of the palms of both hands are exposed. SAL 000001300 5. 150 contacts/workday - presumably an average number of daily contacts. 6. 1% dermal absorption in man - assuming dermal absorption in hairless mice after a single . application is representative of dermal absorption on palm of man after multiple applications. <6.25ML/cm2)(0.88 mg/PL)(0.005)(150 cm2)(150)(0.01) * 6.19 mg benzene absorbed/workday Maibach and Anjo (1981) conducted skin absorption tests using Rhesus monkeys and their results are shown in Table I. Using preliminary data submitted to OSHA by Maibach (1979) comparable to the results in Table I, Johnson (1979) estimated \ the daily benzene exposure via the dermal route was 0.86 mg/workday. His assumptions were: 2 1. 6.82 PL solvent/cm of exposed surface 2. 0.8 g/mL; density of solvent 3. 0.35% benzene in solvent 2 4. 65 cm of exposed palmar surface 5. 30 contacts/workday 6. 2.32% dermal absorption in man <6.82 HL/cm2)(0.8 g/mL)(0.0035)<65 cm2)(30)(0.0232) =0.86 mg benzene absorbed/workday Sal 000ol30l Table I Diluted Benzene (0,35) Undiluted Benzene Dermal Absorption in Monkeys Palm Arm Palm Arm % Absorption Single Application Multiple Application 0.651 (3.448)a 0.0805 0.431 (1.376)a (6.784)a 0.172 0.848 a Assuming the same relationship as found after single application of diluted benzene. SAL 000001302 The 2.32% dermal absorption was derived from data from Maibach (1979) preliminarily submitted to OSHA: 0.309% absorption through the arm of monkeys after multiple application of 0.35% benzene and correcting for the higher amount of benzene absorption through the palm of monkeys by a factor of 7.5. (This factor was determined from single applications of 0.35% benzene to the arm and palm of monkeys). Susten et al. (1985) indicated that if Johnson (1979) had used the same assumptions for the number of contacts per day and the contact surface area, the amount of benzene absorbed per day would have been comparable in the two studies. OSHA also points this out in their preliminary assessment. However, if all the assumptions pertaining to exposure were the same, then using the values reported by Maibach (1979), the results should have been 2.32-fold higher than Susten's (since the amount absorbed in Maibach's study was 2.32-fold higher than in Susten's study). There are three additional considerations that one must be aware of when the above comparison between data from Susten et al. (1985) and Maibach and Anjo (1981) is made. First, in Maibach and Anjo (1981), the value for benzene absorption was measured after multiple dermal application to the arm, then extrapolated to the palm based on an absorption ratio for the palm and arm derived from a single application. It was assumed that the ratio of the absorption through the palm and arm after 000001'03 SAL multiple applications would be identical to the ratio derived from a single application. Second, Maibach and Anjo (1981) found a difference in the amount absorbed through different anatomical locations on the monkey; this would make it unsuitable for comparison with the back of hairless mice unless one better understands the absorption characteristics of the various anatomical locations on the monkey versus the back of hairless mice. Third, Maibach and Anjo (1981) found that the percentage of dermal absorption of benzene in monkeys increased when the benzene concentration increased from 0.35% to 100%. Susten et al. (1985) on the other hand, found no difference in the percentage of dermal absorption of benzene in hairless mice whether it was 0.5% or 100% benzene. Blank and McAuliffe (1985) reported that the rate of benzene absorption was higher using undiluted benzene than diluted (5%) benzene in human abdominal skin in vitro. These studies clearly indicate the need for further experimentation to determine which experimental model would be most appropriate in estimating human dermal absorption of benzene. / What would be better than using animals is to conduct experiments in man. Maibach (1980a,b) presented some preliminary data to OSHA on benzene absorption through the arm and palm of several human volunteers (Table II). From this data and the data from monkeys, one can make extrapolations to determine the absorption of diluted benzene in man after multiple applications (Table II). 000001** Table II Diluted Benzene (0.35%) Undiluted Benzene Dermal Absorption in Man Palm Arm Palm Arm % Absorption Single Application Multiple Application <0.060)b (0.030)c (0.325)b (0.162)^ 0.128 (0.640)b 0.065 (0.320)a a Assuming the same relationship as found in monkeys after single and multiple applications of undiluted benzene on arm b Assuming the same relationship as found in man after single applications of undiluted benzene on palm and arm. c Assuming the same relationship as found in monkeys after single applications of diluted and undiluted benzene on arm. d Assuming the same relationship as found in monkeys after single and multiple applications of diluted benzene on arm. SAL 000001305 Using the extrapolated value of 0.3251 absorption after multiple applications of diluted benzene to the palm of man, the estimated amount of benzene absorbed for a worker in the tire manufacturing industry using the assumptions of Susten et al. (1985) would be 2 mg/workday. Maibach and Anjo (1981) also reported an absorption of 0.909% after a single application of undiluted benzene to "damaged" skin (arm) of monkeys. Damage was induced by repeated application and removal of a strip of cellophane tape until much of the stratum corneum was removed. Using this value to extrapolate to a value for multiple applications to the palm of man, one calculates an absorption of 18.2%. Again, using the assumptions of Susten et al. (1985), a worker would absorb 56 mg of benzene per workday. Little is known about the effect of varying the multiple application regimens on dermal absorption of benzene. In Maibach and Anjo (1981), benzene was applied 10 or n times, once every 10 or 15 minutes. It is very likely that the extent of absorption changes with the periodicity of benzene application. At some stage, absorption from intermittent application should approach absorption from continuous contact. Hanke et al. (1961), estimated the rate of absorption of undiluted benzene through the arms of human volunteers after 1.25-2 hours of continuous contact. Using two different analytical methodologies, the absorption rate of benzene was SAL 000001306 0.24 mg/cm2/hr or2 0.4 mg/cm /hr. This should represent the maximum, or "worst-case", dermal absorption of benzene that one may encounter in the workplace. But if one were to assume that the solvent contained 0.5% benzene, surface area of contact was 150 cm and duration of contact was 8 hr, consistent with the assumptions of Susten et al. (1985), then the resultant exposure representing the "worst-case" would only be 1.44 or 2.4 mg of benzene absorbed per workday depending on whether the lower or higher rate of benzene absorption was used. If a correction for palm versus arm is made, the "worst-case" dermal absorption is still only twice that amount, 2.88 or 4.8 mg/workday. Since Hanke's work was done in 1961, perhaps it would be worthwhile to repeat his work using the more powerful analytical techniques available today. Franz (1984) evaluated dermal absorption of benzene in man and monkeys and found values comparable to the values reported by Kaibach and Anjo (1981). Franz (1984) found that dermal absorption after a single application of undiluted benzene to the ventral forearm of man and monkeys was 0.05% and 0.14%, respectively [as compared to 0.065% and 0.172% reported by Maibach and Anjo, (1981)]. Franz also evaluated in vivo versus in vitro absorption of undiluted benzene in man, monkey, and minipig. He found that the in vivo results were comparable to the in vitro results sAL 000001307 (Table III). Furthermore, he evaluated the role of contact time versus benzene absorption in vitro using human skin and found that the amount absorbed increased linearly with contact time. From his data, one can calculate an absorption rate of 0.2 to 0..3 mg/cm /hr [corresponding to 2.4 to 3.6 mg of benzene absorbed through the palm/workday, using the assumptions of Susten et al. (1985)]. This range compares favorably to the range determined on human volunteers by Hanke et al. (1961) of 0.24 mg/cm2 /hr or 0.4 mg/cm2 /hr (corresponding to 2.88 or 4.8 mg of benzene absorbed/workday). Blank and McAuliffe (1985) reported that the in vitro rate of benzene (undiluted) absorption through human abdominal skin 2 obtained at autopsy was 2.11 + 1.08 Ul/cm /hr. Using a density of benzene of 0.88 g/ml, the rate of benzene absorption 2 is 1.85 mg/cm /hr, a rate approximately 5-10 times higher than that reported by Hanke et al. (1961) or Franz (1984). There are several possible explanations why their rate is higher. First, there is apparently a discrepancy in the rate of benzene absorption as stated in the text versus the rate which can be estimated from their "Figure 1." In their "Figure 2 1", the flux of benzene, in Pl/cm , is plotted vs time, m hours. The flux is linear over a four hour time period except during the first half-hour when a lag-time exists. From the graph, the rate of benzene absorption can be estimated to be approximately 0.64 vU/cm2 /hr, or 0.56 mg/cm2 /hr. Using SAL 000001308 TABLE III Benzene Absorption (% of dose) Man Monkey Mini Pig In Vivo 0.05 0.14 0.09 In Vitro 0.10 0.19 0.23 sal 0oooi3o9 the assumptions of Susten et al. (1985), this corresponds to 6.7 mg of benzene absorbed through the palm per workday. This rate is only 1-2 times higher than those reported by Hanke et al. (1961) or Franz, (1984). Another explanation for the higher rate reported by Blank and McAuliffe (1985) is that they used a thinner layer of skin than that used by Franz (1984). Thus, considering the differences in methodologies used by these authors, the consistency in the rate of benzene absorption is actually remarkable. The percent of benzene absorbed after a single dose reported by Maibach (1980a,b), Maibach and Anjo (1981), and Franz (1984) compare favorably whereas the value reported by Susten et al. (1985) appears high. When extrapolations using the data from Maibach (1980a,b) and Maibach and Anjo (1981) are done to estimate the dermal absorption of diluted benzene through the palm of man after multiple applications, the resultant absorption value of 0.325% and consequent absorption of 2 mg of benzene per workday is below the amount absorbed under "worst-case" conditions as calculated by Hanke et al. (1961) using human volunteers, and Franz (1984), or Blank and McAuliffe (1985) using human skin in vitro. Using the absorption value of Susten et al. (1985), the amount of benzene absorbed is below the amount absorbed under "worst-case" conditions only when using the absorption rate of Blank and McAuliffe (1985). SAL 000001310 Blank and McAuliffe (1985) also estimated the rate of dermal benzene absorption under conditions where the air is saturated with benzene vapor (approximately 13% or 130,000 ppm at 31C). The rate of dermal absorption under these conditions was much.higher than the rate of benzene absorption of solvents containing 5% benzene applied directly on the surface of the skin. Should these highly unrealistic exposure conditions exist in the workplace, it should be obvious that the amount of benzene absorbed via inhalation would be much greater than that absorbed through the skin. Thus, given the available data and making the necessary extrapolations, benzene exposure via dermal absorption appears to be minimal when compared to the amount a worker receives from inhalation exposure to an air concentration of benzene of 1 ppm (3.2 mg/m^) for 8 hours, the proposed OSHA standard (2 mg/workday from dermal versus 15 mg/workday from inhalation*). However, if the 0.5% benzene was replaced by undiluted benzene, the contribution through dermal absorption would increase by a factor of 200. (3.2 mg benzene/m3 of air) x (10 m3 of air inhaled/ workday) x (0.48, inhalation absorption coefficient) = 15.4 mg/workday SAL 000001311 References Blank, I.H., and McAuliffe, D.J. 1985. Penetration of Benzene through Human Skin. J. Invest. Dermatol. 