A “HOT” Summer for Some Food Additives, Contaminants and Herbal Supplements: What are Their Prospects?

James R. Coughlin, PhD CFSPresident, Coughlin & Associates

Aliso Viejo, Californiajrcoughlin@cox.net

www.linkedin.com/in/jamescoughlin

Covance Food Symposium:“Current Approaches to Product Safety

and Risk Mitigation” Madison, Wisconsin

September 10-11, 2013

Outline

n “Tox and Risk 101”n Caffeine and Energy Drinks at FDAn Heat-processed carcinogens (acrylamide,

furan, 4-MEI), including Prop 65 concernsn Lead and arsenic issues (FDA and Prop 65)n Nitrite and nitrate under Prop 65n Key herbal supplements at NTP, IARC and

Prop 65n Consider “Risk-Benefit” evaluation of food

contaminants2

Paracelsus (1493-1541)

THE basic tenet of all Toxicology:

“The dose alone makes the poison.”

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Risk Assessment Paradigm§ Hazard Identification - Determination of adverse effects caused

by high intakes of the chemical (epidemiology, clinical, animal, short-term and specialized studies)

§ Dose-Response Assessment§ Selection of critical data set and toxic effect levels§ Determination of Uncertainty or Safety Factors§ Derive an Acceptable Daily Intake (ADI)

§ Exposure (Intake) Assessment§ Evaluation of the range and distribution of human intakes§ Analytical chemistry’s critical role

§ Risk Characterization§ Estimation of the fraction of the population exceeding ADI§ Evaluation of the magnitude of potential excess intakes.

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n More sensitive analytical methods

n Increasing consumer and media awareness

n Vocal and irresponsible messaging

n Non-balanced discussion

n Regulatory uncertainty and scrutiny

n All lead to confused and concerned consumers

Increasing concerns related to the potential chemical hazards in food

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Food and Chemical Safety Issues§ We usually test individual food chemicals, not the whole foods

or beverages (except with epidemiology)§ For whole foods, we must identify biologically active toxic

component(s)§ Must determine appropriate mechanism of action of specific

chemicals (carcinogens, reproductive toxicants, etc.)§ Key importance of dose-response relationships§ Interactions with diet/nutrients, environment & drugs§ Explore sensitive segments of population (young, pregnant,

aging)

Risk/Benefit Assessment is the crucial need…Goal is NO “significant or unreasonable” risk!!

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Human Relevance of Rodent Cancer Bioassays is Being Questioned

§ Some eminent toxicologists have questioned the human relevance of tumors seen in lifetime rodent bioassays, and they believe it’s time to STOP doing chronic rodent bioassays at the “Maximum Tolerated Dose” (MTD)

§ Toxicologists make two possibly flawed assumptions about chronic cancer bioassay results…§ Dose Extrapolation – effects seen at high rodent doses will

also occur at much lower human doses§ Species Extrapolation – if cancer is seen in rodents, then

cancer probably occurs in humans

§ BUT…we need to understand Mechanisms and Modes of Actionfor a chemical before we can use bioassay tumor results for regulatory or warning purposes.

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Caffeine

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Goal - To bring together and summarize relevant research on the use and biology of Energy Drinks and to highlight the most critical research gaps. Sponsored by NIH Office of Dietary Supplements and several other NIH Institutes. Talks focused on patterns of use, sensitive subpopulations, safety and health effects of Energy Drinks and their ingredients.

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Acrylamide Snapshot: Chemistry and Toxicology

ü Occupational neurotoxin; genotoxic / mutagenic in cell cultures

ü Known rat carcinogen, classified as “probable human carcinogen”

ü Metabolized to glycidamide (an epoxide), also an animal carcinogen

ü Acrylamide & glycidamide can bind to DNA, amino acids and proteins

ü DNA adducts à carcinogenic potential

ü Blood hemoglobin adducts à biomarker of exposure

ü Dietary proteins may reduce acrylamide uptake in humans

ü Protective enzymes can detoxify acrylamide and glycidamideü Discovered by the Swedes in 2002 in hundreds of heat-processed

food products, making up about 40% of our daily calories.

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AmmoniaAlkyl aminesAmino acidsProteinsPhospholipids

AldehydesKetonesSugarsCarbohydratesLipids

CarbonylsEstersAmides (Acrylamide)Heterocyclic Compounds

Amine

Carbonyl

Amino-CarbonylInteraction

(Amador i Products)

HEATHEAT

Furans OxazolesPyrroles ImidazolesThiophenes PyridinesThiazoles Pyrazines

Melanoidins(pigments)

Volatile Compounds(aroma chemicals)

General Scheme of Maillard Browning Reaction

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Food Acrylamide Range (ppb)Baby food/biscuits ND - 442

