Document OE8RBwZOqX0Vkzy82oZBvD8YL

American Journal of Industrial Medicine 15: 283-310 (19*91 Critical Review of Cancer Epidemiology in Petroleum Industry Employees, With a Quantitative Meta-Analysis by Cancer Site Otto Wong, ScO. face, and Gerhard K. Raabe, OrPH, ms A critical review of dose to 100 published and unpublished but otherwise available epidemiologic reports of petroleum industry employees from the United States, United Kingdom. Canada. Europe. Australia, and Japan was conducted. Analyses by duration of employment and latency are discussed, and summary standardized mortality ratios (SMRs) or meta-SMRs are developed for selected cancer sites. Findings indicate that the industry experienced a significantly lower cancer mortality than the general population for all cancer sites combined, digestive system, stomach, and lung. For the industry as a whole. SMRs similar to the general population were observed for skin, brain, pancreatic, prostatic, and kidney cancers. However, some data indicate that certain small groups within the industry might have elevated prostatic and kidney cancer risk. This review supports the conclusion that some refinery employees, particularly those employed before the 1940s. may have been at increased risk of leukemia. There is some indication that cancer of other lymphatic tissue may also be elevated. Unresolved issues affecting these conclusions are discussed, and specific directions for future research are offered. Key words: occupational cancer, petroleum, gasoline, benzene, meta-analysis, meta-SMR INTRODUCTION A large number of epidemiologic studies of workers in the petroleum industry have been conducted. Although these studies differ in design, size, and length of follow-up, they examine the mortality pattern of workers with similar exposures, including refinery process streams chemically similar in composition to commercial gasoline. These workers were exposed to a higher concentration and for a longer duration than the general public. Therefore, these studies represent the best available data on human effects of exposure to gasoline hydrocarbons. Although several epidemiologic reviews have appeared [Raabe. 1983: Savitz and Moure. 1984; EPA. 1987; Harrington, 19871, none of these reviews examined the complete literature systematically or provided a quantitative meta-analysis. The ENSR Health Sciences. Alameda. California (O.W ). Medical Department, Mobil Corporation. New York (G.K.R.). Address reprint requests to Otto Wong. ENSR Health Sciences. 1320 Harbor Bay Parkway. Alameda. CA 94501. '' Accepted for publication September 30. 1988. S 1989 Alan R. Liss, Inc. 448434 284 Wong and Raabe purpose of this review is to examine critically this literature and to develop a quantitive assessment (meta-analysis) of the site-specific cancer mortality patterns that emerge from these studies. Close to 100 published articles and unpublished but otherwise available repons from the United States. United Kmgdom. Canada. Europe. Australia, and Japan have been reviewed. Particular attention has been directed toward the appropriateness and adequacy of study design, study subject selecti . exposure data, and follow-up of study subjects. Since we are dealing with the assessment of carcinogenicity of industrial chemicals, the most appropriate 'ttiu-. design is that of a retrospective or historical cohort mortality study. In a cohort study, the population at risk is defined, and the exposures (at least in general terms) are relatively well documented. Further more. mortality is a valid endpoint for most cancer sites. In addition to study design and data quality, statistical methods have been examined, as well as the validity of interpretations and conclusions. Our assessment is based on relevant and appropriate studies. A number of articles were not included in the final assessment because they were found to be inappropriate or inadequate. We will first describe briefly the studies used in this review. Table I provides some of the basic information for the studies reviewed: company, location of facility, length and period of follow-up, minimum length of employment for cohort eligibility, cohort size, person-years, and the number of deaths. A full report with a summary and comments on each study is available upon request. In the United States, the first large-scale industrywide cohort mortality study in the petroleum industry was sponsored by the American Petroleum Institute (API) and conducted by Tabershaw/Cooper Associates [TCA, 1974], Based on this study, Wong [1980] reported an analysis of brain tumor mortality, which was not included in the original TCA report. Subsequently this API refinery study was updated from 1971 to 1980 [Kaplan, 1986]. Also under the sponsorship of API was the Memorial Sloan Kettering Cancer Center (MSKCC) registry of mortality and cancer incidence of 19 oil companies. The results of the first three years of data were reported by Schotten- feld et al. [1981]. ' A large number of studies on refinery workers have been conducted or spon sored by individual oil companies in the United States. Although the majority of the studies were historical cohort mortality studies in design, a small number of studies was actually based on a limited length of follow-up. From the methodological point of view, these studies fall into a hybrid category between the traditional cohort (longitudinal) study and a cross-sectional survey. The individual company studies that fall into the hybrid category include the AMOCO companywide study [Nelson. 1985]; the Exxon study of the Baton Rouge refinery [Hanis et al., 1982]; the Exxon study of the Baton Rouge, Baytown, and Bay way refineries and chemical plants [Hanis et al., 1985a.b]; and the two Shell studies of the Wood River [McCraw et al., 1985] and Deer Park [Joyner. 1983] refineries. As indicated in Table l. the follow-up was relatively short for these studies with the hybrid design. In most cases, the start date of the follow-up period coincided with the date of the computerization of personnel records. This type of study, although limited from a methodological point of view, was relatively quick and less expensive. . The traditional cohort mortality study, with a much longer follow-up, requires the time-consuming task of manually coding both the demographic and work history 448435 )6; I i n 2= in ri m - - A x-- ri 3? S *T S rai r^- mX a-- cvni -r '/* -- -- "I I-- -- i . ./-l n >/". V. 22 -- <r a -r -- S r i a --S Ma Ca a ---- -- -T --i -- ^ " 1 -- r** <-t ^-- ^X -vcn 5V. X a ^ r- **t ^ Ci*`ii ^ ? a -r r1*i1 i/n ri -a rO- 2ix r--M- 5--a ---c~i a 3 -- -- -- -^ n -- -r a r--t It--. -p -- ZZ ri- - ZZ >y .Ss </> C - - n ifl it =V M * J< ? a a a ? x x r- r- T -r ^ W*, 4a 1>*1i IN ---- XC >s r --3 5 5. 5 i 3 > > := s': J 2 f f >, U 2 i := ,= a -i 5 , *>*,.:s4 TJaai at as u = -- y Sy a y>5 (3 . Cy *a3 =5 m3 =m*.2- w3a-3a*a :2S } : E 3 ; 2 "y = s i i s I aj :=-=-u=rr.3i3j!2t S * ?? y -3 - 3= Sii y: ays z* *y * 3S ; !: a a3 -a 3,, 1 1 * ?*2 wy _ 4 *__ *a -aa s5 2 2 = * *55 ;j ta i ^ X - 2S /I >1 y -2 y S' w wn 1 1 j T A Iil.ls I. I)isiii|du>n id lo liu r l Studies in llie I'rlroleuin Industry 448436 Oioic 286 Wong and Raabe information of the cohort members, usually in the range of several to tens of thousands. Included in this category are the studies of the Chevron Richmond and El Segundo refineries [Wong et al.. 1986]; the Gulf Port Arthur refinery [Wen et al.. 1983, 1984a); the Mobil Beaumont [Morgan and Wong. 1984], Paulsboro [Morgan and Wong, 1985]. and Torrance refineries [EnterF-'e and Henderson. 1985]; and the Texaco companywide study [Divine et al.. 1985; Divine and Barron. 1986, 1987], ' These cohorts have also generated a number of reports based on specific subcohort analyses. For example, the Gulf Port Arthur data were the bases for two subcohorts: employees assigned to the benzene [Tsai et al., 1983] and to the MEK dewaxing units [Wen et al., 1985]. Based on the cohort data, a few nested casecontrol studies have also been conducted. An example was the leukemia study on the Shell employees at the Wood River refinery [Austin et al.. 1986]. In Britain, an industrywide study of eight refineries was conducted [Rushton and Alderson. 1981a). A subsequent case-control study of leukemia was carried out within this cohort [Rushton 3nd Alderson. 1981b]. A study consisting of employees at the distribution centers of three companies in England was also conducted by the same investigators [Rushton and Alderson. 1983], There are also a number of cohort mortality studies of refinery workers from Canada. Australia, and Japan. Hanis et al. [1979] reported the mortality experience of the Imperial Oil (Canada) employees at several refineries and other facilities. The Theriault and Goulet [ 1979] report was based on the mortality experience of the Shell East Montreal refinery, which was subsequently updated by Theriault and Provencher [1987], The Australian study was based on the first 3 years of mortality data accumulated in the prospective registry in the petroleum industry sponsored by the Australian Petroleum Institute [Christie. 