Document mqrLK6Ek7qgkdvZGyZQ2v562d

RE: Seeping of benzene pooled epidemiological analysis From: "Swaen, Gerard (G)" <gswaen@dow.com> To: "Tsai, Shan P SHLOIL-SHS" <shan.tsai@shell.com>, "Roythorne, Christopher" <chris.roythorne@uk.bp.com>, "Satin, Ken (KSAT)" <ksat@chevrontexaco.com>, Urbanus Jan <jan.urbanus@concawe.org>, chris.money@exxonmobil.com, "DeJong, Geert G SI-SHS" <geert.dejong@shell.com>, rolf.ahlberg@nesteoil.com, jeanphilippe.gennart@total.com Date: Fri, 03 Jun 2005 08:16:28 +0100 Shan, I was aware ofthe possibility that I would propose something against an earlier decision. Still I would encourage some more thoughts on including other datasets: 1. 1. Other datasets are available and getting permission would not delay the project very much. 2. 2< The highest exposure to benzene in the petroleum industry is still very low. Some top loading and splash loading of drums may have occurred, but the TWA's would not be higher than a few ppms, I estimate. Now if a dataset with this small dose range will be used to find a threshold, it can never come up with a higher threshold than the highest observed exposure. The point is: Maybe the whole study population is below the threshold and the pooled study can never provide evidence for a threshold. 3 < 3. Including datasets with higher exposures, in which some small effects have been reported in historical exposure situations, would allow us to evaluate a much wider range of the exposure spectrum< This would provide a much clearer dose-response curve. Gerard Gerard Swaen The Dow Chemical Company Epidemiology Health Services tel: 31-43-3626042 -----Orig ina I Message----From: Tsai, Shan P SHLOIL-SHS [mailto:Shan.Tsai@shell.com] Sent: donderdag 2 juni 2005 16:40 To: Swaen, Gerard (G); Roythorne, Christopher; Satin, Ken (KSAT); Urbanus Jan; chris.money@exxonmobil.com; DeJong, Geert G SI-SHS; rolf.ahlberg@nesteoil.com; jeanphilippe.gennart@total.com Subject: RE: Scoping of benzene pooled epidemiological analysis Gents, The objectives of the proposed pool study was 1) to improve the analyses and interpretation of the three existing individual studies, 2) to further clarify the potential risk of overall and cell-type specific leukernia from low-level exposures to benzene, and CGU BEN0000047 2) to exiablish a threshold !or benzene exposures To achieve the above objectives in a "timely" scheclule ancl minimize the potential complications of exposure assessment, it is important that we should not expand IJeyonc! the existing three stuidies, Le., IOL IP, and HW. To extend the follow~up of the IOL and IP would increase the statistical power, however, the time delay (additional 2-3 years) should be a factor to consider. Althou9h the original IOL case-control study includes cases lhorugh 1983, the cohort o! this nested case-control study has been updated thmugh '1994 (Lewis et al. Occup Environ Ivied. 2000 Sep;57(9);595-604). One alternative to consider is to ac!cl only new cases from the IOL that were identified from the updated IOL study and not inclucle the additional update ofthe IP. Regards, Shan P. Tsai, Ph.D. Manager, Epidemiology Shell Health Services Shell Oil Company P 0 Box 2463, Houston, TX 77252-2463, United States of America Tel: +1-713-241-6078 Fax: +1-713-241-5875 Email: shan.tsai@shell.com Internet: http:llwvvw.sile!f.com rhis e~rnai! rnay: ('1) be subject to H~e i\ttorney. ~-C:!ient pfivj!enel (2) contain c:<)NF"![)EN~r!.i\L !V1E!:)!(~)\L !NFC)F~!\/Lt\T!C)N, or (3) be strjcUy conndenbaL Hyou rece!vt:: rt ;n error) y-ou are on notice of jts statu~-;. F~!ease not!fy u~~ ~n1rnecHate!y by reply t:rnaH and then de!eh:~ this rnE.:ssa~~g:~ fron1 your corr~puter systern. F)!eHse do not copy it or use it for ~iny purpose. or discJose its contents to any pt:!rson; to do so c.ou!d be.:.:~ breach of confk.ience. ~rh.:::nk you for your cooperation. -----Orig inaI Message----From: Swaen, Gerard (G) [mailto:GSwaen@dow.com] Sent: Thursday, June 02, 2005 2:49 AM To: 'Roythorne, Christopher'; Satin, Ken (KSAT); Urbanus Jan; Tsai, Shan P SHLOIL-SHS; chris.money@exxonmobil.com; DeJong, Geert G SI-SHS; rolf.ahlberg@nesteoil.com; jeanphilippe.gennart@total.com Subject: RE: Scoping of benzene pooled epidemiological analysis All, In rny perspective Ken and Christopher have both raised sorne very crucial points and I believe the first step should definitely be to avoid comparing apples with oranges, with respect to the exposure characterization as well as with respect to the outcome parameter. If possible, phase 2 should make sure that all contributing participating institutes have done their best to collect specific data on diagnosis" In addition to the points rnade by Ken and Christopher I would like to make the following points: 1. Why is the pooling effort restricted to the three petroleum industry stuclies? Pooling of only three studies will be less informative than if rnore studies would be included. There are several other studies on benzene and leukemia with reliable exposure information that also