Breads/bakery products ND - 364

Cereals 11 - 1057

Chocolate products ND - 909

Coffee (roasted, not brewed) 37 - 374

Coffee (brewed) 5 - 11

Cookies/crackers 26 - 1540

Dairy drinks ND - 43

Dried foods/mixes ND - 1184

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Food Acrylamide Range (ppb)French fries 117 - 1325

Fruits/vegetables (canned) ND - 83

Gravies/seasonings ND - 151

Infant formulas ND

Nuts/nut butters ND - 457

Potato chips 117 - 4080

Snacks (other salty) 12 - 1340

Olives 123 - 1925

Prune juice 53 - 32619

U.S. National Toxicology Program (NTP) –Carcinogen Bioassay of Acrylamide

ü U.S. FDA nominated acrylamide and glycidamide for complete toxicology testing in November 2002 for future risk assessment purposes

ü 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

ü NTP Technical Report No. 575 for Acrylamide was peer-reviewed in April 2011; Panel accepted conclusions that there was “Clear Evidence of Carcinogenicity” in male & female rats and male & female mice

ü For consideration: the observed NTP tumor findings and cancer potencies may be useful in increasing acrylamide’s acceptable risk level

ü Glycidamide’s Draft Technical Report to be released late September 2013; NTP peer review meeting is scheduled for October 29.

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Acrylamide Risk Assessment Considerations Based on NTP Cancer Bioassay

ü FAO/WHO Joint Expert Committee on Food Additives (JECFA) acrylamide risk assessment (2010) used preliminary NTP data on benign tumors in the rat mammary gland and mouse Harderian gland, but these endpoints are not biologically relevant to human risk assessment

ü JECFA and national authorities should reevaluate acrylamide’s potential for human risk based on the lower incidences of more relevant NTP malignant rat and mouse tumor endpoints

ü Lack of human cancer risk must be factored into any risk assessment and risk management plans adopted by national regulatory agencies (FDA, Health Canada, EFSA) and global public health authorities (JECFA, Codex).

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Recent Reviews of Dietary Epidemiology (Human) Studies of Acrylamide

ü Pelucchi et al. 2011. “Exposure to Acrylamide and Human Cancer - A Review and Meta-analysis of Epidemiologic Studies.” Annals Oncology 22: 1487-1499.ü “Conclusions: Available studies consistently suggest

a lack of an increased risk of most types of cancer from exposure to acrylamide.”

ü Lipworth et al. 2012. “Review of Epidemiologic Studies of Dietary Acrylamide Intake and the Risk of Cancer.” Eur. J. Cancer Protection 21: 375-386.üConcluded no increased human risk, and urged that

no further epidemiology studies even be initiated.

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“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)

ü Most countries have advised consumers to follow the dietary recommendations for a balanced diet issued by their food regulatory and public health agencies.

ü The data available to date have been insufficient to warrant any recommendation for a significant change in the dietary recommendations because of acrylamide.

ü Current epidemiological and toxicological evidence is insufficientto indicate that the amounts of acrylamide consumed in the normal diet are likely to result in adverse human health effects, particularly cancer.

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No Significant Risk Level [NSRL] = (1 x 10-5)

Over 500 Carcinogens

MADL = No Observable Effect Level1000

Over 300 Reproductive Toxicants [DARTs]

Exposure (µg/day), Not Concentration!

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Acrylamide Battleground under California Prop 65

ü Listed in 1990 as a carcinogen; “Safe Harbor” level = 0.2 μg/day; must stay below this level to avoid cancer warnings; but if you can detect it, even a 1-ounce serving of any food exceeds this level

ü French fries: Attorney General sued and settled case (2008) against frozen fries/tater tots demanding a 50% reduction in levels; fast-food restaurant fries have had cancer warnings posted for years

ü Potato chips: AG settled case (2008) against chip manufacturers; agreement to cut levels to 275 ppb by end of 2011 (20 - 85% reductions) to avoid warnings; no warnings currently being given

ü Cereals: Private “bounty hunter” lawyers sued cereal manufacturers in 2009; case is still pending.

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Acrylamide in Coffee Battles under Prop 65

ü Private “bounty hunter” group (CERT) sued coffee shops (Starbucks, Peet’s, etc.) in April 2010 for failure to provide cancer warnings (“brewed coffee” suit); in April 2011, the shops began posting 10 x 10 inch cancer warning placards covering coffee, baked goods and other products

ü CERT filed a related suit in May 2011 against coffee roasters, distributors and retailers, over 100 companies are now sued (“roasted coffee” suit)

ü These coffee roasters are fighting hard to avoid cancer warning labels on packaged products; levels average only ~ 10 ppb in brewed coffee

ü “Coffee / Cancer Paradox” - coffee drinking has conclusively been shown to reduce the risk of several forms of human cancer! So, why give cancer warnings on coffee???

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Furan

ü 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

ü “Margin of Exposure” = 750 - 4,300 below the lowest rodent risk level (Carthew et al., 2010) & less potent 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”

ü 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 is reduced significantly during roasting, grinding, storage, brewing and drinking; levels actually closer to 10 - 35 ppb.