1987]. Finally, a brief report from Japan described the results of a mortality study of Japanese petroleum workers sponsored by the Petroleum Association of Japan [Nakamura, 1987], The studies described above have been reviewed in detail. However, because of the limited space available, detailed comments on specific studies will not be discussed here. Because of the study design, the defined population at risk, the availability of mortality rates, the defined exposures, and the completeness and length of follow-up. these studies were judged to be adequate methodologically and to be of sufficient quality to form the basis of our assessment below. A number of studies that we have reviewed were excluded from our assessment because of various serious limitations. Several studies that fell into this category were proportional mortality ratio (PMR) studies based totally on death certificates available to union locals [Thomas et al., 1980; Thomas et al., 1982a; Reeve et al., 1982]. In addition to the well-known methodological deficiencies of PMR studies [Wong and Decoufle. 1982; Wong et al.. 1985], these particular studies also suffered from incomplete ascertainment of deaths [Wong and Tabershaw, 1980]. For example, in the Reeve et al. [1982] study, deaths were identified through local union death notifications, obituaries, word of mouth, and lists of surviving families to whom bibles were sent. In the Thomas et al. [ 1980] study, it was stated that death certificates for 10% of the deaths identified were not retrieved. Furthermore, employment histories were not available for these PMR studies, and the analyses were limited. Finally, the refineries included in these PMR studies have subsequently been studied thoroughly with the cohort study design by individual companies. Based on these considerations, these PMR studies were not included in our assessment. 448437 0666? Cancer Epidemiology in Petroleum Industry 287 Two company-sponsored studies were also excluded from our assessment because of methodological or data deficiencies. The study conducted by Baird [1967] on Humble Oil (Exxon) employees was very crude judging by today's standard. The number of deaths reported m that study was likely incomplete, and the estimate of employees at risk was most likely inaccurate. The Thorpe [1974] study of eight Esso European facilities was likewise based on incomplete death ascertainment and inaccurate estimate of population at risk. In addition to studies conducted on employees in the petroleum industry, there are also a number of population-based case-control studies that included petroleum or petroleum-related occupations in the analysis [McLaughlin et al., 1984; Mommsen et al.. 1983; Lin and Kessler. 1981; McLaughlin et al., 1985; Howe et al.. 1980; Stemhagen et al.. 1983]. The relationship between various occupations and cancers of the bladder, kidney, pancreas, and liver was investigated in these studies. None of these studies provided adequate information about the nature of exposure or details of employment. Methodological problems (such as control selection, recall of employ ment histories, adjustment of confounding factors in analysis) further complicated the interpretation. With the exception of the concern for kidney cancer raised by the API animal work [MacFariand et al.. 1984], none of these cancer sites has been implicated by occupational studies. These studies were excluded from our final assessment. RISK ASSESSMENT BY CANCER SITE In this section, we summarize the epidemiologic data from the cohort mortality studies on petroleum workers by individual cancer site. If a study had been updated, the updated data were used. Industrywide studies are not included in the data summarization, since part of the data overlap those in individual company studies. Subcohort analyses are not included in the data summarization either, since the data for the entire study are utilized. In evaluating the data for causal relationship, some of the criteria set forth by Hill [1965] are used. In particular, we emphasize, to the extent possible, the strength of association, consistency of findings, and dose-response relationship. However, our application of Hill's criteria is limited by the data available from the original studies. An overall index for strengih of association is a summary standardized mortality ratio (SMR) or meta-SMR based on all the available appropriate data. A method of calculating the summary SMR or meta-SMR is given below. In terms of doseresponse relationship, the issue is more complicated. Most of the studies did not provide any dose-response analysis. Few industrial hygiene data existed in the industry prior to the mid-1970s, whereas relevant exposures occurred much earlier. In some studies, broad exposure categories were used. Some used length of employment as a surrogate for length of exposure. Even for these latter studies, the groupings were so different that no quantitative summarization can be done without access to the original data. Thus, dose-response results can only be used in a qualitative manner in our assessment. The statistical procedure for data summarization (meta-analysis) consists of summing up the observed and the expected deaths for a specific cancer site from all eligible studies and calculating the summary SMR or meta-SMR. (The Hanis et al. [1979] study utilizing the direct method of standardization could not be included in this procedure.) This simple procedure treats each study as a separate metastratum in 448438 :ss Wong and Raabe the data summarization, thus "adjusting" for individual studies while preserving the original adjustment using substrata specific to age, sex. race, calendar year, and country. The summary or meta-SMR is automatically weighted by the size of the individual studies (observed and expected deaths). Chi-squares are calculated to test the significance of the summary SMR. Ninety-five percent confidence intervals are also calculated for the summary SMR (presented in the last table). Similar procedures have been used in summarizing data in several epidemiologic reviews: asbestos and gastrointestinal cancer [Morgan et al., 1985], artificial sweeteners and bladder cancer [Morgan and Wong. 1985], formaldehyde and respiratory cancer [Nelson et al.. 1986], chemical dyes and bladder cancer [Matanoski and Elliott, 1981], and radiation and colon cancer [Day. 1985]. In particular, this method was discussed in the interpretation of negative epidemiological evidence for carcinogenicity by the Inter national Agency for Research on Cancer [Wald and Doll. 1985]. Although other statistical procedures for meta-analysis are available, the meta-SMR procedure is used in this review because of its simplicity in computation and interpretation, its preservation of the adjustments in the original studies, and its resemblance to the analyses in the original studies. An additional benefit of meta-analysis is that it comprehends the multipiecomparison problem exhibited in these cohort studies. Most of the cohort studies that we reviewed examined over 40 individual cancer sites each. Statistically significant results for as many as two sites could have occurred by chance alone given a 95% confidence level. By our examination of these multiple sites across these studies, chance excesses or deficits for a particular cancer site in individual studies are less likely to influence the overall interpretation. Since the summary SMR is .based on the expected deaths derived from national mortality statistics in the original studies, the issue of appropriateness of applying national rates to specific locales applies to the meta-analysis in this review as well. To be consistent with the data presented in the original papers, we have kept two decimal places in the expected numbers of deaths. Although the summary SMR gives an overall risk index for the industry as a whole, it has the disadvantage of dilution. If the risk is low and affects only a small portion of the employees instead of the entire industry, an overall summary index may not be sensitive. Therefore, data from each study have to be examined for any dose-response relationship and any significant risk for any subcohort. Unfortunately, few studies provided analysis by length of employment on a comprehensive basis, i.e., for all causes of death. Those reporting comprehensive analysis by length of employment included the Chevron Richmond and El Segundo refineries [Wong et al., 1986], the Mobil Beaumont refinery [Morgan and Wong, 1984], the Mobil Paulsboro refinery [Morgan and Wong, 1985], and the Mobil Torrance refinery [Enterline and Henderson. 1985], Length of employment analysis was done for a few selected causes of death in the Gulf Port Arthur study and in the Texaco study. Rushton and Alderson reported length of employment analysis for selected causes of death as well as selected subcohorts in the British refinery and distribution center studies. In addition to length of employment analysis, another analysis that is helpful in establishing an epidemiologic association is an examination of the data by latency or time since first exposure (usually first employment as a surrogate). Studies providing this type of analysis on a comprehensive basis included the Chevron study, the Mobil studies, and the Shell Canada [Theriault and Provencher, 1987] study. Both the Gulf 448439 '-;c67l Cancer Epidemiology in Petroleum Industry 289 T\BLE II. Summary of Mortality From Cancer of All Sila in Cohort Studio of Refinery and Other Petroleum Employees' Vathoryear Facility Observed Expected Statistical Latency Duration Jeaths Jeaths SMR significance analysis analysis racersnaw Cooper Assc |1974|* !