Coffee and Cancer_Benefit-Risk Evaluation_Coughlin and Nehlig_ASIC Costa Rica_2012


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Coffee and Cancer_Benefit-Risk Evaluation_Coughlin and Nehlig_ASIC Costa Rica_2012

  1. 1. Coffee and Cancer: A Benefit-Risk Evaluation of the Experimental and Epidemiological Evidence James R. Coughlin, Ph.D. Coughlin & Associates, California and Astrid Nehlig, Ph.D. INSERM, France 24th International Conference on Coffee Science San Jose, Costa Rica November 12, 2012
  2. 2. Presentation Outline  Human Epidemiologic Evidence (Dr. Nehlig)  Animal Carcinogens in Coffee  Acrylamide, Furan and 4-MEI  California “Proposition 65” Update  Benefit-Risk Evaluation – The “Holistic Approach”  “Coffee - Cancer Paradox”
  3. 3. A 30-Year Coffee/Health Perspective …on Rats, Mice and Humans …on “Good” and “Bad” Science …on “Good” and “Bad” Media Coverage …on Coffee’s Beneficial Health Effects
  4. 4. Conclusions: 1980 to Mid-1990’s Mostly Bad News! Coffee and Caffeine were being linked to almost every known animal and human disease!
  5. 5. As we entered the 21st Century The preponderance of medical and scientific evidence clearly supported the conclusion that moderate coffee consumption (3 - 4 cups per day), as part of a varied, balanced diet, is safe and is not associated with any adverse human health consequences.
  6. 6. But since 2000 or so…  The “Good News” is that almost all of the Bad News was WRONG!  Evidence has been building strongly that coffee may actually be GOOD for us!!!  Let’s examine the evidence on coffee and cancer…
  7. 7. Human Epidemiologic Evidence
  8. 8. Coffee and Cancer Epidemiology  Coffee consumption is a major and frequent dietary exposure in diverse cultures around the globe, but its safety related to cancer causation has been questioned and studied for decades.  A substantial body of epidemiologic evidence (over 500 studies) relating coffee consumption to cancer of various organ sites has been accumulated to date.  Numerous, organ-specific studies using meta-analysis, as well as comprehensive reviews, have been undertaken more recently.
  9. 9. Lack of association between coffee and some cancer types Type of cancer Number of studies Effect of coffee Doses Oesophagus 17 studies No influence Increased risk sometimes linked to beverage temperature Stomach 23 studies No influence Pancreas 37 studies No influence Ovary 11 studies No influence Kidney 26 studies No influence
  10. 10. Reduced risk for some cancer types Type of cancer Number of studies Effect of coffee Doses Breast 5 recent studies *No effect after menopause *Risk reduced by 40% before menopause, 2570% in women at risk 4 cups/day Effect limited to regular coffee: caffeine involved Upper aerodigestive 10 studies and respiratory tract Risk reduction: 39-44% 4 cups/day Endometrial 9 studies Risk reduction: up to 60% 3 cups/day inverse link with obesity Prostate 14 studies 18% reduced risk for prostate cancer overall, 60% for lethal prostate cancer 4-6 cups/day Both regular and decaffeinated coffee Skin 6 studies Reduced risk in animals Caffeine applied topically In humans reduced risk of basal cell carcinoma (1321%) but not other types 3 cups/day (caffeine is the active ingredient)
  11. 11. Coffee and bladder cancer Date Number of studies Effect of coffee Doses Zeegers et al., 2001 Systematic review 16 studies in men 12 studies in women No link in women, 26% risk increase in men Villanueva et al., 2006 6 case-control studies Variable effects, Increased risk, Increased risk with tap water alone >5 cups/day vs <5 cups/day De Stefani et al., 2007 Case-control study Increased risk, up to 60% 3 cups/day Pelucchi et al., 2009 4 cohort studies 17 case-control studies Some studies show increased risk, but no dose-response     First highlighted by IARC Monograph (1991) – Limited evidence Very variable outcome with possible increased risk in some populations? Possible link with tap water and increased drinking with the disease Presence of many counfounders, especially smoking
  12. 12. Most Recent Epidemiology Study of Coffee and Bladder Cancer  Zhou et al. 2012. “A dose-response meta-analysis of coffee consumption and bladder cancer.” Prev. Med. 55: 14-22  23 case-control studies with 7,690 cases and 13,507 controls, and 5 cohort studies with 700 cases and 229,099 participants  “CONCLUSIONS: Although data from case-control studies suggested that coffee was a risk factor for bladder cancer, there was no conclusive evidence on this association because of inconsistencies between case-control and cohort studies.”
