Document 2JpgV7pzyNEEvnJ3n282Y15dr

Electronically Served 9/22/2017 10:33 PM Hennepin County, MN 27-CV-10-28862 Filed in Fourth Judicial District Court 11/17/2017 7:31 PM Hennepin County, MN STATE OF MINNESOTA DISTRICT COURT FOR THE COUNTY OF HENNEPIN FOURTH JUDICIAL DISTRICT CIVIL ACTION NO. 27-CV-10-28862 STATE OF MINNESOTA, et al. v. 3M COMPANY EXPERT REPORT OF PHILIPPE GRANDJEAN, MD, DMSc PREPARED ON BEHALF OF PLAINTIFF STATE OF MINNESOTA 22 September, 2017 CONFIDENTIAL - SUBJECT TO A PROTECTIVE ORDER ENTERED IN HENNEPIN COUNTY DISTRICT COURT, NO. 27-CV-10-28862 27-CV-10-28862 Filed in Fourth Judicial District Court 11/17/2017 7:31 PM Hennepin County, MN likely to have negative implications regarding cardiovascular disease and mortality. In this regard, the C8 Panel concluded that PFO A is linked to an increased risk o f elevated serumcholesterol, and but not (yet) hypertension and coronary artery disease [263]. As hypercholesterolem ia and cardiovascular disease are of m ajor public health concern, these issues are discussed under a separate heading (Section VII.G). 1. Epidemiological evidence a. Increased serum -cholesterol concentrations at elevated PFC exposures likely relate to toxic effects on liver functions, and increased concentrations o f liver enzymes in serum at higher PFO A exposures support this notion in about a dozen epidem iological studies. An early m ention o f adverse liver effects from PFCs in workers is from 1978, when D uPont medical officers found elevation in liver function tests among a group o f workers leading to the conclusion that "it is possible that C-8 m ay be causing very minimal, and certainly not clinically apparent, toxic effects to the liver. Because the total num ber o f records review ed is small (31), I do not believe any findings o f this study are statistically v alid."pppp It appears th at these results w ere discussed w ith the 3M medical colleagues. External consultant, Professor H arold Hodge in 1978 reported to 3M 's m edical director, Dr. F.A .Ubel: "There appears to be indications o f liver change from the physical exam ination results. In term s o f indicators o f liver disorder, there are [sic] a higher percentage at Chem olite than at D ecatur and the organically bound fluorine level at C hem olite is correspondingly higher." qqqq b. In early 1980, D uPont shared the results o f a pilot study called "liver enzyme study o f w orkers exposed to C-8 at Parkersburg," w here they found elevated mean serum concentrations of aspartate am inotransferase (AST, previously referred to as SGOT) and alkaline phosphatase (A P) am ong w orkers operating the T FE process. rrrr D u P o n t provided m em oranda sum m arizing their findings. On June 9, 1980, the assistant m edical director V ann A. B rew ster w rote to L. F. P ercival th at "I am concerned th at the `D ra ft' im plies th at the M edical D ivision will not continue the study o f liver tests on those em ployees potentially exposed to C-8. Even though w e have found no `conclusive evidence o f an occupationally related health problem ,' w e still cannot explain w hy the m ean SGOT [same as AST] w as significantly higher among TFE process workers and that the mean AP was significantly higher among FEP process and service w orkers." ssss I have b een unable to identify evidence th a t liver tests w ere o f continued. pppp AR226226-1453.pdf, September 20, 1978 - DuPont Washington Work's Medical Director, Dr. Younger pared a memo summarizing his review of the medical records of eleven operators and eighteen laboratorians [at the Washington Works Plant] who have had long-term exposure to C-8. (Exhibit L (EID080236-40)). Page 000135. qqqq3MA00967742. (1978.08.23). Minutes of Meeting with H.C. Hodge, p. 3MA00967744. rrrr AR226226-1465.pdf, January 28 1980, Liver Enzyme Study of Workers exposed to C-8 at Parkersburg, Exhibit CC (EID099433-34). Page 000186. ssss AR226-1469. June 9, 1980 - DuPont prepared a memo expressing his concern that a draft communication to DuPont's Washington Works employees regarding the outcome of DuPont's liver study of employees "implies that the Medical Division will not continue the study of liver tests on those employees potentially exposed to C-8." (Exhibit GG (EID102477)). Page 000192. 