* refineries Wong (N'jOl* 1* reriner.es Kaplan 1 !* refineries SohonenfeM al L' S refineries N'd>on | 19351 :0 refineries Wong ei al , iy,l6| Richmond. El Segundo Refineries Hams et al | 1932!4 Baton Rouge Refinery Hams et at ; [985a! Baton Rouge. Baytown. Bay way Refineries Wen et al {j1" Pori Arthur Refinery Morgan and Wong jl984| Beaumont Refinery Morgan ind Wong [19851 Paulsboro Refinery Emerline and Henderson 11985) Torrance Refinery McCraw et al i. 19851 Wood River Refinery Joyner (19831 Deer Part Refinery Divine et al. (1985| 13 refineries it others Divine and Barrow (1987) Production it pipeline Rushton and Alderson (I98ta| 8 UK Refineries Rushton and Alderson (1983| UK distribution centers Theriault and Goulet (1979)* East Montreal Refineries Theriault and Provencher (1987) East Montreal Refineries Christie (19861 Australia Nakamura [ 1987) 51 Japanese Refineries 265 '93 127 173 4*: :i9 '566 664 3-16 243 56 161 767 393 U47 l .002 25 39 134 327 52 0-30 915 59 168.77 330 10 6io :o 0 37 0 75 0 33 0.75 270 JO 0 92 *05 00 0 94 681 54 360.27 265.24 69 32 H7 00 0.97 0.96 091 0.80 0.91 1.019 40 581.10 1.236.40 1.156.70 23.54 48.82 56 90 176.30 0.75 0 68 0 89 0 87 0.88 0 79 0 91 0 76 f f f e f f f t f f tJ SJ t* tJ t4 tJ r> Total 6.405 7.525 29 0.85 ip< 000011 "Note: Blank entries indicate that the observed and expected deaths are not reported by the authors. 'Excluded from the calculation of summary SMR. "Only refinery employees are included. 'Only male hourly employees with l or more years of employment are included. J Analysis done. `p < 05 ' 'p < 01. and the Texaco studies included some latency analysis by specific causes of death. Finally, several studies [TCA. 1974; Wong et al.. 1986; Wen et al.. 1984a; Rushton and Alderson. 1981a, 19831 provided some analyses by hire date. Cancer of All Sites Combined (ICD8, 140-209) Table II presents the observed and expected deaths and the corresponding SMRs for cancer of all sites from the eligible cohort mortality studies of petroleum employees from the United States. Canada, Great Britain. Australia, and Japan. The all-cancer SMR ranged from 0.68 (p < .011 for Texaco production and pipeline employees to 0.97 for Gulf Port Arthur male workers. Mo study found any excess or trend (significant or otherwise) for ail cancer. In fact, most of the larger studies demonstrated significant deficits for all cancer. The deficit was quite consistent for all the studies. The all-cancer meta-SMR based on 6,405 deaths was 0.85 (p < .00001), significantly lower than the general population. '90 Wong and Raabe T\BLE III. Summary of Moctiiity From DtfHtlvc Ciactr in Cohort Studies of Refinery end Other Petroleum Employees* Author/year Facility Observed Expected Statistical Latency Duration deaths deaths SMR significance analysis analysis Tabennaw Cooper Assc (I97a) Wong [ 19S0|# iCaplan [1986|* Swnortenteid et ij (19811* B Neiion i 19851 Wong et ai [19861 Hams et ai. [ 198-1* Hams cc al. (1985a| Wen ei al. [19831' Morgan and Wong [ 198-*) Morgan and Wong [19851 Enterlme and Henderson [1985) McCraw et al. (1985] Joyner [ 19831 Divine et al. (19851 Divine and Barron [1987] Rushton nd Alderson (198la( Rushcof- .-a Alderson [1983} TheruuU and Goulet (19791* Theriault and Provencher [1987] Chnsiie [1986| Nakamura [ 1987) 17 retinenei 17 refineries 17 refineries l' S rerinenes 10 rerinenes Richmond. 1 Segundo Rerinenes Baton Rouge Baton Rouge. Baytown. Bayway Rerinenes Port .Arthur Refinery Beaumont Refinery Paulsboro Refinery Torrance Refinery Wood River Refinery Deer Park Refinery 13 rerinenes <4 others Production 4 pipeline S UK refineries UK distribution centers East Montreal Refinery East Montreal Refinery Australia 51 Japanese refinenes 31 133 31 97 125 n 1% 86 30 10 :i5 105 12 18 15 95 71 084 :46 9t 4| 12 82 50 174 62 0 90 0 25 1 17 0.7| 74 90 0 97 195.30 1.00 e 113 04 sow 18 30 0 76 0 98 0 54 e 306.80 0.70 168.70 0.62 e e 10.22 13.20 L6.70 1.17 0.98 0.90 xJ x4 x' XJ xJ XJ x' X4 x' X4 x' X-1 Total 947 1.174 86 0.81 (p<.Q000l) 'Note: Blank entries indicate that the observed and expected deaths are not reported by the authors. 'Excluded from the calculation of summary SMR. 'Only refinery employees are included. "Only male hourly employees with I or more yean of employment are included. Jx = Analysis done. 5p < 01. Digestive Cancer (ICD8, ISO-159) For digestive cancer, four studies showed a significant deficit (Table III). Of all the studies listed in Table III. only one study, the AMOCO companywide study, showed a slight nonsignificant excess (SMR = 1.17). A closer examination of the AMOCO data indicated that out of the ten refineries investigated, the digestive cancer excess came from only one refinery (Whiting) and among employees hired before 1940. This isolated finding was not consistent with the rest of the data. For the industry as a whole, the digestive cancer meta-SMR was 0.81 (947 deaths observed), significant at the .00001 level. Stomach Cancer (ICD8,151) Table IV presents stomach cancer SMRs from the eligible cohort mortality studies. No study detected any significant excess. The stomach cancer SMRs ranged from 0.39 (p < .01) for Texaco production and pipeline workers to 1.60 (not significant, p = .20) for the Shell Canada East Montreal refinery, where seven 448441 06c Cancer Epidemiology in Petroleum Industry 291 TABLE IV. Summary of Mortality From Stomach Cancer in Cohort Studio at Rdtncry and Other Petroleum Employee! Author/vear Facility Observed Expected Suusucai Latency Duration Jeatfts deaths SMR significance analysis analysis fioersnaw Cooocr Assc (19*41* 'Votid j 19301* Kaplan i l86|* Scrtottenreid it ii ` Nelson [ I985| '-Von? et il (19861 Hams cl ai. ' W821* Hams et al [[985a| Wen et al. [I98)lc Morgan and Wong (1984] Morgan and Wong (1985] Enterime and Henderson (19851 McCrawctaJ (19851 Joyner (1983| Divine et a]. [[985] Divine and Barron (1987] Rushton and Alderson (I98la| Rushton and Alderson (1983) Thenauit and Gouiet [1979]* Theriault and Provencher {1987] Christie [ 1986] Nakamura [ 1987] Total 1 7 refineries l * refineries 1* refineries U S refineries ;0 refineries Richmond. El Segundo Refineries Baton Rouge Refinery Baton Rouge. Baytown. Bayway Refineries Pon Arthur Refinery Beaumont Refinery Paulsboro Refinery Torrance Refinery Wood River Refinery Deer Park Refinerv 13 refineries & others Production <k pipeline 3 UK refineries UK distribution centers East Montreal Refinery East Montreal Refinery Australia 51 Japanese refineries 43 6 17 :6 11 33 63 :a [4 4 45 13 167 i:j 7 49 585 44 06 5 95 11 90 34 10 0 98 l 00 t 43 0 76 13.70 0.30 34 30 0.96 56 69 26 55 17 <6 3 36 lU 0.90 0.79 L 18 63 90 33 00 160 36 144 47 0.70 039 l.CW 0.85 e f 4 36 1.60 63 90 0.71 659 95 0.89 e <p< 005> x3 X4 i3 x3 X3 X3 l3 X3 X3 X3 X3 Note: Blank entries indicate that the observed and expected deaths are not reported by the authors. Excluded from the calcuiauon of summary SMR. ''Only refinery employees are included. Only male hourly employees with l or more years of employment are included. Jx = Analysis done. `p < .05. ' 'p < .01. stomach deaths were observed and 4.36 were expected. The East Montreal investi gation [Theriault and Provencher, 1987] was a very small study with only 1,207 employees. Another Canadian study based on Imperial Oil employees [Hanis et al., 1979] detected a significant relative risk of esophageal and stomach cancer among the exposed employees when compared to the nonexposed employees (not shown in Table IV): the excess came from refineries in Ontario and Quebec. Exposure classification in this study was based on partial employment histories (post-1964); therefore, misclassification was likely, and analysis based on job or exposure cateaories was subject to error. In both Canadian studies, the stomach cancer excess came primarily from Quebec. The possibility of a confounding factor associated with that region should be investigated. In the United States, Nelson [1985] found a nonsignificant stomach cancer excess in AMOCO employees (SMR = 1.43). Similar to the finding in total digestive cancer, the stomach cancer excess came from the AMOCO Whiting refinery and among men hired before 1940. On the other hand, the two Texaco studies found significant deficits in stomach _____._J ' 448442 06674 292 Wong and Raabe TX8LE V. Summary of Mortality From Pancreatic Cancir in Cohort Studies of Refinery and Other Petroleum Employees* Author 'ear Facility ucershaw Cooper Assc [ I97a|* Wong 19801* Kaolin \ et ai f 198! |*3 Nc^on i i-Klfl Won* et al. [19861 Hams et al 11982]* Hams et al. i I985a| (I983(c Morgan and Wong (1984| Morgan and Wong [1985] Enterlme and Henderson (I985| McCraw et al. [1985] Joyner(19831 Divine et al. [ 19851 Divine and Barron (1987] * Rusnton and Alderson (1981a) Rushton and Alderson (1983) Thenauit and. Goulet (1979]* Thinault and Provencher (1987] CSriitie (19861 Nakamura [1987] 1 ^ refineries 17 refineries 17 refineries C S refineries 10 refineries Richmond. El Segundo Refineries Baton Rouge Refinery Baton Rouge. Baytown. Bavway Refineries Port Artftur Refinery Beaumont Refinery Paulsboro Refinery Torrance Refinery Wood River Refinery Oeer Part Refinery 13 refineries Sc others Production Sc pipeline 8 L'K rerinenes L'K distribution centers East Montreal Refinery East Montreal Refinery Australia 5 ( Japanese rerinenes Total Observed Etrected deaths Ji-ths SMR -u 51 25 0 36 10 1 15 i 12 18 17-30 1 05 20 53 -S 0.59 :3 15 10 1 52 a? 59 :o 1 07 37 37 so 0 99 23 20 14 l 14 15 14 SI 1 01 3 J 96 0 75 62 57 -0 l 07 27 32.00 0 34 50 51 55 0 97 39 A6 89 0 83 336 359 83 0.95 Statistical Latency significance analysis < x* V* XJ V* ip= 32) Duration analysis X1 xJ xa XJ Xs* Note: Blank entries indicate that the observed and expected deaths are not reported by the authors. 