85:522-526. Franz, T.J. 1984. Percutaneous Absorption of Benzene, in: Applied Toxicology of Petroleum Hydrocarbons (H.N. MacFarland, C.E. Holdsworth, J.A. MacGregor, R.W. Call, M.L. Kane, eds.) Princeton Scientific Publishers, pp. 61-70. and Hanke, J., Dutkiewicz, T., and Piotrowski, J. 1961. The Absorption of Benzene Through the Skin in Man. Med. Pracy 12:413-426. (OSHA translation). Johnson, H.L. 1979. Systemic Absorption of Benzene. Evaluation of Experimental Data and Comparison of Dermal and Inhalation Exposure. (Submitted to OSHA, Ex. No. 231-4). Maibach, H.I. 1979. Percutaneous Absorption of Benzene Contained in Rubber Solvent Under Different Experimental Conditions. (Submitted to OSHA, Ex. No. 231-3). Maibach, H.I. 1980a. Percutaneous Penetration of Benzene: Man. (Submitted to OSHA, Ex. No. 231-6). Maibach, H.I. 1980b. Percutaneous Penetration of Benzene: Man. II (Submitted to OSHA, Ex. No. 231-7). Maibach, H.I., and Anjo, D.M. 1981. Percutaneous Penetration of Benzene and Benzene Contained in Solvents Used in the Rubber Industry. Arch. Environ. Health 36:256-260. Susten, A.S., Dames, B.L., Burg, J.R., andNiemeier, R.W. 1985. Percutaneous Penetration of Benzene in Hairless Mice: An Estimate of.Dermal Absorption During Tire-Building Operations. Am. J. Ind. Med. 7:323-335. SAL 0 000013*2 APPENDIX B SAL 000001313 A Preliminary Review of Literature Pertaining to Non-Pliofilm Rubber Worker Benzene Exposure before 1970 Submitted by the American Petroleum Institute: In re: Proposed Standard for Occupational Exposure to Benzene OSHA Docket H-059C March 6, 1966 SAL 000001314 A Preliminary Review of Literature Pertaining to Non-Fliofilm Rubber Worker Benzene Exposure before 1970 Introduction The most relevant quantitative estimates of leukemia risk in present and recent OSHA benzene rulemakings rely on cohorts of exposed Goodyear Pliofilm workers at the Akron and St. Marys sites. A review of the available work history information for the workers studied shows a prevalence of solvent related jobs outside of Pliofilm work for a number of individuals extending back into the 1920's and earlier. API has summarized the duration of exposure in these solvent-related jobs for each worker from the Akron plant for which work records are available and is submitting the summaries in a separate report. At least one group of investigators of the rubber industry has observed that for some period of time in the past, benzene was the solvent of choice in the industry, McMichael, et al. (1978). Moreover, our in-depth study of the solvent-use history of a rubber company indicates that there was intensive use of benzene prior to World War IZ. Arp, et al. (1983). Since current risk assessments neither account for non-pliofilm benzene exposures nor consider dermal absorption as an additional exposure route, the following review was undertaken to document estimates of the potential magnitude of such exposure. Excerpts from literature sources reporting quantitative measures of occupational benzene exposure in the rubber industry are appended to this overview. These citations are categorized in the attachment according to the following topics: 1) rubber industry use of benzene; 2) rubber solvent compositions in use; 3) solvent substitutions for benzene; 4) rubber industry solvent use work practices; 5) dermal contact with rubber solvents; 6) measured occupational benzene concentrations in air. A chronological table of reported occupational benzene exposures is also appended. The remainder of this overview is a brief summary of the citations presented in the attachment. SAL 000001315 2 Summary At the end of World War 1, the resulting excess production of coal tar light oil aromatic hydrocarbons necessary to military explosive manufacture found a ready market as solvents in the rubber industry. Prior to 1914 benzol from Germany was tvice as expensive as petroleum napthas generally used at that time. The post-war glut provided both a better and a cheaper solvent for rubber compounding and fabrication. However, over the next decade an acute occupational benzene poisoning problem became apparent and by the end of the 1930#s use of benzol was declining in favor of less aromatic mixtures, toluene substitution or other solvents. With the advent of World War ZZ, toluene and other aromatics were again preempted for military use. Zn addition, Japanese activities had cut off supplies of natural rubber from the Far East and the synthetic rubbers such as neoprene pressed into service required aromatic solvents. As a consequence, benzene use was again common in the rubber industry. However, by the early 1960's benzene solvent use probably was rare in American industry. Technical (commerical) benzol contained from 50-85% benzene over this time period with the balance predominantly toluene and xylene. Benzols were modified with additives such as carbon tetrachloride which reduced the potential fire hazard. Gasoline (benzine) and petroleum napthas constituted the bulk of the remaining rubber solvents although oxygenated or chlorinated hydrocarbons were added as required to facilitate solution of the synthetic rubbers. The industry increasingly relied on these latter solvents as well as toluene or xylene substitution as a remedy for occupational benzol poisoning. The resulting reduced solvent benzene content generally eliminated acute occupational poisonings and reduced the need for further reductions in benzene exposure. Where solvent substitution was impractical, increased ventilation also succeeded in mitigation of acute responses. However, aromatics often were blended into gasoline and even modern (1961) petroleum napthas have contained benzene to levels approaching 10%. as a consequence residual benzene exposures remained relatively high as compared to the current 10 ppm OSHA standard. Zn the earlier decades rubber workers appeared to be in particularly intimate contact with benzene containing solvents and rubber cements. Both were often applied by hand or in relatively poorly ventilated environments. Articles describe hand feeding of fabric coating blades with naptha-based rubber compounds as late as 1961. Reported benzene vapor exposures of rubber workers generally ranged between 100 and 1000 ppm in the O00l 3l6 3 1924 survey of the industry; the four plant survey of 1942 reports levels- encountered by rubber workers ranging from 10-350 ppa. As late as 1964 reported benzene exposures of Massachusetts fabric coaters range up to 140 ppm froa petroleum naptha solvents containing 3-7.5% benzene. Conclusion and Recommendation The preceeding overview of appended citations suggests that historical benzene exposures in a number of rubber workers included in the Goodyear pliofilm cohort are not zero as assumed in current risk assessments using that data; furthermore, there appears to have been ample dermal exposure which was similarly Ignored. The studies reporting field measurements of benzene exposure to not identify the specific facilities visited. Further inquiry into Goodyear records may verify that such historical exposure data exist for Goodyear vorkers and this inquiry should be pursued to provide a quantitatively improved assessment of occupational risk at the current and proposed benzene standards. SAL 000001317 Appendix I SAL 000001318 'tk* 1*1* 1*31 1*30 1*34 1*43 . 1*45 job rrrt tcitation) IngliM eMntlM tlra rU proofing hellOOH lilrle {Legga - 1*30) iuiy nlantt fabric ClMAtlRf <Pinal Mpert*<>mi) faerie CMtlR9 Uanllton - 1933J > tlpMMM KltlMtM laiMtly mi M4 MUUB JU* urn rang* ean <***> (Mfe> ooo 3*00 310 - 1050 *10 cowor? tire rm 1 fan fen) * tirt roan (Ian *ff> balloon rooo Up to 1000 Up to *0,000 flra baaard above 15,000 tire cor* eMAUi>9 tire making eMAt aiiint rubMr MtiA9 rubber cenantlng (fiMl Mport ... 1*34) 110-340 140-140 *0-340 310-040 40-130 00-130 fabric coating ' balloon fabrication o counting ttblti o floor eeaeubly e Internal seaming fuel tank fabrication 30-150 10-30 40-300 30-00 150-350 30-140 rubber boat fabrication (Thomas - 1943) cementing fabric (Creenburg - 1*45) 30-35 100-340 Up to 700 330 ____ 150 g^er 310 winter 030 wir 90 suamer 100 earner so ventilation Itiifstd for benaol oea vantilatad 40-70 unventilatad unventilatad vantilatad ventilated onventllated mventileted 194* pliofilm unit eolvent storage (It* vlilt-Coedytir Akron -1948) 130 130 1000 500 dryer front apreadcr dryer rear tank top opening SOLVENT NA*uUNcrr mrrwoo beotol * - benaol benaol. ethanol. ethyl- eeatate benaol panpod choree* tube 30 min sample* gravimetric floieh toluene benaol Mine Safety Applaaocee benaol deteetc confirmed with apectrogrephic e tend petroleun oeptha gasoline. petrol ear nepthe toluene benaol benaol SAL 000001319 0?ErO0000 3Tn*W3tdl *i30TiTTTTp ca*q 'tdaavt TW OC-PT 'qn) tI tafTT* pmlwnd (u9vq MTt) vviidva M9?TE vonTTt*tP ptititOat *tdan t OC-PI **% TP ratTT* UBMBftACTM (auaiuaq PP*4-C) Wtrfau ct EE CC OP 0P-*T PP cc-ot PC-4 PC PE-CT tP-PT PC 8P-Ct PP-Pt 4 TP-4T EE-Pt PP OP-EE cc-8 04 -- Mtaartaa TOUh4 Aj*Tjh T -- l 4P-Pt <9 PPftt -- ( A\*c PC-41 ( 0PT-8C (4 CPftT -- (9 *9q PC-4 C9 CP-CC (9 CPftt P ( ttlftY OE-C (9 OP-OT (9 EPftT -- ( '** 9C-T (9 CC-EE (9 tPCt PP-Pt { ** PE-OE (9 Oft (9 TPftt -- (9 *ur PE-4 (9 48 (9 OPftI 4t-Et < <t*f 4E-P (9 dd if <9 OPftt -- (9 Awm numjaiiw 2j% *q* ! 99PTT9 (4ftT - o**ouft4) ajttna ( mow*?** <9 jaunqs turns (* PP-OOftt PC-tt OC-PE PE-tt OE-Pt Pt-tT Ot-P P-0 PE X Oft 04-0P OP-ft cc-tc Pt-tt Ot-f 1-0 (tPftt - oooft*4J 0?tes 9fjq| UTiiinttu iuau9 3TiO*l * t t C j^OMuoa Pt-tt Of-P P-0 "TW1---------------------- rwj----------------- 999V kM wi irr onflfrn taruttk SUMS* JwOfPtM*) sm oor (HI ml Preliminary Anthology of Citations Concerning Benzene (Benzol) Exposure n the Rubber Industry 1900 - 1970 CONCERNING THE DEVELOPING INDUSTRIAL USE OF BENZENE: "The patient was... employed in coating metal rims with rubber solution in the manufacture of pneumatic tires. The use of benzene as a solvent commenced in January, 1918..." -- Legge (1920) "Up to 1914, comparatively little coal-tar benzene (benzol, CgHg) vas used in the United States. Because of its solvent properties, it has long been employed on the continent and to a less extent in England in the manufacture of rubber goods... (b)ut we had not begun to produce it ourselves; ve imported it from Germany, it was more than twice as expensive as the petroleum solvents, and ve therefore used the latter in the great majority of industrial processes. The outbreak of the war did two things: It shut off the supply from Germany... and it created a sudden demand for benzene and toluene for the manufacture of explosives... Then came the armistice, the sudden cessation of the manufacture of explosives, and the need for new markets for the great quantities of coal-tar distillates which were thrown back on the hands of the produces. These markets have been found in the rubber trade, usually for tires, footwear and hose... and as a substitute for gasoline motor car fuel." "Benzene, which is a much more powerful solvent than petroleum benzin[e] and naptha... is now below the latter in price, and the manufacturer has therefore a double (reason] to use it." "To the manufacturer, the introduction of this cheap and powerful solvent may seem an advantage, to the (art of medicine), interested in the producer more than the product, it can only seem a disastrous innovation..." -- Hamilton (1922) "It was not until the outbreak of the World War that benzol poisoning to an alarming extent manifested itself in the United States as a result of the wholesale production of benzene and its derivatives as by products of the benzol manufactured for war purposes." 000001321 SAL -2- "The demand for toluene for the manufacture of explosives during the World War lead to the development of many plants for its production. Along with this enormous production of toluol, benzol was produced in very large quantities, and because of the wholesale increase in the handling of benzol, cases of acute poisoning suddenly increased. By 1916 Alice Hamilton had already collected and reported 14 acute cases, with seven fatalities, in this country. At that time she placed benzene poisoning third on the list of industrial poisons." -- Greenburg (1926) "During the war the production of benzol was greatly stimulated by the demand for toluol along with which large quantities of benzol are commercially produced; a condition which has naturally led to its more wide spread use... in the anilin color industry, in the production of pharmaceuticals, and chemicals for the photographic industry, in addition benzol is used as motor fuel by blending with gasoline, and above all as an organic solvent in the rubber industry..." -- Final Report ...