  13. 13. Coffee and colorectal cancer  Number of studies  5 cohort and 15 case-control studies  Risk reduction 24-60% except in 3 cohort studies  Inverse relation with coffee intake, maximal protection for a consumption over 3-4 cups per day  Possible mechanisms  Presence in coffee of polyphenols and diterpenes with antimutagenic and antioxidant properties  Stimulation of colon motility and hence reduction of time of contact of mutagenic substances with the intestinal mucosa Tavani & La Vecchia 2004; La Vecchia & Tavani 2007; Galleone et al, 2010
  14. 14. Coffee and liver cancer      Meta-analysis of 6 case-control and 8 cohort studies 43% reduction in risk among coffee drinkers compared to nondrinkers Dose-dependent association Both in studies from Europe, where coffee is frequently consumed, and from Japan, where coffee consumption is less frequent Consistency exists between cohort and case-control studies. Bravi et al., 2009
  15. 15. “Epidemiologic Evidence on Coffee and Cancer.” Lenore Arab (U. of California, Los Angeles) Nutrition and Cancer 62: 271-283 (2010) “For most cancer sites, there is a significant amount of evidence showing no detrimental effect of consumption of up to 6 cups of coffee/day in relation to cancer occurrence. In fact, some of the evidence…suggests that coffee might prevent some cancers.” [review based on over 500 publications]      Liver and endometrial cancers - a strong and consistent protective association Colorectal cancer - the association is borderline protective Breast, pancreatic, kidney, ovarian, prostate, gastric cancer - no association Bladder cancer - very weak increase in risk for heavy coffee consumption in some studies, but this may be an indication of confounding by smoking Childhood leukemia - ambiguous risk with mother’s consumption of coffee at high levels of daily consumption, needs further study.
  16. 16. So with all this good news, why are we still concerned? Animal Carcinogens in Coffee
  17. 17. Early Animal Cancer Bioassays of Coffee Wurzner H-P, Lindstrom E, Vuataz L and Luginbuhl H. 1977. A 2-year feeding study of instant coffee in rats. II. Incidence and types of neoplasms. Food Cosmet. Toxicol. 15:289-296. Palm PE, Arnold EP, Nick MS, Valentine JR and Doerfler TE. 1984. Two-year toxicity/carcinogenicity study of fresh-brewed coffee in rats initially exposed in utero. Toxicol. Appl. Pharmacol. 74:364382. Stadler R, Luginbuhl H, Bexter A and Wurzner H-P. 1984. Preliminary findings of a carcinogen bioassay of coffee in mice. In: MacMahon B and Sugimura T, eds., Coffee and Health (Banbury Report 17), Cold Spring Harbor, New York, CSH Press, pp. 79-88.