'Excluded from the calculation of summary SMR. 'Only refinery employees are included. 'Only male hourly employees with I or more years of employment are included. Jx = Analvsts done. ep < 05. ' cancer: the SMR was 0.70 in the refinery employees and 0.39 in the production and pipeline employees. The Japanese industrywide study also found a significant deficit of stomach cancer. Mortality deficits from stomach cancer were also found in other studies. As Table IV indicates, the Chevron Richmond and El Segundo refineries and the Mobil Paulsboro refinery showed a modest deficit in stomach cancer. Rushton and Alderson [ 1983] found a lower than expected stomach cancer mortality in distribution workers (SMR = 0.85. p = .05, borderline significance). Summing over all the eligible studies, the stomach cancer meta-SMR was 0.89 1585 observed deaths, p < .005). Thus, taking all studies into consideration and weighting the finding of each study by its sample size, the petroleum industry as a whole demonstrated a significantly lower stomach cancer mortality. Pancreatic Cancer (1CD8, 157) Mortality from pancreatic cancer among refinery workers is summarized in Table V. Most studies reported an SMR around 1. Wong et al. [1986] reported a % I 066-3 Cancer Epidemiology in Petroleum Industry 293 TABLE VI. Summary of Mortality From Lung Cancar in Cohort Studies of Refinery end Other Petroicum Employees* \dinorvear Facility Observed Expected Statistical Latency Duration deaths deaths SMR significance analysts analysis Tacersnaw Coooer A>sc i l974|* Ann* i(9501* Kapian j I986i* Stnoitemeid si al i 198 1 C 9 Seisun i 1**51 'Aon* et al. [ `.9*61 Hum st al. (19831* Hanis st al. [ l985ai Wen et jl. [19831* Morgan and Wong [ I984| Morgan and Wong (19851 Entertine and Henderson (19851 McCraw et al. [ 1985) Jovner [19831 Divine ct il. [19851 Devme and Barron {19871 Rusfuon and Alderson (l981a| * Ruanton and Alderson (19831 Theriault and Gouiei [1979|* Theriault and Provencher [19871 Christie [19861 Nakamura [ 1987] i 7 refineries 17 refineries 17 refineries L S. refineries 10 refineries Richmond. El Segundo Refineries Baton Rouge Refinery Baton Rouge. Baytown. Bayway Refineries Port Arthur Refinery Beaumont Reftnery Pauisboro Refinery Torrance Refinery Wood River Refinery Deer Park Refinery 13 refineries k others Production & pipeline 3 LX refineries LX distribution centers East Montreal Refinery East Montreal Refinery Australia 51 Japanese Refineries Total 'JO 112.71 0.79 f ro 3i7:: 0 35 e -Hi 65 07 0 73 e 77 125 90 0 61 f 134 185 92 0 66 f 78 85 30 0 91 :o9 319 30 0.95 182 183 22 0.99 101 100 11 ! 00 61 76 38 0.79 34 23 36 1 OO 132 109 416 384 3 7 9 18 1.903 306 00 179 00 532.70 982.83 3.48 15.78 13 30 19 80 0.59 0.61 0 73 0.80 0.35 0.44 0.48 0 91 3.469 60 0.77 r f f t e e ip< oooon 9J V* X4 X4 XJ *9 V1 'Note: Blank emr.es indicate that the observed and expected deaths are not reported by the-authors. 'Excluded from the calculation of summary SMR. "Only refinery employees are included. "Only male hourly employees with 1 or more years of employment are included. Jx = Analysis done. *p < .05. " :p < 01. significantly low mortality from pancreatic cancer among Chevron employees at the Richmond and El Segundo refineries (SMR = 0.59, p < .05). Hanis et al. [1982] reported an SMR of 1.52 (p = .05, borderline significance). However, the subse quent Hanis et al. [1985a,b] study found a much reduced SMR of 1.07 (p = .65, not significant). No dose-response relationship was demonstrated by any of the studies. For the entire industry, the pancreatic cancer meta-SMR was 0.95 (336 ob served deaths, p = .32). The data did not indicate an excess of pancreatic cancer in refinery workers. Lung Cancer (ICD8, 162, 163) As indicated in Table VI, most of the studies showed a significant lung cancer deficit. Four of the five industrywide studies showed a significant deficit. The U.S. industrywide study, based on 270 lung cancer deaths, showed an SMR of 0.85 (p < .05), significantly less than the expected [Kaplan, 1986]. The two industrywide 448444 294 Wong and Raatve studies in Britain also reported similar results: SMR of 0.78 in refinery workers [Rushton and Alderson. 1981a] and SMR of 0.80 in distribution workers [Rushton and Alderson. 1983], both significant at the .01 level. The Australian registry for the petroleum industry also reported a significant lung cancer deficit (SMR = 0.48). The Japanese industrywide study showed a slight nonsir `leant deficit. Significant lung cancer deficits were also detected in AMOCO refineries [Nelson. 1985], Chevron Richmond and Ei Segundo refineries [Wong et al., 1986], Texaco refinery and production workers [Divine et al.. 1985; Divine and Barron. 1987], and the Shell East Montreal refinery [Theriault and Goulet. 1979]. The Imperial Oil study by Hanis et al. [1979] concluded that there was a significant lung cancer excess among the exposed employees when compared to the nonexposed employees (not shown in Table VI). As commented above, because of the limited job history data, misclassification of exposure was likely. Furthermore, most of the lung cancer cases in that study were office workers, cierks. boiler makers, and construction workers. In some of these occupations, asbestos exposure was likely. Furthermore, when the data were examined by exposure category, the medium exposure group had a lung cancer relative risk (RR) of 0.39, when compared to the nonexposed. This was not consistent with a causal relationship. The most serious evidence against the positive finding in this study is that its lung cancer result was totally inconsistent with the rest of the industry worldwide. No study has adequate smoking data for a proper analysis incorporating such information. However, in a few studies, some smoking data were available. In the Nelson [1985] study, smoking data were available on 60% of the cohort members, and among those with such information. 69% used tobacco. In the Exxon cohort, smoking information was available on 70% of the employees, among whom 73% smoked cigarettes [Hanis et al., 1985b]. In the Enterline and Henderson [1985] study, smoking data were collected on 71% of the Mobil Torrance cohort, with 65% among them having ever smoked. Van Peenen et al. [1984] reported that 72% of white male refinery hourly employees studied at Standard Oil of Indiana smoked cigarettes, pipes, or cigars. These figures from the above companies, although limited, were quite comparable to the percentage of smokers in the general population. Thus, smoking was not likely a serious confounder when comparing petroleum employee cohorts to the general population. Summing up all the data on lung cancer, the meta-SMR was calculated to be 0.77. This SMR was extremely stable, with 1.903 observed deaths, and was significant at the .00001 level. Based on the totality of the data, there was a significant lung cancer deficit in petroleum workers. Skin Cancer (ICD8, 172, 173) The reported skin cancer mortality in petroleum workers spread over a wide range (Table VII): from a low of 0.24 among the Mobil Paulsboro employees [Morgan and Wong. 1985] to a high of 2.16 in the British industrywide study of refinery employees [Rushton and Alderson. 1981a], In the Rushston and Alderson study, only melanoma was reported, and 11 of the 14 melanoma deaths came from two of the eight refineries. No dose-response analysis was provided in the study, and no explanation for the excess was offered. In the AMOCO study, the skin cancer SMR of 1.93 (2.01 for white males) was of borderline significance (p = .05). Other studies showing a nonsignificant elevation in skin cancer mortality included the Mobil 448445 0c- Cancer Epidemiology in Petroleum Industry 295 TABLE VII. Summary erf Mortality From Skin Cancer in Cohort Studies of ReAnery and Other Petroleum Employees* Author year Facility Observed Expected Statistical Latency Duration deaths death* 5MR significance analysis analysis Tabershaw Cooper Assc (1974|* Wong (19801* Kiolan i 1986|* - Schonemelti ;i al. [W8l!,a kelson [ 19851 Wong if al. [ 19361 Hams ci al. 119821* Hams it al (I985a| Wen il. [19831* Morgan and Wong [ 1984| Morgan and Wong [ 19851 Enterltne and Henderson (19851 McCraw et al. [[9851 Joyner (1983| Divine ei al {19851 Divine and Barron [1987] Rushton and Alderson (I98lij Rushton and Alderson [19831 Thenauic and Goulet (1979]* Theriault and Porvencher (1987) Chmtie 119861 Nakamura (1987J 1" refineries 17 refineries 17 refineries L' 3 refineries 10 refineries Richmond. El Segundo Refineries Baton Rouge Refinery Baton Rouge. Baytown. Bayway Refineries Port Arthur Refinery Beaumont Refinery Paulsboro Refinery Torrance Refinery Wood River Refinery Deer Part Refinery 13 refineries & others Production it pipeline 3 LK refineries LK Jistnoution centers East Montreal Refinery East Montreal Refinery Australia 51 Japanese rerinenes 15 3imi II 10 9 10 : t timi4 14 7 I4imi4 5 -Mmi* [4 05 i 55 5 '0 10 31 1 07 0 39 l 93 ) 92 9 10 0.99 9 53 5 03 406 l 02 l 05 1.39 0.24 0 98 16.70 9 80 6.48 152 0 34 0.72 2.16 0.59 2.48 1.62 f X* \* xJ V1 xJ X1 XJ XJ X1 Total 93 89 23 1.04 lp=* 70) Note: Blank entries indicate that the observed and expected deaths are not repotted by the authors. * 'Excluded from the calculation of summary SMR. "Only refinery employees are included. "Only male hourly employees with l or more years of employment are included. Jx = Analysis done. e(m) = melanoma only. 