(1926) "In the present operative scheme of the rubber industry [benzol] is of vital importance, both as a solvent and as a drying agent... (f]rom the numerous substances that have been tried benzol and benzine (gasoline) appear to be the ones universally used today." Davis (1929). "Before 1914, the (coke-oven] light oil was of such slight interest that it was permitted to remain in the coal gas used for fuel. Coal-tar refining was limited to a relatively small scale, in proportion to the negligible demand for its products, since most of the tar derivatives at that time were manufactured in Germany, which served as the source of our supply. In the summer of 1914 when the allied blockade of Germany put an end to her export of these products, and with the critical need for aromatic hydrocarbons vital to the development of the new military explosives, attention was sharply focused on the utilization of the light oil and coal tar, which were then the only adequate source of benzene, toluene, phenol and other essential products. Equipment was installed and new plants erected to meet the heavy demands for light oil and tar derivatives." "The principal products obtained (from light oil] in relation to crude oil are motor benzine about 23 %, crude and refined benzene about 45%, toluene about 15%, xylene about 4%, solvent napthas about 3%, and miscellaneous refined products of salable value about SAL 000001322 -3- 9%. Following the greater demands for benzene so urgently needed during world War XX, the refined benzenes were produced in larger quantities than the motor benzine fraction, which in 1939 represented 50% of the crude light oil manufactured." -- Kellan (1957). "The invasion by Japan of those areas of the Orient which supplies the U.S. with most of our natural rubbers has reduced imports of this material almost to the vanishing point." when the war cut off our principle supply of natural rubber from the East Indies it was necessary to find a substitute to carry on the war successfully. The principle types of synthetic rubbers now manufactured in this country are buna S, buna N, butyl rubber and neoprene." -- Schwartz (1945) "The decreased supply of natural rubber and the manufacture of certain war materials has necessitated the use of synthetic rubber cements produced by dissolving these rubbers in organic solvents." -- Greenburg (1945) "Benzol and its homologues, as well as the chlorinated solvents, carbon tetrachloride and ethylene dichloride, are necessary solvents for the greatly increased amount of synthetic rubber now in use, since petroleum naptha will not adequately dissolve these materials". -- Thomas (1943) "Table 1 lists the solvents which are used most frequently with the synthetic rubbers... TABLE 1 Solvents Used with Synthetic Rubbers Solvent Used with Petroleum naptha Benzol Toluol Xylol Trichloroethylene Carbon tetrachloride Ethylene dichloride Propylene dichloride Methyl Ethyl Ketone Buna S, Butyl Neoprene Thiokols, Buna N Thiokols, Buna N Buna N" -- Greenburg (1945) SAL 000001323 -4- "Toluene is now allocated to special war purposes and benzene is once sore in common use in the rubber industry. He trust that adequate precautions will be taken and that vigilance will not be relaxed when toluene again returns to this Industry." "Bunas and butyl rubbers are the only common synthetic rubbers which are appreciably soluble in aliphatic hydrocarbons. If petroleum derivatives used for dissolving these rubbers contain aromatics, as many have been found to do, the suggested safe limit of 1000 ppm (for gasoline) must be scaled downward. -- Van Atta (1944) "The incidence of benzene intoxication in this country has been greatly reduced by the substitution of less toxic solvents in industries such as artificial leather, rubber products manufacture and printing. In our experience benzene as such is how rarely used in large quantities as an industrial solvent. Benzene is known, however, to be present in varying amounts in certain widely used and moderately volatile petroleum napthas. -- Pagnotto (1961) "The solvents used in the plant during the 1961 study were (petroleum) napthas containing 3% and 7.51 benzene. Solvents introduced subsequent to 1964 and currently used are methyl ethyl ketone, mineral spirits and toluene which have been found to be benzene free. -- Pagnotto (1979) II. CONCERNING RUBBER SOLVENT COMPOSITION: "It is important to take into account a possible confusion of names. Benzin(e) is a petroleum distillate, far less toxic than benzene. Another source of confusion is the use in industry of the term 'solvent naptha' to cover, not petroleum naptha, but a mixture of crude benzene, toluene and xylene." "The (fabric) coating mixture consisted at that time [1920] of nitrocellulose,... grain alcohol, benzene and ethyl acetate... The temperature of the (coating) machine is sufficient to evaporate all the solvent... The company had made tests of the air around the coating machines, for it was anxious to prevent the escape of the solvent, which it was trying to recover and use again. Something less than 5 per cent was reported to be the highest concentration of benzene found in the air and it is evident that the officials considered this amount too little to cause any anxiety." -- Hamilton (1922) SAL 000001324 -5- Benzol, synonym benzene, is CgH^.. e hydrocarbon derived by the dry distillation of coal tar... The commercial type contains toluol and xylol. Benzine is often confused with benzene or benzol; but benzine is derived from petroleua distillation and is not so poisonous.* -- Cronin (1924) "Firs 16 -- Manufacturers of benzol - blend gasoline motor fuel... Nervous disturbances and neurasthenia have been noted (in workers) and the firm has at tines been considerably worried as to the situation.* *The commercial uses of benzol rarely require that this substance be chemically pure. In practice three types of benzol are used in industry in addition to various other substances to which the nane benzol is applied although without chemical justification. The usual eosunercial produets are: Pure benzol -- a clear, colorless liquid of a characteristic odor. B.P. 80.2*C. Ninety-percent benzol so called because in the distillation of coal tar 90 percent distills over at a temperature less that 100*C. It is composed of 80-85% benzol, 13-15% toluol, 2-3% xylol and sometimes contains as impurities traces of olefins, parafins, sulphuretted hydrogen and other bodies. Fifty percent benzol -- The substance contains 50% of constituents which distill below 100'C; it is a highly mixed product, with only 40-50% benzol. The other substances often called benzols are various toluols, xylols and solvent napthas. Solvent Naptha - This material is called solvent naptha because it is used extensively (especially in England) for dissolving rubber, it is relatively free from benzol and consists largely of xylol, its homologues and other unknown hydrocarbons." -- Final Report...(1926) "[Benzol] presents a definite fire hazard and because of this fact, it has been combined with other volatile substances, chiefly carbon tetrachloride, which reduces the point of ignition..." -- Davis (1929) "In evaluating the results of the studies reported in this paper it must be borne in mind that other solvents had been substituted [in printing inks) for benzene when the use of the latter was discontinued [in 1938). The great bulk of the solvent material used consisted of various petroleum napthas covering a boiling range of about 150*F to 300*F." -- Goldwater (1941) Benzol and its homologues, as well as the chlorinated solvents, carbon tetrachloride and ethylene dichloride, are necessary solvents for the greatly increased amount 000001325 SM- of synthetic rubber now in use, since petroleum naptha will not adequately dissolve these materials". "fabric Coating - Solvents used for this work varied considerably...(f Jor natural rubber, petroleum napthas were used almost without exception, some toluene being incorporated in occasional formulas. Coatings of synthetic rubbers, however, require solution in the more toxic solvents. At the present time, benzol has been replaced largely by toluol or trade-name processed petroleums which contain a large proportion of toluol. Some synthetic coating mixtures were diluted with small amounts of petroleum napthas." "Balloon fabrication - Solvents used in cements for joining sections of balloon cloth were similar to those [for fabric coating]. Several solvent formulas were encountered including pure benzol, toluol-petroleum naptha mixture, and a mixture of a toluol substitute with carbon tetrachloride and a trace of carbon disulfide. The aromatics or aromatic-petroleum mixtures were most widely used... petroleum napthas were used as washes"... "Rubber Boat and Pontoon fabrication - During this survey, only gasoline or other petroleum napthas were -being used as washes and cement solvents, since the fabric coating was entirely of natural rubber." -- Thomas (1943) "Bunas and butyl rubbers are the only common synthetic rubbers which are appreciably soluble in aliphatic hydrocarbons. If petroleum derivatives used for dissolving these rubbers contain aromatics, as many have been found to do, the suggested safe limit of 1000 ppm (for gasoline) must be scaled downward. -- Van Atta (1944) "Smaller quantities of solvents, such as acetone, ethyl acetate [and butyl acetate] are being used in combination with better neoprene solvents in the manufacture of neoprene cements. Also used as solvents are the aromatic petroleum napthas type I such as Solvesso No. 1, Sovasol No. 73, Union No. 8 and Amsco A. These are essentially mixtures of toluene and petroleum naptha." -- Greenburg (1945) "Petroleum solvents ...were collected without any reference to their original suppliers in order to obtain an overall picture of the benzene content of napthas in current use... benzene ranged from 1.5 to 9.3% by weight" SAL Qooqox 326 7 TABLE 1 Benzene Content of Naptha Solvents Number of Solvents Analyzed Benzene % By Weight IS 6 11 -- Fagnotto (1961) 1.5- 2.S 2.6- 3.5 3.6- 9.3 ZZZ. CONCERNING INDUSTRY SUBSTITUTIONS FOR BENZOL SOLVENTS; "Alternatives to benzol were also considered... from the practical point of view it seems that the 'xylol compound* could be used as a rubber solvent with... very much less danger of causing aplastic anemia ... than benzene." -- Legge (1920) "Benzene, which is a much more powerful solvent than petroleum benzin(e) and naptha... is now below the latter in price, and the manufacturer has therefore a double [reason) to use it." "To the manufacturer, the introduction of this cheap and powerful solvent may seem an advantage, to the [art of medicine], interested in the producer more than the product, it can only seem a disastrous innovation..." -- Hamilton (1922) "...our laboratory investigations make it clear that certain of the higher homologues of benzene, such as Toluol, Xylol and Hiflash naptha, are relatively free from the special hazards which attend the use of benzene itself."' "Firm 5 - A rubber company using about 100 gallons of benzol per week,... [experiments were being made with a carbon tetrachloride - rubber cement to replace the present benzol [cement]." "The Committee stated 'that the serous attention of manufacturers now using benzol should be given to the possibility of substituting one of these [toluol, xylol or Biflash naptha] or other relatively harmless substances, wherever the conditions of a given manufacturing process make it possible to do so*." -- Final Report...(1926) SAL 000001327 8 "In the present operative scheme of the rubber industry (Benzol) is of vital importance, both as a solvent and as a drying agent... (f)rom the numerous substances that have been tried benzol and benzine (gasoline] appear to be the ones universally used today. Benzol is much aore toxic than benzine and Z believe that benzine will replace much of the benzol in use on certain operations in the rubber industry..." ~ Davis (1929) "In evaluating the results of the studies reported in this paper it Bust be borne in Bind that other solvents had been substituted (in printing inks] for benzene vhen the use of the latter was discontinued (in 1938]... The great bulk of the solvent material used consisted of various petroleum napthas covering a boiling range of about 150*F to 300#F." -- Goldwater (1941) "Fabric Coating - Solvents used for this work varied considerably...