This document summarizes a presentation given by James R. Coughlin and Astrid Nehlig at the 24th International Conference on Coffee Science in San Jose, Costa Rica in November 2012. The presentation evaluated the experimental and epidemiological evidence on the relationship between coffee consumption and cancer risk. It discussed hundreds of epidemiology studies that have found no association or an inverse association between coffee drinking and cancers of the esophagus, stomach, pancreas, ovary, kidney, endometrial, prostate, colorectal, liver and skin cancer. However, some studies have found a potential increased risk of bladder cancer among heavy coffee drinkers. The presentation also discussed potential carcinogens found in coffee like acrylamide and fur

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. 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. 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. Conclusions: 1980 to Mid-1990’s
Mostly Bad News!
Coffee and Caffeine were being linked
to almost every known animal and
human disease!

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. 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. Human Epidemiologic Evidence

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. 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. 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. 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. 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. 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. 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. “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.

17. So with all this good news, why
are we still concerned?
Animal Carcinogens in Coffee

19. 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.

20. 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

23. Acrylamide and Furan

26. 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

27. 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]

29. 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.

32. 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 --

33. 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).

34. 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.


35. 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.

37. “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.

38. 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.

39. 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.

41. “Proposition 65”
A California Law “Safe Drinking Water and Toxic
Enforcement Act of 1986”
- Right-to-Know Warnings
- Prohibition of Discharge

43. 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.

44. 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.

45. 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 www.fda.gov. For more information about acrylamide and
Proposition 65, visit www.oehha.ca.gov/prop65/acrylamide.html.

46. 4-Methylimidazole (4-MEI)

47. 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.

48. 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).

49. Benefit-Risk Evaluation –
The “Holistic Approach”

50. 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)

51. “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.

54. 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!

55. “Coffee - Cancer Paradox”

56. 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!

57. Coffee provides 64% of per capita AOXs from beverages
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200
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58. 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.

60. THE Health Beverage!

61. Thank You!
Questions?