'p < 01. ' Beaumont refinery (SMR = 1.39, 7 observed deaths) and the Australian registry of petroleum workers (SMR = 1.62, 4 observed). In both cases, the numbers of observed deaths were small, and the SMRs were not statistically significant. Further more. analyses by length of employment and latency in the Mobil Beaumont study did not find any association between skin cancer and employment [Morgan and Wong. 1984). On the other hand, skin cancer deficits were reported in the Mobil Paulsboro refinery [Morgan and Wong, 1985], the Texaco refinery and production employees [Divine et al., 1985: Divine and Barron. 1987), and the distribution workers of three companies in Britain [Rushton and Alderson, 1983). The meta-SMR for skin cancer based on all the eligible studies in the petroleum industry was 1.04 (93 observed deaths and 89.23 expected), with a p-value of .70. Thus, although the results were not always consistent, the overall data indicated that petroleum workers had a similar mortality experience as the general population. Z96 Wong and Raabe TABLE VUI. Summary oi Mortality From Prootatk Cancw in Cohort Studies of Refiner? and Other Pttrokum Employees Author-year Facility Observed Expected Statistical Latency Duration deaths deaths SMR significance analysis analysis TiOersnaw Cooper Assc (197-1}* Aong i 19301* Kaplan i l986j* hcrtoitenr'eid it al |l98ijja Velson ; 1935] Wong ;t il. 11986} Hants st ii. (19821* Hanis st ai. [ 1985a) Wen ct iJ 11983 Is Morgan and Wong [1984) Morgan ind Wong (19851 Enterline ind Henderson (1985] McCraw it ai. (19851 loyner [19831 Divine :t al. U985I Divine and Barron (19871 Rushton and AUierson [1981a) Rushton and Alderson ([983] Thenault ind Goulet (1979]* Theriault and Provencher (1987] Christie (1986| Nakamura [ 1987] l" rerinenes 17 retlnenes [" retlnenes l' S retlnenes 10 rerinenes Richmond. El Segundo Rerinenes Baton Rouge Refinery 8aton Rouge. Baytown. Bayway Retlnenes Port Arthur Refinery Beaumont Refinery Paulsboro Refinery Torrance Retlnery Wood River Refinery Deer Part Refinery 13 retlnenes St others Production St pipeline 3 UK retlnenes UK distribution centers East Montreal Retlnery East Montreal Refinery Australia 51 Japanese retlnenes 60 5 14 34 19 56 69 36 :s 5 62 41 47 53 53 81 5 30 16 20 43 36 1 02 0 94 0 36 0.78 :s 60 '3 30 0 66 0.76 59 98 3106 10 68 a 33 1 15 u: 1.35 l 10 73.10 43.70 45 37 48.57 0.85 0 94 l 02 1.09 xJ u* XX* X- c* X1 XJ - <4 XJ Total 445 461.35 0.96 Ip- 45) Note: Blank entnes indicate that the observed and expected deaths are not reported by the authors. 'Excluded from the calculation of summary SMR. bOnly refinery employees are included. 'Only male hourly employees with I or more years of employment are included. Jx = Analysis done. 'xx = Analysis done for subcohort only in subsequent report tsee text). However, it must be pointed out that the above assessment of skin cancer based on mortality data is limited, since most forms of skin cancer are not fatal. Prostatic Cancer (ICD8, 185) Table VIII presents the results of prostatic cancer from the cohort studies of petroleum workers. In most cases, the observed mortality was close to the expected. The highest SMR was observed in the Mobil Paulsboro refinery, with a nonsignificant SMR of 1.35 based on 28 deaths. Detailed analysis showed that the white male employees with 20 years of service at the Paulsboro refinery experienced a signifi cantly elevated SMR of 1.60. However, analysis by work location did not reveal any particular high-risk area. Two small studies of Methyl ethyl ketone (MEK)-dewaxing employees at refineries have shown a significantly increased rate of prostatic cancer [Enterline, 1978; Wen et al.. 1985]. These included the Shell Deer Park refinery (SMR = 9.52, 2 observed deaths, p < .01) and the Gulf Port Arthur refinery (SMR = 2.48 for the 448447 Cancer Epidemiology in Petroleum Industry 297 nonwhites based on 7 deaths, p < .05: and SMR = 11.49 for those with 20 - years of service and 20-29 years of latency, p < .05). However, a similar study of MEK-dewaxing employees at the Shell Haven and Stanlow refineries in Britain [Aiderson and Rattan. 1980] did not find any deaths from prostatic cancer, when the expected number was 0.46. Based on these three studies, the meta-5MR for MEKdewa.xina employees was 1.93 ip < .05). It should be noted that all three MEKdewaxing studies were very small. The meta-SMR for the industry as a whole was 0.96. based on 445 observed deaths ip = 451. Thus, petroleum employees as a group had a similar mortality from prostatic cancer as the general population. However, data from some refineries suggested that petroleum employees working at MEK-dewaxing units might experi ence a higher prostatic cancer risk. At this point, a firm conclusion on the relationship between prostatic cancer and employment at MEK-dewaxing units cannot be made based on the currently available data. Kidney Cancer (ICD8, 189) Table IX presents the results of kidney cancer from petroleum cohort mortality studies. Interest in this cancer site was aroused after it was reported [McFarland et al., 1984] that male rats experienced an increase in kidney tumors after chronic exposure to wholly vaporized unleaded gasoline. The lowest SMR was observed in Texaco production and pipeline workers, with an SMR of 0 35 (5 observed deaths p < .05). However, production workers have limited contact with downstream gasoline, and. thus, their mortality experience might not be directly relevant. The Chevron refinery study and the three Mobil refinery studies all reported slight deficits in kidney cancer mortality with SMRs ranging from a low of 0.59 (1 death) to a high of 0.81 (12 deaths). Mortality excess from kidney cancer was observed in both Exxon and Gulf employees. For the three Exxon refineries at Baton Rouge, Baytown, and Bayway, the SMR for kidney was 1.43 (22 deaths, p = .09). The excess came from those hired before 1956. the SMR being 1.47 (22 deaths, p = .07). Unfortunately, no length of employment analysis was done. Wen et al. [1984b] reported some detailed analyses of kidney cancer based on the Gulf Port Arthur study. Overall, the Gulf Port Arthur cohort experienced a nonsignificant SMR of 1.23 based on 22 deaths with a p-value of .33 [Wen et al.. 1984b]. When the data were analyzed by length of employment, a weak upward trend was found. For those who worked for 9, 10-20. and =* 20 years, the SMRs were 0.93. 1.25, and 1.38. respectively. A subsequent nested case-control study detected several areas with nonsignificant increase in kidney cancer. The Japanese industrywide study did not report kidney cancer per se. However, for urinary tract cancer, the Japanese refinery workers experienced a borderline signifi cant excess (p = .05), with 7 observed deaths and an SMR of 2.05 [Nakamura. 1987], As far as downstream gasoline is concerned, the more appropriate group to study is the distribution or marketing employees. In the British distribution employ ees. a nonsignificant excess from kidney cancer of 1.21 (based on 23 deaths, p = .37) was reported [Rushton and Aiderson, 1983]. However, detailed analysis (in the original report to the sponsor but not reported in the published article) showed that drivers, who had the highest exposure to gasoline, experienced an SMR of 1.71 (12 298 Wong and Raabe TABLE IX. Summary of Mortality From Kidney Cancer in Cohort Studies of Refinery and Olhtr Pttroicum Empiovees* Author/year Facility Observed Expected Statistical Latency Duration deaths deaths SMR significance analysis analvsis Taoersnaw Cooper issc i 1974',1 Wong [r980l* Kaplan (1986)* Svhoaenreid ;t al. [I98l|*e kelson 11985) Wong al. 11986) Kants et al. (1982)" Hams et al. (I985a( Wen et ai. (1983}' Morgan and Wong (1984) Morgan and Wong (1985) Emerime and Henderson (1985) McCraw et al. f 1985] Jovner f1983) Divine et ai. (1985) Divine and Barron (1987) Rushton and Aldenon (198 Ul Rushton and AJderson (i983| Theriault and Goulet (1979)* Thenauit and Provencher (1987) Cmsue (19861 Nakamura {1987) 17 refineries 17 refineries 17 refineries U S refineries 10 retmenes Richmond. El Segundo Refineries Baton Rouge Refinery Baton Rouge. Baytown. Bayway Refineries Ron .Arthur Refinery Beaumont Retlnery Piulsboro Refinery Torrance Refinery Wood River Refinery Deer Park Refinery 13 refineries 4 others Production 4 pipeline 8 UK refineries UK distribution centers East Montreal Refinery East Montreal Refinery Australia 51 Japanese refineries 15 9 12 9 yt 19 6 4 l 24 5 22 22.09 0 68 8 40 14 82 t 07 0 31 5 SO 15.40 1.55 1.43 14 37 ".90 6.17 l 69 1.23 0.75 0 64 0.59 25.10 [4 10 21.74 19 05 0.96 0.35 1.01 1.21 f V* XX* XX* X* XJ <J Total 147 149 24 0.98 ip 85) Note: Blank entries indicate that the observed and expected deaths are not reported by the authors. "Excluded from the calculation of summary SMR. "Only refinery employees are included. ""Only male hourly employees with 1 or more years of employment are included. Jx = Analysis done. exx = Analysis done in subsequent report (see text). 