  18. 18. General Scheme of Maillard Browning Reaction Amine Ammonia Alkyl amines Amino acids Proteins Phospholipids Melanoidins (pigments) HEAT Amino-Carbonyl Interaction (Amadori Products) Carbonyl Aldehydes Ketones Sugars Carbohydrates Lipids Furans Pyrroles Thiophenes Thiazoles Oxazoles Imidazoles Pyridines Pyrazines Volatile Compounds (aroma chemicals) Carbonyls Esters Amides (Acrylamide) Heterocyclic Compounds
  19. 19. Acrylamide and Furan
  20. 20. Acrylamide Snapshot: Chemistry and Toxicology  Human occupational neurotoxin, genotoxic / mutagenic in cell cultures  Known rat carcinogen, classified as “probable human carcinogen”  Metabolized to glycidamide (an epoxide), an animal carcinogen  Acrylamide & glycidamide can bind to DNA/amino acids/proteins  DNA adducts  carcinogenic potential  Blood hemoglobin adducts  biomarker of exposure  Dietary proteins may reduce acrylamide uptake in humans  Protective enzymes can detoxify acrylamide and glycidamide  NTP Acrylamide Bioassay in rats and mice (July 2012 Report) – “Clear Evidence of Carcinogenicity” for both species & sexes
  21. 21. U.S. National Toxicology Program (NTP) Bioassay of Acrylamide  2-year cancer bioassay in rats and mice fed acrylamide in drinking water (untreated control + 4 treatment doses), with ancillary studies on metabolism, genotoxicity and toxicokinetics  Draft Technical Report No. 575 was peer-reviewed by the NTP Peer Review Panel in April 2011; Panel accepted the conclusions that there was “Clear Evidence of Carcinogenicity” in male and female rats and male and female mice in numerous organs; Final Technical Report was issued in July 2012  For industry’s consideration: the observed tumor findings and cancer potencies may be useful in decreasing acrylamide’s risk potency [JECFA, various national authorities]
  22. 22. Risk Assessment Considerations based on NTP  JECFA should consider reevaluating its 2010 acrylamide risk assessment by dismissing consideration of the NTP’s benign tumors in the rat mammary gland and mouse Harderian gland as not biologically relevant to human risk assessment  While these were the most sensitive tumor endpoints, they are not malignant tumors, and these two tumor types are not relevant to human risk  JECFA and others (FDA, EU, Health Canada) should reevaluate acrylamide’s potential for human risk based on the lower incidences of relevant NTP malignant rat and mouse tumor endpoints  I firmly believe that acrylamide is too important and too widespread a contaminant in the human diet to have its risk determined by biologically irrelevant rodent tumor endpoints and with no consideration of the lack of increased risk in humans.
  23. 23. Appendix 1. Acrylamide as consumed (ppb) Beverages Coffee, restaurant McDonald's 6 < 10 < 10-11 Coffee, restaurant Second Cup 4 < 10 < 10 Coffee, restaurant Starbucks 6 12 < 10-15 Coffee, restaurant Tim Hortons 6 12 11-14 Classic roast ground coffee Folgers 4 < 10 < 10 Maxwell House Original roast ground coffee Kraft 4 < 10 < 10 Nescafe rich instant coffee Nestle 1 < 10 -- Maxwell House Original roast instant coffee Kraft 2 < 10 < 10 Instant coffee No Name - Loblaw's brand 1 < 10 -- Taster's Choice instant coffee Nestle 1 < 10 -- Mellow blend instant coffee Selection 1 < 10 --
  24. 24. Food Drink Europe “Acrylamide Toolbox” (Sept 2011)  Restructured by Product Category around 3 main foods: potatoes, cereals and coffee  Now includes text on the Concept of ALARA - “As Low as Reasonably Achievable”  Methods of Analysis and Sampling better describe uncertainty and standardization work  Risk/Risk and Risk/Benefit Positioning: re-written to more closely align it with the “General Considerations and Constraints in Developing Preventative Measures” within the CODEX “Code of Practice for the Reduction of Acrylamide in Foods” (2009).