(f]or natural rubber, petroleum napthas were used almost without exception, some toluene being incorporated in occasional formulas. Coatings of synthetic rubbers, however, require solution in the more toxic solvents. At the present time, benzol has been replaced largely by toluol or trade-name processed petroleums which contain a large proportion of toluol. Some synthetic coating mixtures were diluted with small amounts of petroleum napthas." "this (fabric coating ventilation) system had been designed for the possible use of benzol as a rubber solvent, although toluol substitutes were being used at the time" ...the maximum concentration found was 150 ppm of combustable vapor, almost entirely petroleum naptha. This sample was obtained at the head of one (fabric coating) machine while the doctor (spreader] blade was being cleaned with gasoline ...In some plants the rubber suspension was fed to the doctor blade by hand from a pail... Average concentrations of combustible vapor in the workroom were about SO ppm... These results indicate the effectiveness of this (ventilation] system for controlling solvent vapors during fabric coating... it is felt that this system could be safely used with benzol" "Balloon Fabrication - Solvents used in cements for joining sections of balloon cloth were similar to those (for fabric coating). Several solvent formulas were encountered including pure benzol, toluol-petroleum naptha mixture, and a mixture of a toluol substitute with carbon tetrachloride and a trace of carbon disulfide. The aromatics or aromatic-petroleum mixtures were most widely used... petroleum napthas were used as washes"... -- Thomas (1943) SAL 00000132B -9- Toluene is now [1944] allocated to special war purposes and benzene is once sore in common use in the rubber industry. He trust that adequate precautions M will be taken and that vigilance will not be relaxed when toluene again returns to this industry." Bunas and butyl rubbers are the only common synthetic rubbers which are appreciably soluble in aliphatic hydrocarbons. If petroleum derivatives used for dissolving these rubbers contain aromatics, as many have been found to do, the suggested safe limit of 1000 ppm (for gasoline) must be scaled downward. ...solvents used in washing uncured sheets of compounded synthetic rubber are usually toxic... coal tar derivatives are the worst offenders (benzol, toluol)... -- Van Atta (1944) Smaller quantities of solvents, such as acetone, ethyl acetate, (and butyl acetate) are being used in combination with better neoprene solvents in the manufacture of neoprene cements. Also used as solvents are the aromatic petroleum napthas type I such as Solvesso No. 1, Sovasol Ho. 73, Union No. 8 and Amsco A. These are essentially mixtures of toluene and petroleum naptha." Unfortunately [solvent substitution to protect the health of workers) does not lend itself so readily to the problem of the synthetic rubbers, for as indicated earlier, each of these rubbers is soluble in only a limited number of solvents. We were involved in safeguarding the health of some 200 workers engaged in making fuel cells wherein benzol was extensively used as a solvent for neoprene. Fortunately this occured at a time when toluene was still readily available. He were able to recommend an immediate change to the use of toluene instead of benzol without waiting for the installation of proper ventilation. The problem of the use of benzol with synthetic rubbers now (1945) arises only in the use of synthetics soluble only in the aromatic hydrocarbons and when toluene is not available. However, here too it may be possible to find suitable solvents containing no benzol..." "The most recent cases we have encountered of the use of benzol in synthetic rubber cements have been in the manufacture of shoes... [w]e have found benzol in both types of cements -- unnecessarily, since Bunas will dissolve in petroleum naptha alone, and neoprene can be dissolved in one of the aromatic petroleum napthas which contain petroleum naptha and an aromatic hydrocarbon less toxic than benzol, that is, either toluene or xylene." -- Greenburg (1945) SAL 000001329 10 "The incidence of benzene intoxication in this country has been greatly reduced by the substitution of less toxic solvents in industries such as artificial leather, rubber products manufacture and printing, in our experience benzene as such is now rarely used in large quantities as an Industrial solvent. Benzene is known, however, to be present in varying anounts in certain widely used and moderately volatile petroleum napthas. -- Fagnotto (1961) "Rubber coated fabric is produced in this process. A rubber formulation is first prepared by churning rubberstock with solvents for several hours. The resulting homogenous mixture is then added to fabric using saturator and spreader machines. [t)he solvents used in the plant during the 1961 study were [petroleum) napthas containing 3% and 7.5* benzene. Solvents introduced subsequent to 1964 and currently used are methyl ethyl ketone, mineral spirits and toluene which have been found to be benzene free. -- Pagnotto (1979) IV. CONCERNING RUBBER INDUSTRY WORK PRACTICES EMPLOYING SOLVENTS: "The patient was... employed in coating metal rims with rubber solution in the manfuactuce of pneumatic tires. The use of benzene as a solvent commenced in January, 1918... " -- Legge (1920) "Harrington... reports five cases, with three deaths, from an automobile tire factory. These men were using benzene in building automobile tires, applying it by a cloth to the rubber." -- Hamilton (1922) "In the rubber industry benzol finds two exceedingly important uses. In rubber tire building the metal core on which the tire is built is usually painted with [benzol) rubber cement... In the further steps of tire building benzol is used in many plants. The layers of rubberized cord or cloth are carefully placed on the metal tire-building core, each layer being moistened with benzol prior to the application of the next layer of fabric. In addition to these two uses of benzol in the rubber industry there are of course, many others. In fact, this substance has found very wide use due to its excellent solvent properties for rubber." -- Greenburg (1926) "Preparatory to vulcanizing, the tires were wiped with a cloth which had been moistened with benzol, by means of a can so arranged as to deliver a specified amount of benzol on the cloth.' This process of moistening the cloth occurred about 18 times a day." -- Final Report... (1926) SAL 000001330 11 "In the operation known as Baking 'bends4 to be used in tire building, the girls stood at tables upon which lengths of rubberized canvas were spread; dipping a cotton swab on a stick in an open pan of benzol ' standing on a table beside then, they applied it to the material which they shaped on a drum and hung on a rack near at hand to dry. The women on this job used 6 to 7 quarts of benzol daily. Men worked at tire building in another part of the sane room and it was said that in the busy season 50 gallons of benzol were consumed there daily. The work room had very good general ventilation with windows on three sides, but no special ventilating devices to carry off benzol fumes were provided." "There were several jobs requiring the use of a benzol - rubber cement compounded of 1 pound of rubber to 1 gallon of benzol. One of these jobs was cementing the ends of short hose lengths. Here the worker stood before an open pan of cement into which she tipped the ends of the hose, which were then dried in the same room. As a rule she did 500 of these daily. In the same department benzol-rubber cement was used for applying rubber labels to hose and benzol was used freely for cleaning, in another department a woman standing before a long table applied the cement from an open bowl with her fingers to one edge of long strips of rubber to be made into hose, in all these cases general ventilation was good but no provision was made for local exhaust... The attitude on the part of the management toward the benzol hazard in this plant was distinctly casual and the medical department had no particular interest in it. No one seemed to be aware of the need for any precautions in its use except such as concerned the fire hazard." -- Smith (1926) "Skin absorbtion is very small except in those cases where the worker habitually washes his hands and arms in benzol to remove dirt and grease..." -- Davis (1929) "A solution of crude 'Duprene' (neoprene] in benzene is being used continuously in this laboratory (Haskell Laboratory of Industrial Toxicology, Wilmington DE] as rubber cement without giving rise to any (skin] irritation". -- Von Oettingin (1936) "this (fabric coating ventilation] system had been designed for the possible use of benzol as a rubber solvent, although toluol substitutes were being used at the time" ...the maximum concentration found was 150 ppn of combustable vapor, almost entirely petroleum naptha. This sample was obtained at the head of one SAL 000001331 12 (fabric coating) machine while the doctor (spreader] . blade was being cleaned with gasoline ...In some plants the rubber suspension was fed to the doctor blade by hand from a pail... Average concentrations of ' combustible vapor in the workroom were about 50 ppm... These results Indicate the effectiveness of this (ventilation] system for controlling solvent vapors during fabric coating. it is felt that this system could be safely used with benzol* "rinal balloon assembly required a few operators to work inside the partially inflated balloon applying finishing tapes and completing a few terminal seams... Vaporation of solvents ...in such (an unventilated] space may build up rapidly... (o)ver a period of 1 1/2 hours, concentrations of combustable vapor increased regularly to 450 ppm... (if] air was continuously fed ...at a rate of about 1000 cfm ... the concentration increased slowly to only 140 ppm. ...It can be calculated that without ventilation, [the] concentration of benzol within the balloon would have increased in the same length of time to about 350 ppm." -- Thomas (1943) "Styrene Manufacture -... The waste discharged from the reaction of ethylene and benzene (to make ethyl benzene] is a black tarry irritant substance. Therefore, workers handling this waste should also wear rubber gloves, impervious sleeves and aprons." "Rubber to be made into tubes is extruded through a tube shaped die, cut off into suitable lengths and cemented into circular tubes, workers engaged in this operation sometimes get dermatitis from the rubber cement, which consists essentially of rubber dissolved in a solvent. Workers at this operation who develop dermatitis should wear thin washable leather gloves and use a long handled brush for applying cement." -- Schwartz (1945) V. CONCERNING DERMAL CONTACT WITH RUBBER SOLVENTS: "Harrington... reports five cases, with three deaths, from an automobile tire factory. These man were using benzene in building automobile tires, applying it by a cloth to the rubber." "Ideally, strong suction exhaust should be installed at the point of origin of the toxic fumes; but how is this to be done in... spreading fabrikoid on textiles... or building automobile tires? The practical difficulties are insurmountable. The surface covered with benzene is [such] that no artificial exhaust can be so placed as to catch all fumes. Moreover, benzene passes through the skin as well as the respiratory tract." -- Hamilton (1922) SAL 00001332 - 13 - "In the rubber industry benzol finds two exceedingly important uses. Xn rubber tire building the metal core on which the tire is built is usually painted with (benzol) rubber cement... In the further steps of tire building benzol is used in many plants. The layers of rubberized cord or cloth are carefully placed on the metal tire-building core, each layer being moistened with benzol prior to the application of the next layer of fabric. In addition to these two uses of benzol in the rubber industry there are of eourse, many others. Zn fact, this substance has found very wide use due to its excellent solvent properties for rubber.* -- Greenburg (1926) "Preparatory to vulcanizing, the tires were wiped with a cloth which had been moistened with benzol, by means of a can so arranged as to deliver a specified amount of benzol on the cloth. This process of moistening the cloth occurred about 18 times a day.* "In Harrington's study of 120 men employed in tire building, a tire builder stated that 16 to 18 men employed in his department had developed similar lesions to his own. The worker in question had been employed for two years but during the last three months a papular eruption had appeared on his arms, feet and neck. These lesions disappeared when naptha (presumably petroleum naptha) was substituted for benzol." -- Final Report...