70 CONFIDENTIAL - SUBJECT TO A PROTECTIVE ORDER ENTERED IN HENNEPIN COUNTY DISTRICT COURT, NO. 27-CV-10-28862 27-CV-10-28862 Filed in Fourth Judicial District Court 11/17/2017 7:31 PM Hennepin County, MN c. In his thesis, D r. G illiland found increases in serum concentrations o f SGOT and SGPT (now referred to as AST and ALT), as well as a tendency toward low er HDL cholesterol, as m arkers o f adverse effects on liver functionTM O ther cross-sectional studies [191, 248] were not informative in this regard, perhaps because a variety of other factors can impact on liver functions. The studies were reviewed in greater detail in regard to im m une function param eters in Section VII.A. d. The fact that the liver was an im portant target organ recognized by 3M 's Dr. Richard Purdy, and in 1999 he w rote to 3M colleagues, Drs. John B utenhoff and Andrew Seacat that his calculations showed that a "general population m em ber w ith 70 ppb (in one's blood) could have 36 tim es m ore in his liver"uuuu due to life-tim e accum ulation. H ow ever, I have been unable to determine how this conclusion was dealt with at 3M. c. Further analyses o f m edical surveillance data on PFO A -exposed w orkers in M innesota led to a 3M paper that relied on cross-sectional analyses of PFO A and liver function data collected in 1993, 1995 and 1997 [66]. W hile the w ording differs from a previous report [207], the authors concluded that em ployees' serum PFO A levels w ere not positively associated w ith either clinical hepatic toxicity no r hepatic responses to obesity and alcohol.vvvv f. D rs. O lsen and M andel reported in 1998 results on P F O S -exposed Antwerp and D ecatur m ale fluorochemicals production workers, in which they concluded that hematological, clinical chemistry and hormonal abnorm alities were not associated with serum P FO S levels up to 6 ppm (6,000 ng/m L ).wwww A lthough deviations occurred at h igher exposures, the authors disregarded these findings, basing this decision on a determ ination there w ere too few subjects to allow a firm conclusion [264]. A later analysis o f medical surveillance data from a fairly small num ber o f em ployees again howed a positive association betw een the serum -PFOA concentration and both cholesterol and triglycerides. These findings were considered im plausible, as they are not in accordance w ith anim al data at m uch higher exposures.xxxx Another lim itation that the 3M authors emphasized was the possible non-adherence by some w orkers to the fasting requirem ent, although blood-glucose w as not affected.yyyy tttt AR226-0473. Frank Davis Gilliland, Fluorocarbons and Human health: Studies in an Occupational Cohort (October 1992) (unpublished Ph.D. thesis, University of Minnesota), with Summary. Page 003247. uuuu 3MA01403075. Thoughts on human safety factors. Page 3MA01403075. vvvv AR226-0477. Geary W. Olsen, et al., An Epidemiologic Investigation of Plasma Cholecystokinin and Hepatic Function in Perfluorooctanoic Acid Production Workers, 3M Final Report EPI-0003 (1997), with Summary of study, Protocol, and Manuscript accepted for publication in 2000, Drug & Chemical Toxicology. Page 003511. wwwwAR226-0030. An Epidemiologic Investigation of Clinical Chemistries, Hematology and Hormones in Relation to Serum Levels of Perfluorooctane Sulfonate in Male Fluorochemical Production Employees (List of Section Attachments is first page of this File). Page 001074. xxxx 3M_MN02334964. Final report, A Longitudinal Analysis of Serum Perfluorooctanesulfonate (PFOS) and Perfluorooctanoate (PFOA) Levels in Relation to Lipid and Hepatic Clinical Chemistry Test Results from Male Employee Participants of the 1994/95, 1997 and 2000 Fluorochemical Medical Surveillance Program. Page 3M_MN02334966. yyyy 3MA01784788. An AnalYsis of the 2000 Pluorochernical (Perfluorooctanoate, PFOA) Medical Surveillance Program at 3M Company's Antwerp (Belgium), Cottage Grove (Minnesota), and Decatur (Alabama) Facilities. Page 3MA01784817. 