  25. 25. Progress on Acrylamide “Mitigation” for Coffee  Government regulators, university scientists and the food industry have been working together for 10 years to develop/implement feasible ways to reduce the presence of acrylamide in many foods  Studies have demonstrated some mitigation success for foods, but much of the research was lab scale using techniques and ingredients that have little commercial viability or organoleptic acceptability  Unfortunately, there has been very little success with coffee mitigation: Baum M, Bohm N, Gorlitz J, Lantz I, Merz KH, Ternite R and Eisenbrand G. 2008. Fate of 14C-acrylamide in roasted and ground coffee during storage. Mol. Nutr. Food Res. 52: 600-608.  Guenther H, Anklam E, Wenzl T and Stadler RH. 2007. Acrylamide in coffee: Review of progress in analysis, formation and level reduction. Food Addit. Contam. Part A: Chemistry, Analysis, Control, Exposure & Risk Assessment 24 (Suppl 1):60-70.  Lantz I, Ternit R, Wilkens J, Hoenicke K, Guenther H and van der Stegen GHD. 2006. Studies on acrylamide levels in roasting, storage and brewing of coffee. Mol. Nutr. Food Res. 50:1039-1046. 
  26. 26. Recent Dietary Epidemiology Studies of Acrylamide  Pelucchi et al. 2011. “Exposure to Acrylamide and Human Cancer - A Review and Meta-analysis of Epidemiologic Studies.” Annals Oncology 22: 14871499.  “Conclusions: Available studies consistently suggest a lack of an increased risk of most types of cancer from exposure to acrylamide.”  Lipworth et al. 2012. “Review of Epidemiologic Studies of Dietary Acrylamide Intake and the Risk of Cancer.” Eur. J. Cancer Protection 21: 375-386.
  27. 27. “Acrylamide in Foods: A Review of the Science and Future Considerations” David R. Lineback, James R. Coughlin and Richard H. Stadler, Ann. Rev. Food Sci. & Technol. 3: 15-35 (April 2012)  Most of the major countries of the world have advised consumers to follow the dietary recommendations for a balanced diet issued by their food regulatory and public health agencies.  The data available to date have been insufficient to warrant any recommendation for a significant change in the dietary recommendations because of acrylamide.  Current epidemiological and toxicological evidence are insufficient to indicate that the amounts of acrylamide consumed in the normal diet are likely to result in adverse human health effects, particularly cancer.
  28. 28. Does Acrylamide in Food Pose a Real Risk to Human Health?  Risk characterization traditionally includes:  Rodent cancer bioassay results (like the NTP bioassay)  Biomarker and metabolic studies in animals and humans  Bioavailability may be less in human diets than in water  Need more reliable data on human intake estimates  But for acrylamide in heated foods…  Consideration of thresholds and non-linear dose modeling  Dietary epidemiology studies support lack of risk globally  Health-protective, beneficial components of acrylamidecontaining foods must be considered in a risk-benefit evaluation.
  29. 29. Furan  Maillard Browning compound; rat and mouse liver carcinogen (NTP, 1993) and “possibly carcinogenic to humans” (IARC, 1995); FDA, EFSA and Health Canada have all provided data analyses and exposure assessments  “Margin of Exposure” = 750 - 4,300 lower than the lowest risk level (Carthew et al., 2010), better than acrylamide; JECFA (2010) concluded that dietary exposures to furan “indicate a human health concern for a carcinogenic compound which may act via a DNA‐reactive metabolite”  Brewed coffee is about 70% of total furan exposure, the highest dietary contributor of all foods and beverages; up to 200 ppb in some coffees; but coffee PROTECTS against human liver cancer…Benefit-risk argument!  Guenther et al. (2010): furan is reduced significantly during roasting, grinding, storage, brewing and drinking; levels are actually closer to 10 - 35 ppb.