(1926) "In the operation known as making 'bends' to be used in tire building, the girls stood at tables upon which lengths of rubberized canvas were spread; dipping a cotton swab on a stick in an open pan of benzol standing on a table beside them, they applied it to the material which they shaped on a drum and hung on a rack near at hand to dry. The women on this job used 6 to 7 quarts of benzol daily." "There were several jobs requiring the use of a benzol - rubber cement compounded of 1 pound of rubber to 1 gallon of benzol. One of these jobs was cementing the ends of short hose lengths. Here the worker stood before an open pan of cement into which she tipped the ends of the hose, which were then dried in the same room. As a rule she did 500 of these daily... In the same department benzol-rubber cement was used for applyng rubber labels to hose and benzol was used freely for cleaning. In another department a woman standing before a long table applied the cement from an open bowl with her fingers to one edge of long strips of rubber to be made into hose." -- Smith (1928) SAL 0000013B3 - 14 - Skin absorbtion is very small except in those cases where the worker habitually washes his hands and arms in benzol to remove dirt and grease..." -- Davis (1929) "A solution of crude 'Duprene* (neoprene] in benzene is being used continuously in this laboratory (Baskell Laboratory of industrial Toxicology, Wilmington DC] as rubber cement without giving rise to any (skin] irritation". -- Von Oettinger (1936) *this (fabric coating ventilation) system had been designed for the possible use of benzol as a rubber solvent, although toluol substitutes were being used at the time" ...the maximum concentration found was 150 ppm of combustable vapor, almost entirely petroleum naptha. This sample vas obtained at the head of one [fabric coating) machine while the doctor (spreader] blade vas being cleaned with gasoline ...in some plants the rubber suspension vas fed to the doctor blade by hand from a pail... Average concentrations of combustible vapor in the workroom were about 50 ppm... These results indicate the effectiveness of this [ventilation] system for controlling solvent vapors during fabric coating... it is felt that this system could be safely used with benzol". -- Thomas (1943) "Styrene Manufacture ... The waste discharged from the reaction of ethylene and benzene (to make ethyl benzene) is a black tarry irritant substance. Therefore, workers handling this waste should also wear rubber gloves, impervious sleeves and aprons." Rubber to be made into tubes is extruded through a tube shaped die, cut off into suitable lengths and -cemented into circular tubes, workers engaged in this operation sometimes get dermatitis from the rubber cement, which consists essentially of rubber dissolved in a solvent. Workers at this operation who develop dermatitis should wear thin washable leather gloves and use a long handled brush for applying cement." -- Schwartz (1945) "The final rubber coat is applied by the spreading or coating machine. Here a fairly heavy rubber mix is added to the fabric with a ladle or by gravity feed. Frequently the feed stock has a bread dough consistency and the worker is able to handle the mix with cupped hands." -- Pagnotto (1961) SAL 000001334 - 15 - VI. CONCERNING HEASURED LEVELS OF BENZENE ZN AIR: "The patient was... employed in coating metal rims with rubber solution in the manufacture of pneumatic tires. The use of benzene as a solvent commenced in January, 1918... The firm's chemist made determinations of the amount of benzol... in the (large) spreading room (where the workman was employed. These values ranged from 210 to 1050 ppm) Immediate steps were taken to protect the workers on tire manufacture... a fan... was installed and a sample of air with the windows opened but with the fan stopped showed [2800 ppm] benzol... while with the fan running, a sample taken as near as 18 inches from the work performed shoved only (800 ppm}. The result in both cases was satisfactory in that no further cases (of acute poisoning] occurred. -- Legge (1920) "The (fabric] coating mixture consisted at that time [1920] of nitrocellulose,... grain alcohol, benzene and ethyl acetate.. The temperature of the (coating] machine is sufficient to evaporate all the solvent... The company had made tests of the air around the coating machines, for it was anxious to prevent the escape of the solvent, which it was trying to recover and use again. Something less than 5 per cent was reported to be the highest concentration of benzene found in the air and it is evident that the officials considered this amount too little to cause any anxiety." "Recently I was consulted by a large industrial establishment as to the possible danger of exposing men and women to air containing one part of benzene in 200 parts of air, and at times one part in 100." --Hamilton (1922) "Zn the spreader room the fumes of benzene were always heavy, the 35 workers complained bitterly about it... It was surprising to me that they were able to work in the atmosphere at all; for, when Z went into the room, Z usually became dizzy and felt a constriction of my chest. Around the machines, the fumes were sometimes so strong that they made me gasp for fresh air. New employees would be dissatisfied with the work and leave after a few weeks... Zn our spreader room, there was an exhaust that was poorly designed and ineffective." -- Cronin (1924) "Our completed field studies covered 18 different workrooms fairly representative of the conditions under which benzol is used in the rubber, patent leather, and artifical leather industries, in wire insulating, dry cleaning and sanitary can manufacture." SAL 000001335 16 - "With small amounts of benzol in use and with no ventilation, or general ventilation only, (which our studies indicate is wholly inadequate to cope with the benzol problem), ve found average concentrations of 100 to 1360 Ippm benzol). With large amounts of benzol in use under similar conditions, we found average values from 220 to 1600 ppm. On the other hand, in plants using large amounts of benzol but with enclosed systems or local exhaust ventilation, ve found averages only between 70 and 500 ppm. The plant which had the most efficient systems of local exhaust gave us average values lying between 70 ppm in summer and 90 ppm in winter." "...in practice, systems of exhaust ventilation capable of reducing the concentration benzol in the atmosphere below 100 ppm are extremely rare..." -- Final Report...(1926) "Mention has already been made of the wide range (11-1060 ppm) of vapor concentrations that prevailed during the period of benzene exposure. Inasmuch as no radical changes in ventilation or in operating practice were made following the elimination of benzene (in the NY rotogravure printing industry) no great difference in vapor concentrations could have been expected. The few air analysis made confirmed the expected findings.* -- Goldvater (1941) "this [fabric coating ventilation] system had been designed for the possible use of benzol as a rubber solvent, although toluol substitutes were being used at the time" ...the maximum con'centration found was 150 ppm of combustable vapor, almost entirely petroleum naptha. This sample was obtained at the head of one [fabric coating] machine while the doctor [spreader) blade was being cleaned with gasoline ...In some plants the rubber suspension was fed to the doctor blade by hand from a pail... Average concentrations of combustable vapor in the workroom were about 50 ppm... These results indicate the effectiveness of this [ventilation] system for controlling solvent vapors during fabric coating... it is felt that this system could be safely used with benzol" "Balloon Fabrication - Solvents used in cements for joining sections of balloon cloth were similar to those (for fabric coating). Several solvent formulas were encountered including pure benzol, toluol-petroleum naptha mixture, and a mixture of a toluol substitute with carbon tetrachloride and a trace of carbon disulfide. The aromatics, or aromatic-petroleum mixtures were most widely used... petroleum napthas SAL 000Q01336 - 17 vert used as washes*... In one plant area where ventilated tables in were used, table cementers had no exposures to benzol above 20 ppm, their average and peak exposures being that of the general room air in the table cementing area, i.e. 10 to 20 ppm. Vapor concentration in the air entering the [table] ventilating slot was up to 300 ppm. In another area, however, where the ventilating installation had not been completed, operators had an average exposure while cemeting of 60 to 70 ppm benzol, with peak exposures of about 175 to 200 ppm." "Final balloon assembly required a few operators to work inside the partially inflated balloon applying finishing tapes and completing a few terminal seams... Vaporation of solvents ...in such [an unventilated] space may build up rapidly...[ojver a period of 1 1/2 hours, concentrations of combustable vapor increased regularly to 450 ppm... [if] air was continuously fed ...at a rate of about 1000 cfm ... the concentration increased slowly to only 140 ppm. ...It can be calculated that without ventilation, [the] concentration of benzol within the balloon would have increased in the same length of time to about 350 ppm." "Rubber Boat and Pontoon Fabrication - During this survey, only gasoline or other petroleum napthas were being used as washes and cement solvents, since the fabric coating was entirely of natural rubber. Therefore no [air] samples were taken." -- Thomas [1943) "Bunas and butyl rubbers are the only common synthetic rubbers which are appreciably soluble in aliphatic hydrocarbons. If petroleum derivatives used for dissolving these rubbers contain aromatics, as many have been found to do, the suggested safe limit of 10CC ppm (for gasoline) must be scaled downward." -- Van Atta (1944) "Where relatively non-toxic solvents, such as petroleum naptha*. are used, it is often possible to use general ventilation in workrooms of fairly large size in maintaining the concentration of vapors at the comfort level" SAL 0O00l337 18 Table II General Ventilation Requirements Solvent Suggested Approx. Flax. Permissible Concentration for Prolonged Exposure [Vol. of Dilution Air Required to Achieve Permissible Vapor Level from One Gallon of Solvent (ftJ)) Petroleum Naptha (as hexane) 1000 ppm 25,000 Benzol 50 700,000 Toluol 400 75,000 -- Greenburg (1945) "Although in each of these plants the saturator machines had enclosed and mechanically exhausted dryers, the operator's exposure to naptha solvent vapors from the highly diluted [rubber) mix generally used in this process was found... to be as high as 1500 ppm. The benzene content of the napthas in use were 6.2 and 9.3% by weight... (o]n one occasion the concentration of benzene vapor was as high as 125 ppm.