71 CONFIDENTIAL - SUBJECT TO A PROTECTIVE ORDER ENTERED IN HENNEPIN COUNTY DISTRICT COURT, NO. 27-CV-10-28862 27-CV-10-28862 Filed in Fourth Judicial District Court 11/17/2017 7:31 PM Hennepin County, MN g. A lthough these findings w ould justify, at a m inim um , further follow-up, it is not clear if that happened and if the findings were ever analyzed and published. The C8 Health Project exam ined 47,092 adults for effects of PFO A and PFOS on alanine transam inase (ALT), gam m a-glutam yltransferase, and bilirubin as m arkers of liver function. These results showed a positive association betw een serum PFO A and PFOS concentrations and the serum ALT concentration [265], usually interpreted as a sign of hepatocellular damage. i. W hen serum -P F O A concentrations w ere m odeled as cum ulated concentrations, the adverse effect on serum ALT concentrations was replicated in a m ixed Ohio R iver Valley population [266]. j. L ikew ise, in a general population sam ple from the N H A N E S study, liver enzym es showed significant, though small, increases at higher serum -PFO A concentrations [267]. k. Several occupational studies, both cross-sectional and prospective, have assessed liver function param eters in serum, the m ost recent ones [66, 268, 269] showing that, in general, liver enzym es tend to increase, while bilirubin decreases at higher PFC exposure levels. 2. Toxicological evidence a. A lthough liver dysfunction in exposed w orkers w as discovered fairly early, it w as not taken seriously for many years. A study conducted in 1976 by Dr. Taves from the U niversity o f Rochester reported PFO A stim ulated lipid peroxidation (LP) in an in vitro experim ent. T he author noted that, at the tim e, in vivo effects o f P F O A w ere u n k now n.zzzz b. The liver w as early identified as a m ain target organ in rodents [44]. A lthough toxic m echanism s m ay differ betw een rodents and hum ans [7, 17], as I discussed above, the PPA R -related m echanism is no longer believed to be the differentiator 3M once m ade it out to be [10]. c. Detailed discussion o f liver toxicity in experimental m odels is included in recent evaluations by regulatory agencies [4, 148, 149], to w hich little recent evidence adds only little. d. One aspect deserves consideration, i.e., the intrahepatic lipid m etabolism. Some PFA Ss have the potential to induce hepatic lipid accum ulation in cynomolgus m onkey [270] and induce lipid synthesis gene expression in hum an hepatocytes [271]. c. In mice, PFO S adm inistration induced hepatic steatosis in tim e-and dosedependent m anner along with corresponding CD36 and Lpl expression induction and decreased m itochondrial P-oxidation in m ice [272]. Also, in exposed animals, accum ulation o f lipid zzzz 3MA02512169. Comparison of Lipid Peroxidation by Perfluoro-Octanoic Acid or CCL4. Page 3MA02512169. 72 CONFIDENTIAL - SUBJECT TO A PROTECTIVE ORDER ENTERED IN HENNEPIN COUNTY DISTRICT COURT, NO. 27-CV-10-28862 27-CV-10-28862 Filed in Fourth Judicial District Court 11/17/2017 7:31 PM Hennepin County, MN com pany b u t not governm ental in stitutions.66666 I did not find any such reports, and perhaps this judgm ent explains the apparent secrecy about any findings o f adverse effects. c. As late as 2003, 3M authors argued that a positive association betw een PFO A exposure and cholesterol in 3M w orkers "is contrary to the substantial body of toxicological literature that suggests a negative association in laboratory anim als" [217]. However, in a m ore recent article [274], the 3M authors relied on a species difference in liver metabolism (associated with the PPA R receptor) and for this reason concluded that hepatocellular tumors in rats are "not likely to be relevant to hum ans." However, these positions are inconsistent. It is not appropriate in one connection to require sim ilar hepatotoxic effects in different species and in another to raise doubt about such similarity. f. In regard to liver steatosis, up to 10% o f adolescents have non-alcoholic fatty liver disease (NAFLD) [275, 276]. As a considerable and apparently grow ing public health problem o f partially unknow n origin, this outcom e requires attention in future studies o f PFCassociated adverse hum an health effects. H. Risk factors