'p < 05. ' deaths, p = .05, borderline significance). A significant excess was detected among men aged 55-64 years (SMR = 1.89. p < .05). For the industry as a whole, the kidney cancer meta-SMR was 0.98, based on 147 deaths. The data were somewhat conflicting. On the one hand, production workers at Texaco experienced a significantly low kidney cancer mortality. On the other hand, drivers among British distribution workers experienced a borderline significant increase. The results from refinery studies ranged from nonsignificant deficits to nonsignificant excesses. Additional data, particularly from those exposed to downstream gasoline, are needed to resolve this issue. Brain and Central Nervous System (CNS) Cancer (IC08,191-192) Several studies of petroleum employees showed some nonsignificant excess of brain and CNS cancer (Table X). The API-MSKCC registry showed an SMR of 1.63 (p = 16. not significant). Among the Gulf nonwhite males [Wen et al., 1983], a 448449 Cancer Epidemiology in Petroleum Industry 299 T VBLE X. Summary of Mortality From Brim Cancer in Coirart Studio of Refinery and Other Petroleum Employees* \uthonyear Facility Observed Expected Statistical Latency Duration deaths deaths SMR significance analysis analysis Tibcnhaw Cooper Assc. (1974}* 17 refineries `Von? [19801* 17 refineries Kaoian | I9t!6j* -* 17 refineries Schoctenteid et al. [19811*'* Nelson [ 1985| 10 refineries Wong et al. [ 19861 Richmond. El Segundo Refineries Hants et al. [19821* Baton Rouge Refinery Hants et ol. [ 1985a| Baton Rouge. Baytown. Bayway Refineries Wenetal (19831* Port Arthur Refinery Morgan and Wong (198*1 Beaumont Refinery Morgan and Wong (1985] Paulsboro Refinery Enterlme and Hendenon (19851 Torrance Refinery McCraw et ol. (1985} Wood River Refinery Joyner[1983| Deer Park Refinery Divine et al. [1985] i 3 refineries it omen Divine and Barron 11987) Production it pipeline Rushton and Alderson (I98la| 8 UK refineries Rushton and Alderson (1983) UK distribution centers Theriault and Goulet (1979J* East Montreal Refinery Thenauit and Provencher (1987] East Montreal Refinery Christie (1986] Australia Nakamura (1987] 51 Japanese Refineries 3 22 8 S :: 5 13 13 9 7 3 31 LI 36 39 3 4 2 tl 29 24 63 4.90 9 60 17 48 0.71 0.89 1 63 0 83 1 25 490 13.00 1 02 1.15 22.35 3.26 6 64 2.09 1 01 1 09 1.03 1.43 :8 oo 15.90 44 77 36.54 0.77 1.87 :.:o l.U 0.69 0.30 1.07 3.89 2.13 0.74 V* X* XX* XX* X4 X* ta X* X* XJ t* x* X* Total 210 209.7 100 (p- 99) `Note: Blank entries indicate that the observed and expected deaths are not reported by the authors. 'Excluded from the calculation of summary SMR. 'Only refinery employees are included. 'Only male hourly employees with 1 or more years of employment are included. Js = Analysis done. 'tx = Analysis done in subsequent report (see text). brain cancer SMR of 1.63 was detected (not significant). In the Mobil Torrance refinery, an SMR of 1.43 based on 3 deaths was repotted (p = .50, not significant). In Canada, the Shell Canada East Montreal refinery employees had an SMR of 2.13 (p = . 12. not significant). All these studies were based on very small numbers (Table X). Based on the PMR study of the Gulf and Texaco Port Arthur refineries, Thomas et al. [1980] repored higher than expected brain cancer morality among the refinery employees. A' subsequent PMR study of brain cancer of the Gulf and Texaco Por Arhur and the Mobil Beaumont refineries also repored elevated brain cancer PMRs [Thomas et al., 1982b]. Other subsequent studies addressing the issue of brain cancer and benign brain tumors were also repored [Wong, 1980; Wen et al., 1982]. Wong [1980] concluded that there was no brain cancer excess in the TCA industrywide study (SMR = 0.71 based on 8 deaths), which was confirmed by a later update of the study (SMR = 0.89 based on 22 deaths) [Kaplan, 1986], Wen et al. [1982] analyzed both malignant and benign brain tumors in the Gulf Por Arthur refinery employees. 448450 JOO Wong and Raabe Although the SMR of 0.97 (30 deaths) for the entire refinery was similar to the expected, those with 20 or more years of employment experienced an SMR of 1.43 (p = .10. not significant), which was more than twice that for those with less than 10 years of service (SMR = 0.59). A subsequent case-control study by Thomas et aJ. [1984] on three Texas refineries including the Gulf Port Arthur plant did not find any work category associated with b.-.u turnor mortality. Another approach to evaluate the issue of brain cancer in petroleum workers is to examine the data for any dose-response relationship. A few studies provided analyses by length of employment. No trend was found for brain cancer with respect to length of service in the Chevron Richmond and El Segundo refineries [Wong et al., 1986], the Mobil Beaumont and Paulsboro refineries [Morgan and Wong. 1984, 1985], and the laboratory workers at the Texaco refineries [Divine and Barron.-1987], Thus, analysis by length of service did not support a causal association between refinery employment and brain cancer. Brain cancer is a highly fatal disease. Little is known about its etiology, and no preventive behavior or medical intervention has demonstrated any significant bene fits. As such, brain cancer in industrial groups is not expected to be influenced by the healthy worker effect, and the corresponding SMR, in the absence of any occupa tional carcinogens, is expected to be close to 1. Overall, the petroleum workers experienced an identical brain cancer mortality as the general population (meta-SMR = 1.00, p = .99). Although some studies showed nonsignificant excesses from brain cancer, these studies were small. It has been demonstrated that industrial workers were more likely to have an overdiagnosis of brain tumors as a result of more complete medical evaluation, "diagnostic sensitivity bias" [Greenwald et al.. 1981]. It has also been demonstrated that socioeconomic class can also influence diagnostic sensitivity for brain cancer [Levine. 1985], Further inves tigations in this direction on petroleum workers are needed. Lymphatic and Hematopoietic Cancer (ICD8, 200-209) Of the studies listed in Table XI, a few studies showed modest increases in lymphatic and hematopoietic cancer. A significant excess was found in Mobil Beaumont refinery employees (SMR = 1.47. 47 deaths, p < .05). Similar excesses, although not statistically significant, were also found in the Shell Wood River refinery and the participants in the Australian registry. The .AMOCO study showed a signif icant deficit (SMR = 0.60. p < .05). Other studies based on a reasonable number of deaths indicated that the mortality was similar to the expected. Several studies with length of service analysis indicated an increased mortality from lymphatic and hematopoietic cancer with increasing length of service. These studies included the Chevron Richmond and El Segundo refineries [Wong et al., 1986], and the Mobil Beaumont refinery [Morgan and Wong, 1984], On an industry basis, the meta-SMR was 1.03 (based on 46C deaths, p = .58). Individual study results were not consistent. Both significandy high and low SMRs were reported. It would, perhaps, be more informative to examine the specific subgroups within the broad category of lymphatic and hematopoietic cancer. Lymphosarcoma and Rectlculosarcoma (ICD8, 200) For lymphosarcoma and recticulosarcoma. three cohorts with reasonable num bers of deaths reported nonsignificant excesses (Table XU). In the Chevron study, the 448451 'JtC'dO ...... Cancer Epidemiology in Petroleum Industry 301 TABLE XI. Summary of Mortality From Lymphopoietic Cancer in Cohort Studies of Refinery and Other Petroleum Employes* Author'ea/ Facility Observed Expected Statistical Latency Duration deaths deaths SMR significance analysis anaivsts Tubersnaw Cooper Assc. |l97a| l? refineries Wong (11801' 17 refineries Kaplan (11861' ! 7 retinenes Schoctenreid et ai. ,'1981!** L' 5 refineries Nelson 11985) [0 refineries Wong et ai. i |986i Richmond. El Segundo Refineries Hams 6t al [ 19821* Baton Rouge Refinery Hams et il. [ 1985a) Baton Rouge. Baytown. Bayway Refineries Wen et ai. (I983|e Port Arthur Refinery Morgan and Wong [ 1984} Beaumont Refinery Morgan and Wong [I985| PauJsboro Refinery Entertme and Henderson (19851 Torrance Refinery McCnw et aJ. (1985| Wood River Refinery Joyner(1983) Deer Park Refinery Divine et al. (1985) 13 refineries it others Divine and 8arron {1987} Production it pipeline Rushton and Alderson (I98la| 8 I'K refineries Rushton and Alderson (1983) L'K distribution centers Theriault and Couiet (1979)* East Montreal Refinery ThenauJt and Provencner (1987) East Montreai Refinery Christie (1986) Australia Nakamura (1987) 5! Japanese Refineries *8 17 64 M 55 62 47 Z3 5 8 "1 106 48 3 3 % 82.50 l 07 :3.;o 0 60 60.97 l 05 :j oo 1 09 61 30 0 39 58 62 31 39 mn 6.63 15 :o 1 06 1.47 0 93 0 75 l 44 96.70 1 10 54 60 0 38 2.36 4 44 434 t 27 0.67 1.63 t S V1 Xs \J IJ IJ Total 460 448.71 l 03 ip* 58) Note: Blink entries indicate 'Sat the observed and expected deaths are not reported by the authors. 