contain relevant information ancl woulcl increase the exposure range under investigation (indispensable for threshold analyses) and would significantly increase the poweL Some other interesting studies that could be included are the Monsanto study, the recent Dow study and the recent DSM study. The advantage of including the Dow study and the Monsanto study is that they report an excess in the high close group and thus contain information on a possible thresholcl. The IOL IP anc! HW do not contain such clear dose-response curves, if any. Even including the pliofilm cohort would have CGU BEN0000048 my preference, but I realize we run into trouble because of the different exposure estimates that are available. An extended pooled analysis would also have a better chance of evaluating the relevance of peak exposures. One of the most probable mechanisms for leukemogenesis is thought to work through bone marrow toxicity. Including bone marrow toxicity in the study opens the opportunity to study the relevance of bone marrow toxicity as the mechanism. If we include more studies we can test the hypothesis that increased leukemia rates have been restricted to cohorts or sub cohorts in which bone marrow toxicity has occurred or at least has been reported. 2. If point 1 is no option, I very much support the option to extend the follow-up of the three studies. If no new cases are added to the IOL, IP, and HW current databases a pooled analysis will only have a limited added value. 3. Including cell type information is very impmiant. Given the very small excesses, if any, it is very important to have the outcome parameter as specific as possible. If not, the dose-response analysis will become diluted. In addition, the results can be criticized for not having information on cell type. 4. I do find the estimated costs on the high side. The total is over one million Euro. For such a budget we could have a complete new study done. With respect to cell types: Have you seen the recent publication on Benzene workers in the UK by Sorahan, Kinlen and Doll in Occupational and Environmental Medicine? He concludes that effects are limited to ANL. Gerard Swaen Gerard Swaen Th.t Dow Ch.tmka1 Company Epidemiology Health. Services tel: 31-43-3626042 -----Orig inaI Message----From: Roythorne, Christopher [mailto:chris.roythorne@uk.bp.com] Sent: woensdag 1 juni 2005 09:02 To: Satin, Ken (KSAT); Urbanus Jan; shan.tsai@shell.com; chris.money@exxonmobil.com; Swaen, Gerard (G); geert.dejong@shell.com; rolf.ahlberg@nesteoil.com; jean-philippe.gennart@total.com Subject: RE: Scoping of benzene pooled epidemiological analysis All, I think !<en has raised sorne interestin9 points and hi9hli9htecl some si~V1ificant challenges with respect to exposure and cell type diagnoses which are the two critical factors. Leaving the exposure issue to one side I see the task of obtainin9 specific cell type results as a huge task and one that rnay not be achievable to the extent that would be of value across all of the studies. There is also another aspect to consider, that of original cell type diagnoses. Having recently been in Shanghai my understanding is that the study there is developing what I woulcl describe as very interesting data regarcling cell types which will have, in my vievv, significant implications for previously published studies. As a consequence, not withstandin~1 the hu~~e practical difficulties of any vmrk, I would be reluctant to embark on any further work until we unclerstand what the implications of the China Study are Re9ards Chris From: Satin, Ken (KSAT) [mailto:KSAT@chevrontexaco.com] CGU BEN0000049 Sent: 31 May 2005 23:36 To: Urbanus Jan; shan.tsai@shell.com; chris.money@exxonmobil.com; gswaen@dow.com; geert.dejong@shell.com; rolf.ahlberg@nesteoil.com; jean-philippe.gennart@total.com; Roythorne, Christopher Subject: RE: Scoping of benzene pooled epidemiological analysis Gentlemen: Jan's scoping outline pretty rnuch covers the full range or options. I think most are important to consider. but given monetary and time constraints (altl1ough at this point in time I don't know what those are), it is likely the entire scope would not be aweed to up front. This suggests a phased approach might be better, vvith each subsequent phase contingent on the successful completion or the previous, Of course. this coulcl make the whole project take longer and cost more than beginning all aspects at the same time. Neve1iheless, assuming a phased approach is most practical, I vvould suf:jgest the follovving phases: 1. Rationalize exposure across the studies. We are trying to quantify a relationship so unless we can achieve consistency acmss studies. there is liUie basis for cornbining data and thinking we vvill o!Jtain a meanin~1ful estimate of effect. Tl1is should !Je the first step. If it can't be done. we need to rethink what outcome vve want from the project. 2. 