Document 6bkVX47ZOMvyjMqK19p1M6YGR

Corporate Health Physics Corporate Occupational Medicine Corporate Product Responsibility Corporate Toxicology 3M Medical Department 3M Center, 220-2E-02 PO Box 33220 St. Paul, MN 55133-3220 651 733 1110 Serum Fluorochem ical trends of out-of-county residents in CLUE I (1974) and CLUE II (1989) epidemiologic investigations. This project is a joint collaboration between 3M and Johns Hopkins University School o f Public Health researchers. The objective o f this study is to analyze 358 adult sera samples that were collected in 1974 and 1989 as part o f the CLUE I and CLUE II studies conducted in W ashington County, Maryland. The sera samples represent out-of-county residents who participated in the study. A total of 59 samples are from individuals who donated in both 1974 and 1989. An additional total o f 120 samples will be analyzed in each year o f different individuals. Fluorochemicals to be measured include perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), perfluorohexanesulfonate, N-ethyl perfluorooctanesulfonamidoacetate (PFOSAA), N-methyl perfluorooctanesulfonamidoacetate (M570), perfluorooctanesulfonamidoacetate (M556), and perfluorooctanesulfonamide (PFOSA). The timeline for study completion, estimated at January 1, 2001, is entirely dependent upon a validated analytical method to analyze 1 ml o f human serum for these fluorochemicals with a lower limit o f quantitation o f < 10 ppb, based on high performance liquid chromatography electrospray tandem mass spectrometry methods. 000949 TITLE OF RESEARCH PROPOSAL Serum fluorochem ical trends of out-of-county residents in CLUE I (1974) and CLUE II (1989) epidemiologic investigations 1 RESEARCH QUESTION: Are fluorochem icals detectable in the serum samples of individuals who donated blood to a community-based specimen bank in 1974 and 1989 and to what extent do levels change over time? 2 RATIONALE/BACKGROUND: The 3M C om pany (sponsor of this proposal) manufactures widely-used products that contain fluorochemicals. Fluorochemicals transform metabolically to perfluorooctane sulfonate (PFOS) as an endstage metabolite. PFOS is a surfactant and used in industrial and commercial processes. PFOS concentrates in the liver and undergoes enterohepatic circulation. Subchronic studies in rats and primates suggest a cumulative to x icity resulting in lowered serum total cholesterol levels and metabolic w asting. These effects may be due to effects on fatty acid transport, metabolism, m em brane functions, and peroxisome proliferation. Exposure rates to these chemicals among the general population are unknown. Occupationally exposed individuals have been monitored for the presence o f fluorochemicals (O lsen et al). Among male production employees the m ean levels o f perfluorooctane sulfonate (PFOS) in 1995 and 1997 were 2.19 ppm and 1.75 ppm, respectively. N o substantial changes in serum hepatic enzymes, cholesterol, or lipoprotein levels were noted among individuals with levels less than 6 ppm. Only 7 individuals in 1995 and 5 in 1997 had levels in excess o f 6 ppm; no marked changes in lipid or hepatic enzymes were noted. It is unknown to what extent these levels can be detected in the general population. This proposal is an exploratory study to determine for the first time whether serum concentrations of fluorochemicals among a non-occupationally exposed population increase over time and whether concentrations vary by gender or age. 3. M E T H O D S From A ugust through November, 1974, the Campaign against Cancer and Stroke was conducted in Washington County, MD. Referred to as CLUE I (from the slogan, "Give us a Clue to Cancer"), a total o f 25,802 persons donated blood, o f whom 20,305 w ere county residents. The brief history form was completed at the time o f blood collection (Appendix 1). The Campaign against Cancer and H eart Disease (CLU E II) was similar to CLUE I in most respects. It was conducted from M ay through O ctober, 1989. Brief histories (Appendix 1) and blood pressures were taken, and 20 m l o f blood were drawn. Participants were given a food frequency questionnaire (A ppendix 1) to complete at home and were asked to return it with a toenail clipping for trace metal assays. A total of 32,898 persons participated (table 1 ). 000950 For this project we will use specimens from participants who are not Washington C ounty residents and who, therefore, are not in the analytic cohort. These individuals are referred to as the "out-of-county" group. A total o f 358 samples will be selected for assays (see table 1). Fifty-nine individuals in the "out-of-county" group gave blood samples in 1974 and 1989. The age distribution o f these 59 individuals in 1974 was as follows: age 25-44 years - 28; age 45-64 years - 20; age 65+ years -1 1 . We will analyze all of this group for serum fluorochemical levels to determ ine change in concentrations overtime within individuals. An additional sam ple o f 120 individuals from CLU E I and CLUE II will be selected stratified by gender and age. Table 1. Demographic Distribution of Total Number (N = 358) of Serum Samples to be Analyzed Same individuals both years in = 59/yr) Females* Males* Number of Subtects 1974 1989 32 32 27 27 Different individuals each year (1974.1989) Females <40 yrs 40-60 yrs >60 yrs 20 20 20 20 20 20 Males <40 yrs 40-60 yrs >60 yrs 20 20 20 20 20 20 Age in 1989 is provided below (1974 data and distribution by age by gender was not known at the time this proposal was written) Assuming the correlation between the two measurements obtained in 1974 and 1989 is 0.8, the sample size of 59 provides a statistical power of 85% to detect a 10% difference between