for cardiovascular disease It is my opinion, based on the w eight o f the epidem iological evidence, and supporting toxicity evidence, that PFCs pose a substantial present and potential hazard to human health due to elevated cholesterol and increased risk o f cardiovascular disease. Based on the available evidence, the kidney may also be a likely target organ for PFC toxicity in hum ans as in animals. How ever, this evidence is yet uncertain, as decreased kidney function of other causation may im pair the elimination of PFCs and thereby indirectly cause elevated serum-PFC concentrations. The evidence is nevertheless strong that PFCs cause adverse cardiovascular effects, in part associated w ith elevated cholesterol and w hether or not kidney disease is a contributing factor. An autopsy study showed that PFBA in particular lodges in the hum an kidney [52], but virtually no inform ation is available on nephrotoxicity and cardiovascular toxicity related to this PFC. As discussed above, serum concentrations o f total cholesterol and other important serum lipid param eters increase at higher PFC exposures. Even a small increase w ould likely have negative im plications regarding cardiovascular disease and possibly mortality. The C8 Panel concluded that PFO A is linked to an increased risk o f hypertension in pregnancy, elevated serum-cholesterol, and potentially also coronary artery disease, although the latter was not considered sufficiently supported by the evidence available at the time. eeeee 3MA00000688. Email between Jeffrey H. Mandel and Dokter Schmickler with the subject "reporting." Page 3MA00000688. 74 CONFIDENTIAL - SUBJECT TO A PROTECTIVE ORDER ENTERED IN HENNEPIN COUNTY DISTRICT COURT, NO. 27-CV-10-28862 27-CV-10-28862 Filed in Fourth Judicial District Court 11/17/2017 7:31 PM Hennepin County, MN Due to the high incidence o f cardiovascular disease, even a small increase in life tim e risk is o f serious public health importance. An article recom m ends im m ediate action to prevent even `b a c k g ro u n d ' exposures to P F O A [277]. 1. Epidemiological evidence a. The early 3M occupational study by Dr. G illiland addressed serum chemistry abnorm alities in exposed w orkers [207] and showed an inverse correlation (adverse effect) betw een organic fluorine compounds (assum ed to be m ainly PFO A) and HDL cholesterol. b. In other 3M production plant w orkers, serum PFO A and total organic fluorine (TOF) were positively and significantly associated with cholesterol and triglycerides in a longitudinal study. fffff A positive correlation (adverse effect) w ith total cholesterol (PFO S and PFO A) and triglycerides (PFOA) was later found in regard to PFC concentrations in serum in one study, though not in another [217, 278]. c. A later study o f current and form er Cottage Grove em ployees showed both PFO A and PFOS were positively and significantly associated w ith total cholesterol, LDL, and triglyceride levels above healthy reference ranges.ggggg PFO S w as significantly associated w ith m etabolic syndrome, as well. Oddly, 3M discontinued this study showing significant adverse effects in its w orkers.hhhhh d. Similar evidence from cross-sectional and, in particular, prospective studies o f workers at other plants also suggested that increased PFO A exposure is associated w ith higher serum -cholesterol concentrations [268, 269, 279]. Cross-sectional data on 1216 subjects from the 1999-2003 NH AN ES showed that increasing serum-PFOA concentrations were positively associated with self-reported cardiovascular disease, including coronary heart disease and stroke, and objectively m easured peripheral arterial disease (an ankle-brachial blood pressure index o f less than 0.9). The highest PFO A quartile showed a doubling o f cardiovascular disease after confounder adjustm ent [280]. f. C om m unity and general population groups w ith low er levels o f P F O A exposure have also revealed positive correlations (adverse effects) betw een PFO A and cholesterol concentrations in serum [65, 281-283]. g. In som e populations, other PFC s w ere also m easured, and positive associations were found in regard to PFOS exposure [281-283], a finding that we have replicated fffff 3M_MN02334964. Final report, A Longitudinal Analysis of Serum Perfluorooctanesulfonate (PFOS) and Perfluorooctanoate (PFOA) Levels in Relation to Lipid and Hepatic Clinical Chemistry Test Results from Male Employee Participants of the 1994/95, 1997 and 2000 Fluorochemical Medical Surveillance Program, page 3M_MN02334966. ggggg 3MA02543911. Untitled draft. See also Deposition Testimony of Dr. Geary W. Olsen (Sept. 8, 2017), 142:13 150:21. hhhhhDeposition Testimony of Dr. Geary W. Olsen (Sept. 8, 2017), 158:24-160:06. 