'vVe would like leukemia cell-type specific results so the next question is whether we can f:!et this rrorn the data. I vvould think rationalizing diagnoses across studies would entail obtaining l1istoric medical records. Depenclin!J on the availability and access issues related to such data, the goal of this phase may not !Je achievable. Therefore, I propose a feasibility study to see vvhat additional data could be obtained frorn a sarnple of each studies' cases. I would run this pilot concurrently with the exposure rationalization. In the event this task cannot be completed successfully, it is not necessarily a show stopper to pe1iorming a pooled analysis. For example, if cell-specific information was not available, the analysis of the case-control results could be run (as a series of simulations) based on rnodelin~! the cell-specific outcomes based on the ''usual" celltype distribution for a given time and study location and seeing how sensitive the results are to Hw assumed cell-type distribution ancl number of imprecise or inconsistent leukemia diagnoses such estimating must be applied to. 3. i\ssurnin~! phases 1 and 2 are successful, the analysis could be run ncNJ. This approach would be the least tirne and money intensive. Hovvever. the number or cases in the low exposure range might still be too small to yielcl t11e effect resolution we're looking for. Therefore. this is the time to consider further updating the parent coho1is to identify more cases. Note for example, that in the IOL cohort that the case-control study was based on only I I 0!.' of the cohort had died (3909i34597). This is a low percentage and may not be representative or the cohort's exposure experience so updating the vital status of coh01i members is probably a good idea. To save time, this phase could be started as soon as it appeared that the exposure rationalization was going to be successful. 4. Conduct the pooled case-control analysis using "modern statistical methods". Since Hw issue here vvas the elimination of arbitrary exposure categorizations, I suspect the goal is to use a regression technique, My caveat here is that we need to !Je careful that the analysis is not limited to, or for that matter, even includes, (lor,l) linear models. Instead, a general additive model mif:jht be the default used. Note that there is another implication of using nonlinear models-- narnely, average or unweighted cumulative exposure metrics will not be particularly meaningful. Consequently, some special modeling may !Je needed to pursue the application of a nonlinear exposure-response curve. Note that instead of using regression techniques, the arbitrariness of exposure categorization can be looked at by testing different category cutpoints and seeing the impact on the leukemia risk. I'm not sure how one would interpret tl1e results if we found the effect was very sensitive to the cutpoint, but it might tell us something about our data. 5. Sensitivity modeling of exposure-response curve. \!Vhile the essence ofthis task might contained in the analysis as I've described it in Phase 4, I don't think doing a sensitivity analysis for its own sake is vvorth it If the rnodeling results are similar. we've not leamed very rnuch other than may be our data is lackinf:l in its ability to achieve the resolution we are interested in. On the other hand, if the results of different exposure-response rnodels are different, vve will have interpretability problems since vve lack the golden ruler to tell us wliict1 is correct I would pursue CGU BEN0000050 sensitivity modeling only i! we had leltover funding. Ken Satin, DrPH ksat@chevron.com T: 510 242-1610 F: 510 242-7022 -----Orig ina I Message----From: Urbanus Jan [mailto:jan.urbanus@concawe.org] Sent: Tuesday, May 24, 2005 6:21 AM To: Satin, Ken (KSAT); shan.tsai@shell.com; chris.money@exxonmobil.com; gswaen@dow.com; geert.dejong@shell.com; rolf.ahlberg@nesteoil.com; jean-philippe.gennart@total.com; chris. roythorne@ uk. bp .com Subject: Scoping of benzene pooled epidemiological analysis Dear Colleagues, As requested at our recent Health Management Group meeting, I have drafted a first attempt at scoping out a pooled analysis project of the 3 nested case-control studies of benzene-exposed workers (attached). I would like to encourage you to comment on this via the 'reply all' function, so that we can develop this idea further into a more realistic scope. Please note I have agreed with Louis Bloemen that he would contribute to the Benzene DCR project as a consultant (after leaving Concawe member company Dow) up to the finalisation of the Phase 1 IOM/IRAS report, and hence he is not part of this next stage. I have included the remaining STF-30 members (Ken and Shan), supplemented with some HMG members- I trust you don't mind, but please advise if you feel we need others to contribute as well. Jan Urbanus Technical Coordinator, Health Issues CONCAWE (the oil companies' European organisation for environment, health & safety) Boulevard du Souverain, 165 B-1160 Brussels, Belgium T: +32-2-566 9163 F: +32-2-566 9181 E: jan.urbanus@concawe.orq CGU BEN0000051