** "Benzene concentrations in the churn (mixer) rooms were somwhat lower than one would expect from the urinary phenol values found on the churn men. This can be explained by the fact that it was not always possible to be on hand to make air tests of such activities... done intermittently... Readings of 900, 500 and 350[ppm naptha vapors) at the top of the tub level, breathing level of the operator, and floor level respectively were reported in one plant and these are typical findings." -- Fagnotto (1961) "Spreader and saturator operators made good subjects because their solvent exposure did not usually fluctuate markedly during a work-run." "[The saturator operator] was on this job in 1957 and was still performing his task in 1977. From his urine phenol values it was determined that his average benzene exposure (from 3 to 7.5% benzene containing petroleum napthas] was frequently above 25 ppm... and as high as 90 ppm... Air tests on the saturator taken during 8 plant visits between 1960 and 1964 (range from 10 to 140 ppm)... Although [the 10 to 30 min samples] do not represent time vighted averages, it is clear the worker experienced extremely high benzene exposures." SAL 000001338 19 "Benzene exposures measured by (urinary phenol values in churn men] ranged from 10 to 60 ppm." "Air tests taken on spreader operators showed that benzene exposures ranged from 5 to 39 ppm... Air test findings agree with phenol results... which indicate average benzene exposures were usually below 40 ppm". -- Fagnotto (1979). SAL 0000l339 Bibliography Arp. E.W., et al., "A Retrospective Assessment of Solvent Exposure ancFthe Relationship to Lymphatic Leukemia," Presented at the Southeastern Occupational Health and Safety Conference, Hilton Head, S.C., November 9-11, 1978. Cronin, H.J., "Benzol Poisoning in the Rubber Industry," Boston K&5 J., 1164 Dec. 18, 1924. Davis, P.A., "Toxic Substances in the Rubber Industry - Benzol," The Rubber Age, July 10, 1929, p. 367. rinal Report of the Committee on Benzol, National Safety Council, Chemical and Rubber Sections, National Bureau of Casualty and Surety Underwriters, Kay 1926. Goldvater, L.J., M.F. Tewksbury, "Recovery Following Exposure to Benzene (Benzol)*," J. Ind. Hyg. t Tox. 2^, 217 (1941). Greenburg, L., "Benzol Poisoning as an Industrial Hazard," Public Health Reports, 4^, 1357 (1926). Greenburg, L. S. Koskowitz, "The Safe Use of Solvents for Synthetic Rubbers," Ind. Ked. 1_4, 359 (1945). Hamilton, A., "The Growing Kenace of Benzene (Benzol) Poisoning in American Industry," JAHA 78, 627 (1922). Legge, T.K., "Chronic Benzol Poisoning," J. Ind. Hyg. 1, 539 (1920). HcKichael, A.J., et al., "Solvent Exposure and Leukemia Among Rubber Workers: An Epidemiologic Study," J. Occ. Ked. 17:234-239 (1975). (OSHA docket * B059a, document I 64.B-8). Mellan, I., "Handbook of Solvents," Reinhold Pub. Corp. New York, 1957. Pagnotto, L.D., H.B. Elkins, H.S. Brugsch, J.E. Walker, "Industrial Benzene Exposure from Petroleum Naptha: I Rubber Coating Industry," Amer. Ind. Hyg. J. 22, 417 (1961). Pagnotto, L.D., H.B. Elkins, H.G. Brugsch, "Benzene Exposure in the Rubber Coating Industry - a Follow-up," Amer. 2nd. Hyg* J. 40, 137 (1979 ). Smith, A.R., "Chronic Benzol Poisoning Among Women Industrial Workers: A Study of the women Exposed to Benzol Fumes in Six Factories," J. Ind. Hyg. 10, 73 (1928). $al. -2- Schwartz, L., "Skin Hazards in the nanufaeture and Processing of Synthetic Rubber," JAJIA 122* 389 (1945). Thomas, T.R., B.D. Tebbens, "Control of Solvent Exposures in the Rubber Industry," Ind. Red. 12, 255 (1943). Van Atta, F.A., A.K. Noyes, "Industrial Hygiene Problems in the Synthetic Rubber Industry," Xnd. Red. ^3, 354 (1944), Von Oettingin, W.r., W. Deichmann-Gruebler, "The Toxicity and Potential Dangers of Crude Duprene," J. Znd. Hyg. & Tech. 18, 271 (1936). -- S*L 0013<H APPENDIX C SAL 000001342 Prepared by American Petroleum Institute Case-Control Analysis of Ott, et al. Cohort -To investigate whether the Ott, et al. cohort presented good evidence for a relationship between increasing exposure to benzene and increasing risk of leukemia, a conditional logistic regression was performed on the Ott, et al. data set available in the OSHA benzene record {Docket H-059B Ex. 173). The analysis involved three different sets of cases. The first set included the two cases from the original Ott, et al. study where the death certificate showed leukemia as the underlying cause of death. The second set added the individual from the original study who had leukemia noted as an "other significant condition." The third set included all five leukemias described in the draft update submitted by Dow (Docket H-059C, Ex. 201-28). 1/ The analysis followed the same procedure used by Rinsky, et al. (1985) (Doc. H-059B, Ex. 176) to evaluate the results of the NIOSH Pliofilm cohort. Specifically, for each of the three data sets in the Ott cohort described above, ten con trols were matched to each case based on date of birth and 1/ The fifth leukemia case, described on p. 6 of the Dow submission was not included in the data set available from OSHA. Fortunately, the Dow draft provided enough detail on the individual to permit matching and analysis. gOOOOl^^ sM- -2- data of first employment in a benzene exposure job. 2/ The cumulative benzene exposure was computed for each cohort member using the Ott, et al. estimates of benzene exposure level and the original researcher's designations of jobs as high benzene exposure to very low benzene exposure. 3/ Table 1 reports the results of the conditional logistic regression analyses for the three sets of data. Table 1 Set Analyzed Original Study (2 cases) Original Study (3 cases) Update (5 cases) 6 -0.0114 -0.0092 0.0030 D-value .6143 .6062 .5137 Std. Error .0226 . 0178 .0045 In each case, the beta value is highly non-significant (all p-values are greater than 0.5), indicating that no sta tistically significant relationship exists between increas ing cumulative benzene exposure (according to the Ott, et al. estimates) and increased risk of leukemia. The results 2/ The controls were picked only from the OSHA data set, which does not contain information and new individuals found in Dow's study update. 3/ The maximum estimated cumulative exposure for the cohort was 870 ppm-years, about seven times as high as the assumed level of 125 ppm-years used in the White, et al. risk assessment. sAL OOOOOI344 3 of this analysis would change somewhat if the data set from the full Dow study update was used for matching, although judging from the high p-values obtained in this analysis it is unlikely that a significant relationship would be obtained. > SAL OOOOO1345 APPENDIX d SAL 00000X346 A STATISTICAL ANALYSIS OF THE RINSKY DATA SET ON BENZENE EXPOSURE Vernon M. Chlnchllll, Ph.D. Department of Biostatistics, Box 32 Medical College of Virginia Virginia Commonwealth University Richmond, Virginia 23298-0001 March 21, 1986 0000013VT SAL 1. INTRODUCTION This report concentrates on the case-control study conducted by Rlnsky, et al. (1985) for assessing the risk of leukemia due to benzene exposure. The / cohort considered by Rlnsky, et al. consists of exposed, non-salarled employees of rubber hydrochloride plants at two locations in Ohio. Rlnsky, et al. (1985) classified a worker as exposed If he/she experienced at least one ppm-day of benzene exposure prior to December 31, 1965. The Rlnsky cohort is a very valuable epidemiological data set for assessing the risks of benzene exposure because It provides an estimate of exposure for each Individual In the cohort. Classical epidemiological analysis is very crude In comparison, as usually exposure Is categorized as yes/no or as one of k levels (such as none, low, medium, and high). In many Instances categorical data may be all that Is available. However, when exposure Is measured on a continuum for each Individual In the study, categorization results In a loss of precision and reliability. 2. LOGISTIC REGRESSION There are a variety of models to determine how a continuous measurement of exposure affects the response outcome of disease status. One reliable approach, and certainly the most popular. Is logistic regression (Cox 1970). Logistic regression is analogous to multiple regression/analysis of variance. In the latter case a continuous response variable is expressed as a linear function of some predictor variables, whereas In logistic regression the response variable Is dichotomous (such as diseased or not diseased) and the logit function of the probability of response Is expressed as a linear function of some predictor variables. In particular, let X [X, ... Xk]' denote the vector of k predictor variables. Let p9 denote the probability that an Individual becomes a case 2 SAL 000001348 for the situation when X * x. Then the probability logit Is modeled as a linear function of x, l.e., l09(Fp~] * + " + Mi* [1] where A0, A,, ... , Afc are unknown parameters estimated from the data set. A statistical test of the hypothesis that A; 0 reveals whether the j,h predictor variable, 1 i j c k, significantly affects the probability of response pB. 3. PROPORTIONAL HAZARDS REGRESSION If the response variable Is measured In terms of time to death due to the disease, rather than presence/absence of disease, then another class of models can be used to model the effects of exposure. An Individual who has not died at the end of the study or who has died of other causes Is considered a censored observation. Regression models for survival data of this type can Incorporate the partial Information from censored observations. The proportional hazards regression model. Introduced by Cox (1972), Is a nonparametrlc model which only assumes that the hazard functions are proportional for different realizations of the vector of predictor variables X. The hazard function x(t) represents the Instantaneous rate of death due to disease at time t, conditional upon survival to time t. The proportional hazards regression model Is expressed as x(tiX x) x,,(t)exp(p,x, + ... Ml,), [2] where x(tiX * x) Is the hazard function evaluated at time t for the realization x of the predictor variables X, x0(t) Is some unknown baseline hazard function evaluated at time t, and At* ... , Ak are unknown parameters estimated from the data set. As before, a statistical test of the hypothesis that Aj - 0 reveals whether the jth predictor variable, 1 t j * k, significantly affects the hazard function. 3 SAL 000001349 4. REDUCTION OF BIAS IN RETROSPECTIVE STUDIES It might appear that a straightforward application of either logistic regression or proportional hazards regression to the Rlnsky cohort Is appropriate. The vector X of predictor variables could consist of cumulative benzene exposure (ppm-years), peak benzene exposure (ppm-days), age of first employment, date of first employment, etc. However, there Is another Issue to be considered before such steps are undertaken. Most case-control studies are observational by nature. In the sense that Individuals are not randomly allocated to different exposure levels, but rather the individual exposure levels are determined retrospectively from medical and/or work records. Therefore, case-control studies contain bias from non-random assignment to levels of exposure (Cochran 1965). This bias prevents a precise and reliable statistical analysis. Several methods have been proposed for eliminating or reducing bias in observational studies (Cochran and Rubin 1973, Rubin 1977, and Rosenbaum 1984). Two widely-accepted approaches are analysis of covariance (ANCOVA) and matching. An ANCOVA approach in a logistic regression or proportional hazards regression setting requires that covariables, such as age, race, sex, diet, etc., be included along with exposure In the models given by equations [1] and [2]. An alternative approach to this Is matching. In which k U 1) controls are matched to each control with respect to the covarlables. The purpose of the matching Is to arrive at a set of controls that are very similar to the case, except possibly for exposure. Unlike ANCOVA In which all members of the cohort are Included In the analysis, a matched analysis is applied to the reduced data set of cases and matched controls. One approach Is not uniformly better than another, l.e., each study needs to be evaluated separately In terms of whether ANCOVA or matching Is more SAL 000001350 4 appropriate. In order for ANCOVA to be effective, a large pool of possible covariables Is needed from which an appropriate subset of covariables Is determined. Matching with respect to a few covariables has a tendency to balance out the effect of other unmeasured covariables, so that matching may yield a more reliable analysis when few covariables are available. On the other hand, a matched analysis uses only a portion of the Individuals In the cohort. A great deal of care and effort Is needed In conducting a matched analysis to ensure that the matching criteria do not Introduce any new biases due to analyzing only a portion of the cohort. Excluding the Information from work histories, there are few covariables available In the Rlnsky cohort, so It is best to conduct a matched analysis which uses only the cases and their matched controls. It has been documented that there Is no added benefit to matching more than five or six controls for each case (Klelnbaum, Kupper, and Morgenstern 1982, pp. 396-397). Rlnsky, et al. (1985) matched ten controls (probably because of the small number of cases) to each case according to date of birth and date of first employment. Also, Rlnsky, et al. (1985) required that a matched control be alive at the time of the death of the case. A discussion of the Rlnsky matching criteria Is presented In section 6 of this report. In a matched case-control data set, the similarity of a case and its controls within each stratiAi Is not accounted for In either logistic regression or proportional hazards regression. Conditional logistic regression, however. Is a version of logistic regression which does accomodate this. The Importance of conditional logistic regression In matched casecontrol studies only recently has been recognized. Examples and statistical derivations are provided by Breslow and Day (1980, chapter 7) and Klelnbaum, Kupper, and Morgenstern (1982, chapters 18 and 24). Analogously, stratified 5 SAL 000001351 proportional hazards regression Is a version of proportional hazards regression which accomodates a matched case-control data set (Kalbflelsch and Prentl.ce 1980, section 4.5). In the current situation In which each stratum represents a case and Its matched controls, conditional logistic regression and stratified proportional hazards regression yield the exact same results. 