75 CONFIDENTIAL - SUBJECT TO A PROTECTIVE ORDER ENTERED IN HENNEPIN COUNTY DISTRICT COURT, NO. 27-CV-10-28862 27-CV-10-28862 Filed in Fourth Judicial District Court 11/17/2017 7:31 PM Hennepin County, MN in elderly subjects from the Faroe Islands, where exposure levels are sim ilar to background levels in the US (unpublished results). h. D ata from the C8 project show ed that total cholesterol and LD Lcholesterol increased at higher PFO A exposures (and HD L increases in w om en) [235]. The variability in PFC -associated cholesterol changes is quite large [8], although a variety o f factors, such as age, sex, and body mass index could affect the degrees o f the relationship [284]. i. Indirect evidence suggests th at PFC m etabolism is n ot linked to changes in lipid m etabolism (which w ould suggest a reverse causation), thereby rejecting a hypothesis that both PFCs and cholesterol could be affected by a comm on cause that would produce apparent positive associations betw een PFCs and cholesterols in serum. Thus, subjects w ho are taking statins to decrease their serum -cholesterol do not show any low er serum -PFC concentrations [282]. This report agrees w ith our findings in the Faroes (unpublished). j. W hile early data from C ottage G rove suggested no risk, an increased risk o f cerebrovascular disease was indicated by a m ortality study that relied on com parisons w ith the general population [285]. The subsequent 3M -supported follow-up [76] again showed strongly elevated risk of cerebrovascular death in workers with high exposure, especially when compared to an internal control group. The draft report by Drs Lundin and A lexander from the University o f M in nesotaiiiii provides a b alanced presentation, b u t the published article th at w as co-authored by 3M 's Dr. Olsen calls the association "inconsistent" because the m ortality was not clearly elevated when compared to the general M innesota population. k. C ross-sectional N H A N E S data suggest that serum -PFO A concentration is associated w ith systolic blood pressure and the risk o f hypertension [286]. H ypertension may relate to an increased risk o f cerebrovascular mortality. l. N H A N E S data suggest th at increased serum concentrations o f P F O A and PFOS are associated with an increased risk of chronic kidney disease, as defined by a low g lom erular filtration rate [287].JJJJJ H ere, reverse causation cannot be ruled out, i.e., th at kidney disease prevents PFC excretion via the urine[59]. A m ajor caveat, however, is that PFB A was not considered, as it may not have been detectable in the serum, while the m ajor accum ulation in the body is in the kidneys [52]. m. Regarding uric acid, the C8 Project exam ined its association w ith serum PFO A levels after adjustm ent for potential confounders. An increased risk o f elevated uric acid was found in adults, including clinically defined hyperuricem ia [288]. Again, this evidence is yet somewhat uncertain, as reverse causation may be present. 111113MA02557439.pdf. Final report, Mortality of Employees of an Ammonium Perfluorooctanoate Production Facility, August 22, 2007. jjjjj I note that the first author of this article, and co-author of five other publications on cardiovascular outcomes in PFOS-exposed populations, has provided erroneous information to the West Virginia University regarding his educational background. The articles in question were co-authored be established colleagues, and none of them has been retracted. 76 CONFIDENTIAL - SUBJECT TO A PROTECTIVE ORDER ENTERED IN HENNEPIN COUNTY DISTRICT COURT, NO. 27-CV-10-28862