'Excluded from the calculation of summary SMR. "Only refinery employees are included. 'Only male hourly employees with 1 or more years of employment are included. Jx = Analysis done. 'p < 05. ' SMR was 1.26. Length of employment indicated that those with 15 years of employment had an SMR of 1.62 (14 deaths, p = .07, not significant). In 1947, the recommended benzene standard [8-hour Time-Weighted Average (TWA)] in the United States was lowered from 100 ppm to 50 ppm. and in 1948, it was further lowered to 35 ppm. To determine the impact of this significant reduction in the benzene standard, analysis by hire date was done in the Chevron study. Among those hired before 1948 at the Richmond refinery, the SMR was 1.87 (13 deaths, p = .05), whereas there was no excess among those hired after 1948. Although this analysis by hire date was somewhat confounded by latency, an adequate latency (some with over 30 years) was achieved by those hired after 1948. Thus, there was some suggestive evidence that historical benzene exposure might be related to an increase in lympho sarcoma and recticulosarcoma. At the Mobil Beaumont refinery, the analysis by length of service did not show any pattern, but the analysis by latency showed an upward trend. The Exxon cohort showed a slight, nonsignificant excess. All other studies with a reasonable number of deaths showed a deficit from this 448452 06684 302 Wong and Raabe TABLE XII. Summary of Mortality From Lymphojaixoma in Cohort Studio at Rtflntrv and Other Petroleum Employees* Author-year Facility Observed Expected Sutisncal Latency Duration Jeachs deaths R significance analysis anaivsis Titxrcnaw Cooper Assc (1974|* 17 refineries 'Aon* ; 19801* l" refineries Kaolan 17 refineries Swhottenteld et al 111 T 3 L'.S. refineries Nelson 11985] 10 refineries W'ong et ai (1986) Richmond. E! Segundo Refineries Hams et ai |198I]4 Baton Rouge Refinery Hams et ai. [ I985a| Baton Rouge. Baytown. Bayway Refineries Wen et ai. (I983|c Port Arthur Refinery Morgan and Won* [I9ga| Beaumont Refinery Morgan and W'ong (19851 Pauisboro Refinery EruerUne and Henderson {19851 Torrance Refinery McCraw et ai. {19851 Wood River Refinery Joyner[1983] Deer Part Refinery Divine et ai. (19851 *13 refineries 8c others Divine and Barron (I987| Production & pipeline Rushton and Alderson (I98la| 3 L'K refineries Rustuon and Alderson (19831 CK distribution centers Thenauit and Goulet (1979|# East Montreal Refinery Thenauit and Provencher 11987J East Montreal Refinery Christie [19861 Australia . VaJcamura [ 1987] 51 Japanese Refineries 16 17 5 13 10 3 l 0 :o 7 16 7 l 17 '8 0.90 13 aj i :s 9 :o 11.40 1.19 1.14 11 69 6.31 5.36 l 55 :.80 0.17 1 46 0.55 0.64 0.00 :: :o 11.30 16.26 8.05 0 90 0.59 0.98 0.87 0.40 2.48 i XJ \4 K* XJ XJ Total 97 111.75 0.87 ip- -is* "Note: Blank entries indicate that the observed and expected deaths are not reported by the authors. JE.\duded from the calculation of summary SMR. "Only refinery employees are included. 'Only male hourty employees with l or more years of employment are included. J\ = Analysis done. ' 'p < 01. cause of death. The lowest SMR was observed in white male employees at the Gulf Port Arthur refinery, 1 observed vs. 10 expected. None of the studies reporting a deficit based on a reasonable number of deaths made any attempt to analyze the data by length of employment. For the industry as a group, the meta-SMR was 0.87 with a p-value of . 16. Although the Chevron data were consistent with an increase, the increase was modest and was associated with historical exposure. The weight of the evidence favors a conclusion of a similar or slightly lower mortality risk from this cause for petroleum workers when compared to the general population. Leukemia (IC08, 204-207) Because of potential exposure to benzene in the petroleum industry, leukemia is perhaps one of the most serious concerns as well as one of the most studied causes. In addition to analysis in the cohort studies, some case-control studies within the 448453 Cancer Epidemiology in Petroleum Industry 303 TABLE XIII. Suranurv af Mortality from Lruktola la Cohort Studies of R<fiot7 tad Other Pttrokuat Employers* Vutnor/vear Facility Observed Expected Statistical Uieacy Dunoon deaths deaths SMR significance analysts analysis Tabersnaw Cooper Assc. [1974|* 17 refineries Wong [ 19801* (7 refineries Kaplan [ 19861* 17 refineries Schouenfcid et il [19811* 0 U S. refineries kelson [19851 10 refineries Wong et al. (I986| Richmond. El Segundo Refineries Hams et al, [19821* Baton Rouge Refinery Hams et li [I985a| Baton Rouge. Baytown. Bayway Refineries Wen ei al. [19831* Port Arthur Refinery Morgan and Wong (1984) Beaumont Refinery Morgan and Wong [ 19851 Paulsboco Refinery Emerhne and Henderson (19851 Torrance Refinery McCraw et al. [19851 Wood River Refinery Joyner(19831 Deer Part Refinery Divine el il. [1985] 13 refineries A others Divine and Barron [19871 t Production A pipeline Rushton and Aldenon [198la| 8 UK refineries Rushton and Alderson [19831 UK distribution centers Theriault and Goulet [ 19791* East Montreal Refinery Theriault and Provencfter [1987] East Montreal Refinery Chnstie (1986) Australia NaJcamun (1987) 51 Japanese Refineries 10 32 4 4 Tty 9 20 33 23 10 2 14 6 48 a 30 23 3 9 12.18 0.82 31.63 5.98 9 70 24.92 1.01 0.66 0.41 0.88 9 30 0.97 25.90 0.77 33.08 13 31 10.28 2.54 6 60 3.60 40.70 22.70 31.96 26.82 1 32 1.72 0.97 0.78 2.13 2.30 1.18 1.10 0.94 1.04 1.93 8.3 2.39 1.06 r f f f X4 X4 XX* XX* X4 X4 X4 X4 X4 X4 X4 X4 XX* Total 279 233.34 1.10 (p - .10) Note: Blank entries indicate that the observed and expected deaths are not reported by the authors. 'Excluded from the calculation of summary SMR. ~ sOnly refinery employees are included. - "Only male hourly employees with 1 or more years of employment are included. Jx = Analysis done. *xx = Analysis done in subsequent report (see text). 'p < .03. ' petroleum industry have also been done. Table XIII shows the results of the cohort studies. Most of the studies reported either a similar or a higher leukemia mortality experience. Only the AMOCO study reported a significant deficit in leukemia. The number of deaths involved was oniy 4. This result was inconsistent with the rest of the industry. Several studies reported significant leukemia excesses. Although the original Gulf Port Arthur refinery study. [Wen et al., 1983] found a nonsignificant leukemia excess (SMR = 1.32, Table XIII). an unpublished update of the study through the end of 1983 [Wen et ah, 1984c] showed a significant leukemia excess among employees with 20 or more years of service (SMR = 1.63, p < .01). The excess came mainly from lymphocytic and other unspecified cell types. Furthermore, an upward trend was found by length of service. According to the updated data, of the 43 leukemias at Gulf, 28 had a latency of 30 or more years. The Mobil Beaumont refinery showed a significant leukemia SMR of 1.72 for 448454 056 304 Wong and Raabe the entire cohon (23 deaths, p < .05). Analysis by length of employment among the white males detected a significant SMR of 2.35 for those with 30 or mote years of service. Similar analysis showed a significant SMR of 2.14 in white males with a latency of 20-39 years. Different cell types were observed. Elevated leukemia mortality was found at the Shell refineries at Wood River and Deer Park. At Wood River. 14 leukemias were seen when only 6.6 were expected [McCraw et al., 1985]; the SMR was 2.13 (p < .05). The excess was associated predominantly with acute myelogenous leukemia (SMR = 3.94, p < .01); however, leukemias of other cell types were also observed. A similar significant excess was also found at the Shell Deer Park refinery [Joyner. 1983], Six leukemia deaths were identified, producing an SMR of 2.30 (p < .05). Three of the leukemias were acute myelogenous leukemia, and the corresponding SMR was 3.60 (p < .05). However, a subsequent nested case-control study failed to identify any specific locations or jobs responsible for the excess [Austin et al.. 1986], The Australian registry, even though the follow-up was very short, detected an increase m leukemia mortality (5 observed. SMR = 2.59. p < .05). Although the industrywide refinery study [Rushton and Alderson. 1981a] in Britain found a leukemia mortality for the entire cohort similar to that for the general population, a subsequent case-control study [Rushton and Alderson. 1981b] found a more than threefold risk among those with either medium or high exposure when compared to those with low benzene exposure. Although the industry overall experienced only a small excess in leukemia (meta-SMR = 1.10. p = . 