5. INCONSISTENCIES IN THE COHORT AND THE CASE-CONTROL STUDY There is much confusion as to how the Rlnsky cohort was established and how matched controls were selected from this cohort. The original cohort, as analyzed by Crump and Allen (1984), consisted of 1868 workers from the rubber hydrochloride plants at two locations In Ohio. When attempting a standard mortality ratio (SMR) analysis on the white males, Rlnsky, et al. (1985) listed the number of workers In this cohort as 1291. Apparently they arrived at this number by eliminating 577 workers whose estimated exposure was zero or whose first exposure occured after December 31, 1965. Although this report does not address the SMR analysis In any detail, It Is felt that the reduction from 1868 workers to 1291 workers was inappropriate, especially because Crump and Allen (1984) considered every worker to have some benzene exposure. In the next step prior to the SMR analysis, Rlnsky, et al. (1985) arrived at a cohort of 1196 workers by eliminating 95 of the remaining 1291 workers as follows: (1) 66 for being female; (2) 13 for being non-white; (3) 2 for net reaching the minimum exposure; (4) 13 for having date of death prior to January 1, 1940; (5) 1 for having work histories prior to the exposure period. However, Rlnsky, et al. (1985) used the original cohort of 1868 workers for selecting a matched case-control set of 99 white males (9 cases and 90 matched controls). Sixteen of the 90 selected controls were not members of the cohort of 1196 and were estimated as having zero exposure. Rlnsky, et al. (1985) should have been consistent In their use of the cohort by using the same data SAL 000001352 6 set for the SMR analysis and the case-control analysis. In the copy of the data file of the 1291 Individuals, received via the Freedom of Information (FOI) request, 13 Individuals are listed as unknown with respect to sex and 569 (Including one leukemia victim) are listed as unknown with respect to race. The date on this file is October 3, 1985 (two months later than the report by Rlnsky, et al. 1985), so It Is likely that API was not sent an outdated version of the data file. Yet Rlnsky, et al. (1985) assumed all these "unknown" Individuals to be white males. The reviewer had no other recourse but to follow suit. In order to conduct a thorough analysis of the entire cohort, the reviewer needed the entire data file on the 1868 workers. Only the file on the subset of 1291 was received from the FOI request, so the data tape on 1868 workers, used by Crump and Allen (1984), was merged with the data on this subset of 1291 workers. Unfortunately, this data tape was constructed In 1981, so the work records on It have not been updated to the same degree as the work records for the subset of 1291 workers. Again, the reviewer had no choice but to use this merged data set on the 1868 workers. 6. COWENTS ON THE RINSKY MATCHING CRITERIA As discussed earlier, the purpose of matching In retrospective case-control studies Is to remove some of the bias and to make the estimates of risk more precise. Matching accomplishes this by selecting controls which are very similar to the case, except possibly for exposure. Rlnsky, et al. (1985) matched controls with cases according to date of birth and date of first employment. Also, the matched controls were selected from those workers alive at the time of death of the case, which ensures an appropriate latency period for the controls. The level of matching used by Rlnsky, et al. (1985) Is Inadequate because the controls may not be very similar to the cases. For 7 sal 000001353 example, one particular leukemia victim worked 20 years, whereas five of his matched controls worked for very brief periods at either location (1 day, 2 weeks, 1 month, 4 months, and 5 months). There are two problems with these matched controls. The first Is that some of them worked at location 1, so that they may differ from the case In terms of regional and geographic effects. The locations are 200 miles apart and one of them Is much more Industrialized than the other, so that exposure to other toxic chemicals is not constant across locations. Secondly, the controls with such short durations of employment may differ from the case In terms of socio-economic status, lifestyle, etc., as they may have moved on to other occupations and/or salaried positions. In order to eliminate the geographic differences between cases and controls, location should have been used as an additional criterion for matching. The second problem Is more difficult to handle. Information on socio-economic status and lifestyle Is not available for members of the cohort, so a surrogate variable Is needed. The only possible surrogate Is duration of employment (or equivalently, dates of first and last employment). Matching on duration of employment provides an Important view of benzene's relationship with leukemia. However, duration of employment also might be a surrogate for exposure, so its use as part of the matching criteria Is not ideal. * Finally, there appear to be some discrepancies In the work histories of three of the cases when the data tape and the hard-copy of the work records are compared. The reviewer In this Instance assumed that the hard-copy records are accurate, so that the estimates of exposure for these three cases differ slightly than those obtained by Rlnsky, et al. (1985) and by Crump and Allen (1984). s*l ooo01354 8 7. STATISTICAL ANALYSES USING CONDITIONAL LOGISTIC REGRESSION Three different exposure matrices were Implemented In the statistical analyses, as suggested by the American Petroleum Institute (API). These are described below. Exposure Matrix # 1: This Is the Rlnsky, et al. (1985, Appendices 3 and 4) exposure matrix. A few minor alterations In the Rlnsky exposure estimation were Imposed, In that all departments, except for departments 3 and 52 (the dry-side workers), were assigned exposure. Rlnsky, et al. (1985) did not assign exposure to workers In departments 3, 4, 5, and 52. Including departments 4 and 5 did not cause a significant change In the exposure estimates. Also, there were a few discrepancies between the tables of Appendices 3 and 4 of the Rlnsky, et al. (1985) manuscript and the hard* copy of the tables received via the FOI request. The reviewer proceeded as If the manuscript contained the correct estimates. Exposure Matrix # 2; This Is the Crump and Allen (1984, Tables B5 and B6) exposure matrix. Exposure Matrix # 3: This is the revised Crump and Allen (1984, Appendix B) exposure matrix. In which Crump and Allen downgraded some of the exposure estimates from Exposure Matrix # 2. Rlnsky, et al. (1985) truncated the work histories of the matched controls at the time of death of the cast. This results In an underestimation of the exposure experienced by the controls In the case-control study. The reviewer did not feel justified In following this procedure, so that the exposure estimates reported here for some workers In the case-control study are higher than what Rlnsky, et al. (1985) used. An analysis based on the truncated work histories Is briefly discussed In section 8 of this report. An attempt was made to Incorporate Into the analysis the exposure from SAL 000001355 9 non-pliofilm work histories at location 2 (API found no evidence of such exposure at location 1). From the FOI request, the non-pliofilm work histories were obtained on 225 deceased workers out of the 824 workers at location 2. Unfortunately, It Is not possible to conduct a thorough analysis with such Incomplete data. However, some conjectures are made about the non-pliofilm exposure and analyses are discussed In section 8. Ideally, dermal exposure and exposure from jobs outside these manufacturing plants also should be incorporated, but such records do not exist. In conjunction with the different exposure matrices. It Is also possible to revise the selection of the matched controls for the case-control study. Four different sets of controls were generated as follows. In each set, the matched controls were alive at the time of death of the case. Control Set # 1: This Is the set of 90 matched controls selected by Rlnsky, et al. (1985). Control Set # 2: This Is a set of 90 matched controls selected according to the matching criteria used by Rlnsky, et al. (1985), l.e., date of birth and date of first employment. Control Set # 3: This Is a set of 90 matched controls selected according t to location, date of birth, and date of first employment. Control Set # 4: This Is a set of 90 matched controls selected according to location, date of blrtfr, date of first employment, and date of last employment. The use of different control sets attempts to overcome some of the problems In the Rlnsky analysis, such as Inadequate matching criteria. Control Set # 2 served as a check on the results of Rlnsky, et al. (1985). Conditional logistic regression analyses were applied to various combinations of exposure matrices and control sets. A number of variables 10 SAL 000001356 were employed alone and In combination to determine which. If any, were significantly correlated with the Incidence of leukemia: cumulative exposure (ppm-yrs), peak exposure on any given day (ppm-days), duration of exposure, rate of exposure, the log of the cumulative exposure, the square of the cumulative exposure, and various interaction terms. In all Instances either the cumulative exposure by Itself or the log cumulative exposure by Itself provided the best fitting model. Peak exposure by Itself usually was marginally significant, but In a multiple model with cumulative exposure or the log cumulative exposure It was not significant. Along with the mean estimates of cumulative benzene exposure for cases and controls. Table 1 lists the beta estimates, standard errors, and p-values for the model with cumulative exposure applied to the 12 combinations of exposure matrices and control sets. The odds ratio provides a natural measurement for assessing the effects of exposure. It Is easily defined from the conditional version of the model In equation [1] as P /1~P OR, m p /i-p " +***+fkXfc), [3] where p, represents the probability of a case given the situation X = x and ptt represents the probability of a case given the situation X - 0 (l.e., zero exposure). Using the estimate of p, - 0.00707 (White, Infante, and Chu 1982), pB can be determined from equation [3] as P, " P,*0R#/{(l-p,) + (p,*0R.)}. [4] Table 2 lists estimated values and 95% confidence intervals for OR, and p, at 4.5, 45, and 450 ppm-years cumulative exposure. Again, only the model with cumulative exposure is presented, as the model with the log cumulative exposure exhibited much more instability In the estimates of OR, and p, at 450 ppm-yrs of exposure. The Increase in risk over background can be found as pB 11 SAL 000001357  pt p, - 0.00707. A risk assessment based on p,, - p. Is equivalent to using a logit model (which does not differ very much from the probit model), whereas previous authors, such as White, Infante, and Chu (1982) and Crump and Allen (1984), used linear models which are additive. There has been much controversy In the literature as to which models are appropriate for risk assessment. Linear models generally behave well when an extrapolation to a low-dose region Is necessary. In this particular study, however, there is only Interpolation within the observed dose region. Also, the conditional logistic regression model should provide a more accurate and reliable model because the exposure estimates are not categorized as In the models used by the above authors. 