Coffee and Cancer: A Benefit-Risk Evaluation of the Experimental and Epidemiological Evidence

James R. Coughlin, Ph.D.Coughlin & Associates, California

andAstrid Nehlig, Ph.D.

INSERM, France

24th International Conference on Coffee Science

San Jose, Costa RicaNovember 12, 2012

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”

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

Conclusions: 1980 to Mid-1990’s

Mostly Bad News!

Coffee and Caffeine were being linked

to almost every known animal and

human disease!

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.

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…

Human Epidemiologic Evidence

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.

Lack of association between coffee and some cancer typesType of cancer Number of

studiesEffect of coffee Doses

Oesophagus 17 studies No influence Increased risksometimes linkedto beveragetemperature

Stomach 23 studies No influence

Pancreas 37 studies No influence

Ovary 11 studies No influence

Kidney 26 studies No influence

Reduced risk for some cancer typesType of cancer Number of

studiesEffect of coffee Doses

Breast 5 recent studies *No effect aftermenopause*Risk reduced by 40% before menopause, 25-70% in women at risk

4 cups/dayEffect limited to regularcoffee: caffeine involved

Upper aerodigestiveand respiratory tract

10 studies Risk reduction: 39-44% 4 cups/day

Endometrial 9 studies Risk reduction: up to 60%inverse link with obesity

3 cups/day

Prostate 14 studies 18% reduced risk for prostate cancer overall,60% for lethal prostate cancer

4-6 cups/dayBoth regular and decaffeinated coffee

Skin 6 studies Reduced risk in animals

In humans reduced risk of basal cell carcinoma (13-21%) but not other types

Caffeine appliedtopically

3 cups/day (caffeine isthe active ingredient)

Coffee and bladder cancerDate Number of studies Effect of coffee Doses

Zeegers et al., 2001 Systematic review16 studies in men12 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 tapwater 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 studies17 case-control studies

Some studies show increased risk, butno 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

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.”

Coffee and colorectal cancer

Tavani & La Vecchia 2004; La Vecchia & Tavani2007; Galleone et al, 2010

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 antimutagenicand antioxidant properties

Stimulation of colon motility and hence reduction of time of contact of mutagenic substances with the intestinal mucosa

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

“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 evidenceshowing no detrimental effect of consumption of up to 6 cups ofcoffee/day in relation to cancer occurrence. In fact, some of theevidence…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.

So with all this good news, why are we still concerned?

Animal Carcinogens in Coffee

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. 74:364-382.

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.

AmmoniaAlkyl aminesAmino acidsProteinsPhospholipids

AldehydesKetonesSugarsCarbohydratesLipids

CarbonylsEstersAmides (Acrylamide)Heterocyclic Compounds

Amine

Carbonyl

Amino-CarbonylInteraction

(Amadori Products)

HEATHEAT

Furans OxazolesPyrroles ImidazolesThiophenes PyridinesThiazoles Pyrazines

Melanoidins(pigments)

Volatile Compounds(aroma chemicals)

General Scheme of Maillard Browning Reaction

Acrylamide and Furan

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

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]

Risk Assessment Considerations based on NTP

JECFA should consider reevaluating its 2010 acrylamide risk assessment by dismissing consideration of the NTP’s benigntumors 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.

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 --

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 uncertaintyand 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).

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.

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: 1487-1499. “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.

“Acrylamide in Foods: A Review of the Science andFuture 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.

Does Acrylamide in Food Pose a Real Risk toHuman 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 acrylamide-

containing foods must be considered in a risk-benefit evaluation.

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 to10 - 35 ppb.

“Proposition 65”

A California Law -“Safe Drinking Water and Toxic

Enforcement Act of 1986”

- Right-to-Know Warnings

- Prohibition of Discharge

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.

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.

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.

4-Methylimidazole (4-MEI)

4-Methylimidazole (4-MEI)

Maillard Browning Reaction chemical proposed for carcinogenlisting 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.

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 formulationsnationwide, 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).

Benefit-Risk Evaluation –

The “Holistic Approach”

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)

“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 SciencesInstitute/Europe” Process Related Compounds Task Force

(12 collaborating institutes, universities and companies)

1. Studied the impact of pre-harvest, post-harvest and processing conditions on acrylamide formation in potatoes, cereals and coffee.

2. Considered the nutritional value and beneficial health impact of consuming these commodities.

3. Calculated the impact of mitigation using probabilistic risk-benefit modeling to demonstrate the principle of this approach.

Problems Presented by Focusing on a SingleToxic 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!

“Coffee - Cancer Paradox”

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!

BEVERAGE - PER CAPITA AOX’S

Coffee provides 64% of per capita AOXs from beverages

0

100

200

300

400

500

600

700

800

Coffee

Black T

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ag)

Beer (

Lage

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ine (R

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Orang

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Grape

Juice

(Red

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Grape

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Cranb

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Juice

Pine

apple

Juice

mg

AO

X/da

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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 dosesDo more research / evaluation on qualitative and

quantitative assessment of the benefits of whole foodsConsider the health benefits of protective compounds

naturally occurring and produced by heatingAssess the safety and benefits of the whole food, not

just individual food carcinogens / toxicants one by one.

THE Health Beverage!

Thank You!

Questions?