the two time periods. Assuming the mean PFOS levels in the age group <40, 40-60 and >60 are 25, 30, and 36 ppb, respectively, and the standard deviation is 12 ppb for each group, we estimate 120 samples (40 in each age group) will provide a statistical power of more than 95% to detect a 20% difference among age groups. This sample size will also allow for a statistical power of 78% to detect a 20% difference between two groups (eg., men and women). Assay Measurements Northwest Bioanalytical will analyze for up to 8 serum organofluorochemicals (including PFOS) using high pressure liquid chromatography//electrospray tandem mass spectrometry (HPLC/ESMSMS) and evaluate versus an extracted curve. Because general population serum samples range in the area of the lower limit of quantitation (LLOQ) for PFOS that is currently 000951 used by Northwest Bioanalytical, samples from this study will not be analyzed until the LLOQ for PFOS (3 1 ppb) at Northwest Bioanalytical can be reduced by approximately I order of magnitude. This validation effort is currently underway 4 RISKS/BENEFITS For the assessment of the proposed biomarkers, data and blood were collected previously in 1974 and/or in 1989 when the subjects volunteered to participate in a campaign to collect blood for a serum bank and signed an informed consent. We cannot conceive of any potential risk at this time except for possible breaches of confidentiality. The proposed substance to be measured have not been associated with adverse health outcomes in humans. This study is the first step to determine if exposure (as measured by internal dose) has even occurred among non-occupationally exposed individuals. No information will be given to individuals. Sera will be assayed and analyzed without individual identifiers. Statistical data will be presented by groups, without individual identifiers. At this point, there is no individual benefit and virtually no individual risk. Protection against unauthorized access will be obtained by keeping the forms and computer files in rooms that are locked when not in use, and in a wing o f the Health Department that is also locked when not in use. Access to these records are authorized only for students, employees of the Training Center and collaborators of approved studies who have signed a confidentiality pledge. 5. PISCLOSURE/CONSENT Persons were recruited in 1974 and in 1989. At the times of blood donation, participants signed a general consent form, allowing their blood and data to be used for research purposes. For each of these campaigns, the consent form and history form were approved by the School's Committee on Human Research at its January, 2000 meeting. 6. CONFIDENTTALITY/INSURANCES All persons who are permitted to have access to our records must have a legitimate purpose and must sign a pledge of confidentiality. Records for this study that contain personal identifiers are kept in rooms that are locked when not in use and in a wing of the Health Department that is also kept locked when not in use. This wing is rarely used by anyone other than employees of the Training Center or Health Department. Personal information that might be considered sensitive such as date of last menstrual period, and use of oral contraceptives or hormones is coded in a way that cannot be interpreted without a key. The key is kept in a different room from the files. When data are to be used outside of the Training Center, names and addresses are removed. In more than 36 years of the existence of the Training Center, we know of no breach of confidentiality. The responsible persons are Dr. George W. Comstock, Director o f the Training Center for Public Health Research, Ms. Sandra C. Hoffman, Asst. Director, (301-791-3230) and Dr. Kathy J. Helzlsouer, Director of the Specimen Banks, 410-955-9727. 7. COLLABORATIVE AGREEMENTS: This proposal is not binding until a signed agreement is executed between the 3M Company and Johns Hopkins University. 000952 8. OTHER IRB APPROVALS N/A 9. SINGLE P R O JE C T ASSURANCE N/A 10. PUBLICATIONS It is 3M's intent to co-author information with Johns Hopkins University researchers derived from this study. The details of this will be outlined in the project research contract. Under this agreement Johns Hopkins University would retain the right to publish information from this study solely for its own teaching and research purposes. 11. PRO PRIETA RY DATA Proprietary information will be addressed in the final agreement signed between the 3M Company and Johns Hopkins University. 12. BUDGET The budget for the work contribution of the investigators from Johns Hopkins University is attached. Personnel (On-campus) Name Role on Proiect Kathy H elzlsouer Principal investigator Han-Yao H uang Co-investigator Gloria Zepp Secretary Total On-Cam pus Personnel R ate/hr $1,000 500 200 T o tal* $30,000 45,000 18.000 $93,000 Personnel (Off-campus) Sandra Hoffm an Project coordinator Clara Krumpe Laboratory Technician Judith Bolton Data manager Total Off-Campus Personnel $ 400 300 250 $ 4,000 18,000 5,000 $27,000 Serum B ank M ain ten an ce Costs (Maintenance, electricity, replacements) Cost Per Participant Sample $225.00 x 300 samples = $ 67,500 O ther Expenses Laboratory supplies (specimen tubes, pipettes) Computer Supplies Shipping costs (FedEx, dry ice shipping containers) Total Other Expenses $225.00 200.00 150.00 $ 575 Total Project Costs (Johns Hopkins University) * Total is an estim ate o f time to complete work. 000953 $188,075 Travel costs by Johns Hopkins University investigators will be billed directly to 3M. All other research study costs (e.g., analytical costs by Northwest Bioanalytical) will be paid by 3M. 000954