8. DISCUSSION It should be noted that the confidence Intervals for the odds ratio are very large when the exposure Is 450 ppm-years. This Is because 450 Is In the upper tall of exposure measurements, especially when the Rlnsky, et al. (1985) method of exposure was used (Exposure Matrix # 1). Therefore, the estimates of risk In terms of pB are not reliable at 450 ppm-years of cumulative exposure. However, 4.5 and 45 ppm-yrs exposure (corresponding to 1 and 0.1 ppm-years exposure per year for 45 years, respectively) are within the middle portion of exposure levels, and the confidence Intervals reflect this as they are very tight. Also, at 4.5 and 45 ppm-years exposure, the estimation of risk in terms of p, Is considered an Interpolation rather an extrapolation. So assuming that the exposure estimates are accurate and that the cohort and matched controls have been properly defined, the estimate of pB and Its 95X confidence Interval are reliable. Notice that the significance of the beta coefficient Is evident (p-value ^ 12 SAL 000001358 0*05) In all situations except one. Even when matching for duration of employment (Control Set # 4), cumulative exposure Is significantly related with le* ukemia Incidence. Also notice that the estimates of the beta parameter among Control Sets 1, 2, and 3 do not change very much for a particular Exposure Matrix. In this reviewer's opinion. Control Sets 3 and 4 are the ones that should be considered. It was mentioned In a previous section how Rlnsky, et al. (1985) truncated the work histories of the matched controls. For the sake of comparison, the reviewer conducted an analysis with the truncated work histories using Control Set # 1 and the three different exposure matrices. The greatest change In the conditional logistic regression model Is observed for the Rlnsky exposure matrix In which the beta coefficient Increases from 0.0081 to 0.0123. Surprisingly, the significance decreases (p 0.0017 to p - 0.0109) because the standard error of the beta coefficient Increases. This contradicts what Rlnsky, et al. (1985) observed using the truncated work histories (beta = 0.0135 and p * 0.0058). The discrepancy is probably due to the revised work histories for three of the leukemia victims. The analyses change very little when the truncated work histories are used for either of the Crump and Allen (1984) exposure matrices. ` API provided exposure assumptions for the non-pliofilm work histories of 225 deceased workers from location 2. Three different sets were Incorporated In an exposure assessment, assuming a low, moderate, or high scenario of exposure. For a worker from location 2 whose non-pliofilm work histories are not available, his/her non-pliofilm exposure was estimated by matching him/her to four of the workers out of the group of 225, according to date of birth and date of first pliofilm-related employment. Then he/she was randomly assigned the same amount of non-pliofilm exposure as one of the four matches. The 13 SAL OOOOQ1359 reviewer conducted conditional logistic regression analyses using total exposure (pliofilm plus non-pliofilm) and Control Set # 1. Although this Is certainly not a rigorous approach. It provides Insight as to how accounting for non-pliofilm exposure may affect the statistical results. Table 3 lists the mean cumulative exposure for cases and controls, along with the beta coefficients, standard errors, and p-values, for these analyses. There are no dramatic changes from the corresponding entries of Table 1, except that the high scenario of non-pliofilm exposure appears to reduce slightly the significance of the relationship between cumulative exposure and leukemia Incidence. SAL 000001360 TABLE 1: Mean cumulative benzene exposure (ppm-years) for cases and controls, and estimates of the beta parameters from the conditional logistic regression models with cumulative benzene exposure for the 12 different combinations of Exposure Matrices and Control Sets. Exp.Mat. 1 2 3 Con.Set 1 1 1 Beta 0.00S1 0.0017 0.0033 Std.Err. 0.0026 0.0006 0.0012 P-Value 0.0017 0.0087 0.0042 Mean Cum. Exp. Cases Controls 252.91 56.60 654.60 184.63 477.39 129.25 1 2 0.0091 0.0031 0.0029 252.91 58.48 2 2 0.0020 0.0008 0.0134 654.60 196.00 3 2 0.0042 0.0016 0.0090 477.39 139.51 1 3 0.0072 0.0025 0.0045 252.91 61.05 2 3 0.0016 0.0007 0.0154 654.60 216.51 3 3 0.0031 0.0012 0.0091 477.39 150.25 1 4 0.0063 0.0025 0.0122 252.91 105.15 2 4 0.0012 0.0006 0.0636 654.60 298.62 3 4 0.0025 0.0011 0.0292 477.39 218.05 SAL 000001361 15 TABLE 2: Estimates and 95% confidence Intervals for OR, and p, at various levels of exposure, using the model with cumulative benzene exposure. Exo.Mat. 1 1. 1* Con.Set 1 1 1 DDTTl-vrS 4.5 45.0 450.0 OR. 1.037 1.438 37.88 95% Cl for OR, (1.013,1.061) (1.141,1.814) (3.724,385.3) P. 0.0073 0.0101 0.2124 95% Cl for p. (0.0072,0.0075) (0.0081,0.0128) (0.0258,0.7329) 2 1 4.5 1.008 (1.002,1.013) 0.0071 (0.0071,0.0072) 2 1 45.0 1.079 (1.018,1.143) 0.0076 (0.0072,0.0081) 2 1 450.0 2.140 (1.198,3.822) 0.0150 (0.0085,0.0265) 3 1 4.5 1.015 (1.005,1.026) 0.0072 (0.0071,0.0073) 3 1 45.0 1.164 (1.047,1.295) 0.0082 (0.0074,0.0091) 3 1 450.0 4.585 (1.583,13.27) 0.0316 (0.0111,0.0864) 1 2 4.5 1.042 (1.014,1.071) 0.0074 (0.0072,0.0076) 1 2 45.0 1.509 (1.145,1.987) 0.0106 (0.0081,0.0140) 1 2 450.0 61.02 (3.875,961.0) 0.3029 (0.0268,0.8725) 2 2 4.5 1.009 (1.002,1.017) 0.0071 (0.0071,0.0072) 2 2 45.0 1.096 (1.017,1.181) 0.0077 (0.0072,0.0083) 2 2 450.0 2.508 (1.192,5.276) 0.0175 (0.0084,0.0362) 3 2 4.5 1.019 (1.004,1.034) 0.0072 (0.0071,0.0073) 3 2 45.0 1.206 (1.045,1.393) 0.0085 (0.0074,0.D098) 3 2 450.0 6.525 (1.551,27.45) 0.0444 (0.0109,0.1635) 1 3 4.5 1.033 (1.010,1.057) 0.0073 (0.0071,0.0075) 1 3 45.0 1.382 (1.100,1.736) 0.0097 (0.0078,0.0122) 1 3 450.0 25.47 (2.603,249.3) 0.1535 (0,0182,0.6397) 2 3 4.5 1.007 (1.001,1.013) 0.0071 (0.0071,0.0072) 2 3 45.0 1.074 (1.013,1.139) 0.0076 (0.0072,0.0080) 2 3 450.0 2.039 (1.133,3.669) 0.0143 (0.0080,0.0255) 3 3 4.5 1.014 (1.003,1.025) 0.0072 (0.0071,0.0072) 3 3 45.0 1.150 (1.033,1.280) 0.0081 (0.0073,0.0090) 3 3 450.0 4.050 (1.385,11.84) 0.0280 (0,0098,0.0778) 1' 4 4.5 1.029 (1.006,1.052) 0.0073 (0.0071,0.0074) 1 4 45.0 1.325 (1.059,1.659) 0.0093 (0.0074,0.0117) 1 4 450.0 16.69 (1.766,157.8) 0.1062 (0.0124,0.5291) 2 4 4.5 1.005 (1.000,1.011) 0.0071 (0.0071,0.0071) 2 4 45.0 1.055 (0.996,1.118) 0.0075 (0.0070,0.0079) 2 4 450.0 l'707 (0.959,3.040) 0.0120 (0.0068,0.0212) 3 4 4.5 1.011 (1.001,1.022) 0.0071 (0.0071,0.0072) 3 4 45.0 1.119 (1.009,1.240) 0.0079 (0.0070,0.0088) 3 4 450.0 3.076 (1.098,8.617) 0.0214 (0.0078,0.0578) SAL 000001362 16 TABLE 3: Mean cumulative benzene exposure (ppm-years) for cases and controls, and estimates of the beta parameters from the conditional logistic regression models with cumulative benzene exposure for Control Set # 1 and the different scenarios for pliofilm and non-pliofilm exposure. Pliofilm Exo.Mat. 1 2 3 Non-pllo ExDosure low low low Beta 0.0047 0.0016 0.0029 Std.Err. 0.0017 0.0006 0.0011 P-Value 0.0065 0.0067 0.0068 Mean Cum. Exp. Cases Controls 5Q7.62 126.35 909.30 254.38 732.09 199.00 1 moderate 0.0021 0.0009 0.0196 762.32 196.10 2 moderate 0.0014 0.0005 0.0075 1164.00 324.13 3 moderate 0.0020 0.0008 0.0088 986.79 268.76 1 high 2 high 3 high 0.0009 0.0009 0.0009 0.0004 0.0004 0.0004 0.0270 0.0149 0.0205 1271.72 1673.41 1496.19 335.61 463.64 408.27 v 17 SAL 000001363 REFERENCES Breslow, N.E., and Day, N.E. (1980). Statistical Methods In Cancer Research, Volume l - The Analysis of Case-Control Studies. Lyon, France: IARC Scientific Publications. Cochran, W.G. (1965). The plannlnlng of observational studies of human populations. Journal of the Royal Statistical Society, Series A 123, 234-255. Cochran, W.G., and Rubin, D. (1973). Controlling bias In observational studies: a review. Sankhya, Series A 35, 417-446. Crump, K.S., and Allen, B.C. (1984). Quantitative estimates of risk of leukemia from occupational exposure to benzene. Unpublished report for the Occupational Safety and Health Administration. Cox, D.R. (1970). The Analysis of Binary Data. London: Chapman-Hall. Cox, D.R. (1972). Regression models and life tables (with discussion). Journal of the Royal Statistical Society, Series B 34, 187-220. Kalbflelsch, J.D., and Prentice, R.L. (1980). The Statistical Analysis of Failure Time Data. New York: John Wiley & Sons. Klelnbaum, D.G., Kupper, L.L., and Morgenstern, H. (1982). Epidemiologic Research: Principles and Quantitative Methods. Belmont, California: Lifetime Learning Publications. Rlnsky, R.A., Smith, A.B., Hornung, R., Fllloon, T.G., Young, R.J., Okun, A.H., and Landrlgan, P.J. (1985). Benzene and leukemia: an epidemiologic risk assessment. Unpublished report for the National Institute for Occupational Safety and Health. Rosenbaum, P.R. (1984). The consequences of adjustment for a concomitant variable that has been affected by the treatment. Journal of the Royal Statistical Society, Series A 147, 656-666. Rubin, D.B. (1977). Assignment to treatment group on the basis of a covariate. Journal of Educational Statistics 2, 1-26. White, M.C., Infante, P.F., aqd Chu, K.C. (1982). A quantitative estimate of leukemia mortality associated* with occupational exposure to benzene. Risk Analysis 2, 195-204. 18 $al 00001364 Addendum At the time my testimony was filed, I had determined based on some sample calculations that, the truncation of work histories had little effect on resulting risk estimates. At API's request I undertook a complete analysis of the impact on risk estimates of the truncation procedure. All the analyses in the body of the text were repeated with work histories truncated in the manner of Rinsky, et al. (1985). Although there are some differences between the tables below and those in the body of my report, the estimates of px and associated confidence intervals change very little. * SAL 000001365 2 Table 1-A Exp.Mat. i 2 3 1 2 3 1 2 3 1 2 3 Con.Set 1 1 1 Beta 0.0123 0.0017 0.0037 Std.Err. 0.0048 0.0007 0.0013 2 0.0144 0.0055 2 0.0021 0.0008 2 0.0046 0.0018 3 0.0106 0.0037 3 0.0017 0.0007 3 0.0036 0.0014 4 0.0070 0.0026 4 0.0012 0.0007 4 0.0027 0.0012 P-Value 0.0109 0.0083 0.0053 Mean Cum. Exp. Cases Controls 252.91 50.13 654.60 178.09 477.39 122.72 0.0082 0.0130 0.0104 252.91 654.60 477.39 52.28 189.73 133.23 0.0045 0.0132 0.0084 252.91 654.60 477.39 52.96 208.00 141.74 0.0078 0.0572 0.0231 252.91 654.60 477.39 98.86 292. f4 212.17 SAL 000001366 3 Table 2-A Exp.Mat. Con.Set ppo-vrs ORx 95% Cl for ORx Px 95% Cl for P~ 1 1 4.5 1.057 (1.012,1.104) 0.0075 (0.0072,0.0078) 1 1 45.0 1.738 (1.126,2.684) 0.0122 (0.0079,0.0188) 1 1 450.0 251.7 (3.267,19391) 0.6419 (0.0227,0.9928) 2 1 4.5 1.008 (1.002,1.014) 0.0071 (0.0071,0.0072) 2 1 45.0 1.082 (1.019,1.148) 0.0076 (0.0072,0.0081) 2 1 450.0 2.193 (1.209,3.977) 0.0154 (0.0085,0.0275) 3 1 4.5 1.017 (1.005,1.029) 0.0072 (0.0071,0.0073) 3 1 45.0 1.183 (1.049,1.335) 0.0084 (0.0074,0.0094) 3 1 450.0 5.375 (1.608,17.97) 0.0369 (0.0113,0.1135) 1 2 4.5 1.067 (1.016,1.121) 0.0075 (0.0072,0.0079) 1 2 45.0 1.916 (1.172,3.132) 0.0135 (0.0083,0.0218) 1 2 450.0 665.7 (4.875,90900) 0.8258 (0.0335,0.9985) r 2 2 4.5 1.010 (1.002,1.017) 0.0071 (0.0071,0.0072) 2 2 45.0 1.100 (1.019,1.187) 0.0078 (0.0072,0.0084) 2 2 450.0 2.585 (1.204,5.550) 0.0181 (0.0085,0.0380) 3 2 4.5 1.021 (1.005,1.038) 0.0072 (0.0071,0.0073) 3 2 45.0 1.232 (1.047,1.449) 0.0087 (0.0074,0.0102) 3 2 450.0 8.032 (1.578,40.88) 0.0541 (0.0111,0.2255) 1 3 4.5 1.049 (1.014,1.085) 0.0074 (0.0072,0.0077) 1 3 45.0 1.611 (1.152,2.254) 0.0113 (0.0081,0.0158) 1 3 450.0 117.8 (4.102,3380.9) 0.4561 (0.0284,0.9601) 2 3 4.5 1.008 (1.001,1.014) 0.0071 (0.0071,0.0072) 2- 3 45.0 1.079 (1.015,1.148) 0.0076 (0.0072,0.0081) 2 3 450.0 2.145 (1.159,3.968) 0.0150 (0.0082,0.0275) 3 3 4.5 1.016 (1.004,1.029) 0.0072 (0.0071,0.0073) 3 3 45.0 1.177 (1.040,1.331) 0.0083 (0.0074,0.0094) 3 3 450.0 5.081 (1.481,17.43) 0.0349 (0.0104,0.1104) 9 1 4 4.5 1.032 (1.008,1.057) 0.0073 (0.0071,0.0075) 1 4 45.0 1.372 (1.082,1.741) 0.0097 (0.0077,0.0122) 1 4 450.0 23.68 (2.197,255.2) 0.1443 (0.0154,0.6450) 2 4 4.5 1.006 (1.000,1.012) 0.0071 (0.0071,0.0072) 2 4 45.0 1.057 (0.997,1.121) 0.0075 (0.0071,0.0079) 2 4 450.0 1.747 (0.972,3.140) 0.0123 (0.0069,0.0219) 3 4 4.5 1.012 (1.001,1.023) 0.0072 (0.0071,0.0072) 3 4 45.0 1.127 (1.014,1.252) 0.0080 (0.0072,0.0088) 3 4 450.0 3.307 (1.154,9.475) 0.0230 (0.0082,0.0632) SAL 000001367 Table 3-A 4 Pliofilm Exo-Mat. 1 2 -3 1 2 3 1 2 3 Non-plio Exposure low low low moderate moderate moderate high high high Beta 0.0051 0.0017 * 0.0031 - 0.0022 0.0014 0.0020 0.0009 0.0009 0.0010 Std.Err. 0.0019 0.0006 0.0012 0.0009 0.0005 0.0008 0.0004 0.0004 0.0004 P-Value 0.0080 0.0067 0.0074 0.0200 0.0072 0.0086 0.0266 0.0146 0.0203 Mean Cum. Exp. Cases Controls 507.62 909.30 732.09 119.69 247.85 192.47 762.32 1164.00 986.79 189.64 317.60 262.3 1271.72 1673.41 1496.19 329.15 457,11 401.74 SAL 000001368