  30. 30. “Proposition 65” A California Law “Safe Drinking Water and Toxic Enforcement Act of 1986” - Right-to-Know Warnings - Prohibition of Discharge
  31. 31. Acrylamide Battleground under Prop 65  Industrial chemical listed in 1990 as a carcinogen, with an adopted “Safe Harbor” level = 0.2 μg/day; must stay below this level to avoid giving cancer warnings; but if you can detect it, even a 1-ounce serving of any food exceeds this level  French fries: Attorney General sued and settled case (2008) against Heinz frozen fries/tater tots for $600,000 and demanded a 50% reduction in levels; fast-food restaurant fries have had cancer warnings posted for years  Potato chips (crisps): AG settled (2008) the case against Frito-Lay & others; agreement to cut levels to 275 ppb by end of 2011 (20 - 85% reductions) to avoid warnings; much browner chips (e.g., Kettle chips) will be difficult to mitigate to these lower levels  Cereals: Private “bounty hunter” group sued cereal manufacturers (Cheerios, etc.) in 2009; the case is still pending.
  32. 32. Acrylamide in Coffee under Prop 65  Private “bounty hunter” group (CERT) sued 11 coffee shop chains (Starbucks, Peet’s) in April 2010 for failure to provide cancer warnings (“brewed coffee” suit)  In April 2011, some retail coffee shops began posting 10 inch x 10 inch cancer warning placards covering coffee, baked goods and other products  CERT filed a related suit in May 2011 against coffee roasters, distributors and retailers, over 100 companies are now sued (“roasted coffee” suit)  These coffee roasters are fighting hard to avoid cancer warning labels on packaged products; Acrylamide levels average only about 10 ppb in brewed coffee.
  33. 33. Text of Coffee Shops’ Warning “Proposition 65 WARNING. Chemicals known to the state of California to cause cancer and reproductive toxicity, including acrylamide, are present in coffee, baked goods, and other foods and beverages sold here. Acrylamide is not added to our products, but results from cooking, such as when coffee beans are roasted or baked goods are baked. As a result, acrylamide is present in our brewed coffee, including coffee made at home or elsewhere from our beans, grounds or instant coffee, baked goods or other foods sold here, in grocery stores or other retail locations. Your personal cancer risk is affected by a wide variety of factors. The FDA has not advised people to stop drinking coffee or eating baked goods that contain acrylamide. For more information regarding FDA’s views, see For more information about acrylamide and Proposition 65, visit
  34. 34. 4-Methylimidazole (4-MEI)
  35. 35. 4-Methylimidazole (4-MEI)  Maillard Browning Reaction chemical proposed for carcinogen listing based on the NTP bioassay in Jan. 2008, then listed in Jan. 2011 after we waged a strong scientific battle; but IARC (Feb. 2011) also classified 4-MEI and 2-MEI as Group 2B “possibly carcinogenic to humans” (based on sufficient evidence in animals)  Occurs naturally in added caramel colors (cola beverages, darker beers) and in many browned foods/beverages (coffee, soy sauce, others)  NTP oral cancer bioassay (2007) showed only increased lung tumors in mice; however, 4-MEI reduced many other tumors in rats, but that made no difference to the state agency  The state adopted a “Safe Harbor” level = 29 µg/day in February 2012 after industry efforts failed o raise it from a lower draft level (16 µg/day); we still believe it should be a much higher number.
  36. 36. 4-Methylimidazole (4-MEI) – cont’d  Our Industry coalition sued the state to reverse the listing in February 2011 but lost this case in November; case went to appeal in February 2012, but industry abandoned the appeal in August  Center for Environmental Health threatened lawsuits early this year against Coca Cola, PepsiCo, Dr. Pepper Snapple Group and numerous supermarket chains for “failure to warn”  Major cola manufacturers switched to lower 4-MEI formulations nationwide, with significant cost upcharge  Prop 65 does have “reach” – Brazil, UK, others clamoring for the “safer” caramel in cola beverages  We in coffee worry about the global “reach” of potential cancer warnings on coffee products (acrylamide, furan, 4-MEI).