10). there is suggestive evidence that some small groups within the industry may have had significantly elevated leukemia risk. This conclu sion is based on several considerations; the significant excesses observed for the entire refineries in several studies [Morgan and Wong, 1984; McCraw et al., 1985]; increased risks with increasing length of service [Wen et al.. 1983; Morgan and Wong. 1984]; and case-control studies within the industry [Rushton and Alderson, 198lb]. However, several issues remain unresolved at this time. First, high-risk groups have not been identified, and only a few studies provided job- or area-specific analyses. Most of the leukemia cases in the petroleum industry were not found among those who worked on benzene units directly [Tsai et al.. 1983; McCraw et al.. 1985]. Large case-control studies with detailed employment and exposure data are needed to identify high-risk groups. Second, except for the two Shell refineries, most refinery studies reported a variety of cell types, not limited to acute myelogenous leukemia alone. The issue of whether benzene or other petroleum hydrocarbons can affect only acute myelogenous leukemia or other cell types as well remains unresolved. Third, diagnostic specificity (or lack of) for lymphatic and hematopoietic diseases on death certificates, particularly on older death certificates, may result in inaccuracy of underlying cause of death classification. This misclassification may confound site-specific analyses. Fourth, latency in these leukemia cases was of the order of 20-30 years, different from the short latency reported for benzene-related leukemias in the early literature. By comparison, benzene exposure at refineries is much lower than those reported earlier (e.g.. shoemakers in Turkey) [Aksoy and Erdem. 1978], The data suggest that latency is inversely related to intensity of exposure. This hypothesis needs verification. Fifth, it is not clear at this point whether benzene was the only responsible agent or if other chemicals were also involved. 448455 f- ,j '-.VS Cancer Epidemiology in Petroleum Industry 305 TABLE xrv. Summary of Mortality From Other Lymphatic Tissue Cancer ia Cohort Studies of Rctlnery and Other Petroleum Employees' Author-year Facility Observed Expected Statistical Latency Duration deaths deaths SMR significance analysis analysis Tubersnaw Cooper Assc. 119741* 17 refineries Wong 119301" 17 rennenes Kaplan [19861* 17 rennenes Scnonemeld tt al j 19811*0 l' 5 rennenes Nelson (19851 .0 rennenes Wong ci ai. [ 1986) Richmond. El Segundo Rerinenes Hams et jJ. [ 1982!* Baton Rouge Refinery Hams ei ai. (,1985a) 9aton Rouge. Baytown. Bayway Rerinenes Wen et al. [19831' Port Arthur Rerinery Morgan and Wong (1984) Beaumont Refinery Morgan and Wong [ 1985] Paulsboro Refinery Entenine and Henderson (1985) Torrance Refinery McCraw et ai. (1985) Wood River Refinery Joyner(1983) Deer Park Refinery Divine et aJ. (1985) 13 rennenes it others Divine and Barron (1987) Production & pipeline Rushton and Aldenon (1981a) 3 UK rerinenes Rushton 3nd Aldenon (19831 UK distribution centers ThenauJt and Gouiet (1979|* East Montreal Refinery Thenauit and Provencher (1987] East Montreal Refinery Chnsue 119861 Australia Nakamura (19871 51 Japanese refineries 30 :o 7 15 [4 12 8 6 :5 12 6 2 22.32 l 31 14 12 l 41 7 :o 0 97 18.60 0.81 13 23 7 62 5 66 1.96 4 30 1.05 1.57 1.4) 1.02 1.26 21.30 1.15 13.50 0.89 3.63 1.65 1A7 1.36 ** V1 Total 122 106.39 1.15 <p- 13) "Note: Blank entries indicate that the observed and expected deaths are not reported by the authors. "Excluded from the calculation of summary SMR. ""Only refinery employees are included. 'Only male hourly employees with l or more years of employment are included. Jx = Analysis done. . Cancer of the Other Lymphatic Tissue (ICD8, 202, 203, and 208) Table XIV shows the SMRs for cancer of other lymphatic tissue from the eligible cohort studies. For most studies, the SMR was slightly above the norm. These included the API industrywide study [Kaplan, 1986], the Chevron refineries [Wong et al.. 1986], the Mobil refineries at Beaumont and Paulsboro [Morgan and Wong. 1984. 1985], the Shell Wood River refinery [McCraw et ai., 1985], and the British distribution workers [Rushton and Alderson. 1983], Only two studies showed an SMR less than 1: 0.81 for the three Exxon refineries and 0.89 for the Texaco production workers. As stated earlier, the exposure of production workers might not be similar to the refinery workers. Overall, the meta-SMR was l. 15 fp = . 13). Although the excess is not statistically significant, several points need to be addressed. In regard to the relationship between "cancer of the other lymphatic tissue" and leukemia, recent immunologic studies have shown that there are stem cells that appear to have the capacity to develop into the following different cell lines: T-cell lymphocytes, plasma cells, granulocytic series cells, erythrocytes, and monocytes 448456 0668S 306 Wong and Raabe TABLE XV. Power Analysis by Cancer Site* Cancer site All Digestive Stomach Pancreatic Lung Skin Prostatic Kulnev Brain Lymphopoietic Lymphosarcoma Leukemia Other lymphatic tissue Observed deaths 6.405 947 535 336 1.903 93 -U5 U7 210 460 97 279 122 Expected deaths 7.525.29 1.174 36 659 95 354,33 2.469 60 39.23 461 35 149 24 209.70 448.71 111.75 253.54 106 39 SMR 0.85 0.31 0 39 0.95 0.77 1.04 0.96 0.98 1.00 1.03 0.37 1.10 1.15 95% Cl LL 0.83 0.76 0.82 0.85 0 74 0.34 0 37 0.33 0.87 0.94 0.71 0.97 0 95 L'L 0 37 0.36 0 96 1 05 0.81 1.23 1.05 1.15 1.15 1.13 1.06 1 23 1.38 p-value < 00001 < 00001 < 005 = 32 < 00001 = 70 = 45 = 35 = 99 = 58 = 16 = 10 = 13 MIN SMR 1.03 1.07 1.10 1 14 1.05 1 23 1 12 1.21 1.18 1.12 1.25 1.16 1.25 95% Cl = confidence interval iupper and lower limits [LL. UL|); MIN SMR = minimum SMR detectable at 05 level with 30% power. [Minowada et al., 1981]. Further work by Bakhshi et al. [1983] demonstrates that the major clone in chronic myelocytic leukemia involves cells capable of lymphocytic, granulocytic, and erythrocytic differentiation and has led to the conclusion that a transformation event occurs at a very early multipotent stem cell level. Because this [CD group consists of several lymphatic and hematopoietic cancers, little attention has been focused on this category. Because of the diagnostic overlap, the natural course of various lymphatic cancers [Jaffe and Berard, 1978], and the multipotent stem cell theory [Minowada et al., 1981; Bakhshi et al., 1983; Kersey, 1983], cancer of other lymphatic tissue should be combined with other lymphatic and hematopoietic cancers for analysis [Wong, 1987; Heath, 1982; Decout'le et al.. 1983]. A thorough examination of the industry data in this direction will help to resolve this issue. CONCLUSIONS Based on this review of the pertinent epidemiologic studies in the petroleum industry, we conclude that employees in this industry with potential exposure to petroleum products including gasoline-like hydrocarbons are not at increased risk for most cancers examined. The statistical power of the combined data from these epidemiologic studies in detecting a modest risk in most cancers is quite high (Table XV). In fact, the review indicates that these employees experienced a significantly lower mortality than the general population from the following cancers: all sites combined, digestive system, stomach, and lung. For skin cancer and brain cancer, the results from various studies were not always consistent. However, the overall data indicated that the mortality experience for these two cancers of petroleum employees was similar to that in the general population. . For prostatic cancer and kidney cancer, the employees in the petroleum industry as a whole experienced a similar risk as the general population. However, there are 448457 Cancer Epidemiology in Petroleum Industry 307 data indicating that certain small groups within the industry might have an elevated risk. For prostatic cancer, employees at the MEK-dewaxing units may be at higher risk, but the numbers in these studies were very small, and the results were not replicated in a subsequent study. For kidney cancer, one study indicated that gasoline truck drivers were at higher risk. Additional studies of these sites that include exposure information are needed before any relevance to hydrocarbon exposure can be determined. The review supports the conclusion that some subgroups of petroleum employ ees. particularly those with more than 20 years of service and employed before the 1940s in the petroleum industry, may have been at increased risk of leukemia. This conclusion is based on the fact that several studies of refinery workers showed a significant excess, on the consistency of the data, on the positive trend with increasing length of employment and latency, and on the results of detailed casecontrol studies within the industry. Unfortunately, accurate historical exposure data are lacking. In most refineries, industrial hygiene-monitoring data were not been routinely collected until the mid-1970s, whereas relevant exposures in these cohort studies occurred much earlier. A risk assessment by quantitative exposure data cannot be made based on the currently available data. An industrywide case-control study of leukemia, with a strong focus on historical exposure data, would be helpful in such a risk assessment. Furthermore, there is some indication that mortality from cancer of other lymphatic tissue might also be elevated. Owing to the reasons provided earlier, this broad ICD category should be given mote attention in the future. 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