  37. 37. Benefit-Risk Evaluation – The “Holistic Approach”
  38. 38. Benefit-Risk Evaluation to Assess the Safety of Foods Containing Heat-produced Carcinogens  Doing it the WRONG WAY for decades, by simply evaluating the risk of individual chemicals in a food one by one  Going forward, the RIGHT WAY is to evaluate the safety of the whole food (compare its risks vs. benefits)  Use the “Holistic Approach”  Various “Benefit-Risk” evaluations have recently been published –  U.S. FDA’s 2009 “Draft Risk and Benefit Assessment of Fish” (Methyl mercury risks vs. Omega-3 fatty acid benefits)
  39. 39. “Risk-Benefit Considerations of Mitigation Measures on Acrylamide Content of Foods – A Case Study on Potatoes, Cereals and Coffee.” Seal et al., Br. J. Nutr. 99 [Suppl 2]:S1-S46 (2008). Expert Report commissioned by the “International Life Sciences Institute/Europe” Process Related Compounds Task Force (12 collaborating institutes, universities and companies) 1. 2. 3. Studied the impact of pre-harvest, post-harvest and processing conditions on acrylamide formation in potatoes, cereals and coffee. Considered the nutritional value and beneficial health impact of consuming these commodities. Calculated the impact of mitigation using probabilistic riskbenefit modeling to demonstrate the principle of this approach.
  40. 40. Problems Presented by Focusing on a Single Toxic Chemical in a Food or Beverage  Consumer confidence in the food is eroded by media scares  Disruption of business & international trade  Scarce resources do not always go to the most critical risks (trace chemicals vs. microbiological and nutritional threats); do we have the resources to pursue all these individual chemicals in food as major issues?  There is no end in sight…new chemicals are coming to the forefront all the time; analytical advances drive detection levels to near “zero”; continued high-dose animal testing identifies potential health problems that will probably never occur in humans  Can’t toxicology and epidemiology guide us to agree on some toxicologically insignificant level of a chemical compared to the benefits of the whole food? I believe they can!
  41. 41. “Coffee - Cancer Paradox”
  42. 42. The “Coffee / Cancer Paradox”  Coffee contains ~ 2,000 identified compounds (hundreds are flavors and aromas), including trace levels of many animal carcinogens (such as acrylamide, furan, 4-MEI, various aldehydes, PAHs, ochratoxin A, etc.)  But global health and regulatory authorities now agree that coffee drinking is NOT causing any increased risk of human cancer  In fact, epidemiological studies show significant risk reductions for liver, colorectal, breast and endometrial cancers in spite of the presence of numerous animal carcinogens  How can this be?  Naturally occurring antioxidants (chlorogenic acids)  Heat-formed antioxidants (the brown melanoidin polymers)  Inducers of detoxification enzymes (Glutathione-S-transferase) So, here is the Paradox – Coffee is loaded with carcinogens but most likely reduces human cancer risk!
  43. 43. Coffee provides 64% of per capita AOXs from beverages B C la ck off Te ee a (b ag B ee ) r (L ag er W ) in e (R O ed ra G ng ) ra e pe Ju Ju ic e ic e (R ed A ) pp G le ra Ju pe ic fr e ui C tJ ra ui nb ce er ry P in Ju ea ic pp e le Ju ic e m AOX/day g BEVERAGE - PER CAPITA AOX’S 800 700 600 500 400 300 200 100 0
  44. 44. Use the Holistic Benefit-Risk Approach  The beneficial health effects of certain whole foods may outweigh the effects of trace levels of animal carcinogens and other toxicants – COFFEE is one of these foods!  We must press global health and regulatory authorities to:  Use improved toxicology and risk assessment methods on individual chemicals tested at high doses  Do more research / evaluation on qualitative and quantitative assessment of the benefits of whole foods  Consider the health benefits of protective compounds naturally occurring and produced by heating  Assess the safety and benefits of the whole food, not just individual food carcinogens / toxicants one by one.
  45. 45. THE Health Beverage!
  46. 46. Thank You! Questions?