ü But coffee PROTECTS against human liver cancer: “Coffee / Cancer Paradox”

ü Furan is listed as a Prop 65 carcinogen…but no activity to date!29

4-Methylimidazole (4-MEI)

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4-Methylimidazole (4-MEI) under Prop 65ü Maillard Browning Reaction chemical occurs naturally in added caramel colors

(cola beverages, darker beers) and in many browned foods/beverages (coffee, soy sauce, others); JECFA set level not to exceed 200-250 ppm Class III and IV)

ü Proposed for carcinogen listing by “AB” (NTP bioassay) in Jan. 2008; listed in Jan. 2011 after we waged a fierce scientific battle

ü NTP cancer bioassay (2007) showed only increased lung tumors in mice; but it reduced many other tumors in rats; this made no difference to OEHHA

ü OEHHA adopted safe harbor NSRL = 29 µg/day in Feb. 2012; we believe it should be much higher

ü Industry coalition sued OEHHA to reverse listing Feb. 2011 but lost case in Nov; went to appeal Feb. 2012, but appeal abandoned by industry Aug. 2012

ü Center for Environmental Health, 60-Day Notices (Jan/Feb. 2012): Dr. Pepper Snapple Group, Safeway, Save Mart Supermarkets, Wal-Mart, Coke, Pepsi, Cott, Trader Joe’s, Walgreen; lawsuits were threatened

ü Cola manufacturers switched to lower 4-MEI formulations nationwide; Brazil, UK, others now clamoring for the “safer” caramel in cola beverages.

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NTP Bioassays – Food & Supplement IngredientsSubstance Levels of Evidence Likely to be

ListedRemarks

Chromium PicolinateGinseng αβ-ThujoneMilk Thistle Extract

NOT SUFFICIENT NO

Goldenseal Root Powder C – C – S – N YES Final TR 562(2010)

Ginkgo Biloba Extract S – S – C – C YES Final TR 578(2013)

Aloe Vera Whole Leaf Extract C – C – N – N YES Final TR 577(2013)

Kava Kava Extract E – N – C – S Probably Final TR 571(2012)

Isoeugenol[Methyleugenol listed 2001]

E – N – C – E Maybe Final TR 551(2010)

Pulegone (mint oils) N – C – C – C YES Final TR 563 (8/20/13 OEHHA Tracking)

β-Myrcene (citrus, other oils) C – E – C – E YES Final TR 557 (8/20/13 OEHHA Tracking)35

IARC Evaluations (June 2013)Published July 5, Lancet Oncology

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Arsenic and Lead

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Environmental Law Foundation Suit in Alameda County Superior Court over Lead

ü Major victory for food industry – no need for birth defects warnings for lead

ü Defendants presented substantial evidence that each of the products tested meets the no observable effect test (the "NOEL") by showing that the average user who consumed their products was exposed to less than 0.5 micrograms per day of lead (the “MADL”), averaged over a scientifically-appropriate period of fourteen days

ü The judge also decided, however, that the defendants did not show by a preponderance of the evidence that Prop 65 is:

1) Federally preempted or2) That the regulatory defense of “naturally occurring” is applicable

to their products.

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FDA Chemical Contaminant of Concern in Food - Inorganic Arsenic ü FDA’s Total Diet Study (TDS) had been measuring arsenic

in food commodities for over 20 years

ü Arsenic can be found in foods because of its presence in water & soil

ü TDS revealed presence of arsenic in foods, including apple juice and rice

ü TDS measures only total arsenic

ü Inorganic arsenic is the most toxic, organic forms less toxic

ü FDA began to “speciate” retail food samples - separating and quantitating organic and inorganic components.

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Arsenic/Apple Juice “Action Level”ü Using new QRA/chronic exposure (0-50 years) and cancer endpoints, new

data on total and iAs levels and manufacturer achievability, FDA proposed an action level for iAs in single-strength apple juice of 10 µg/kg (10 ppb)[same as EPA drinking water standard]

ü FDA said It is appropriate to set an action level for iAs because their sampling data show that inorganic arsenic is the main form of arsenic in apple juice and because iAs is considered more toxic than organic arsenic species

ü FDA will continue to screen apple juice samples for total arsenic, prior to speciating for iAs in samples with total arsenic levels above 10 ppb

ü FDA concluded that 10 ppb iAs is achievable under GMPs based on evaluation of recent FDA data on arsenic levels in apple juice samples purchased at retail

ü FDA also concluded that an action level of 10 ppb is adequate to protect the public health based on its risk assessment.

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Inorganic Arsenic in Rice Data Evaluationü ~ 1,300 data samples (200 samples from Sept. 2012)

ü Rice grain range: 2.6 - 7.2 µg/servingRice products range: 0.1 - 6.6 µg/serving

ü FDA’s main message – “Amount of detectable iAs is too low in the rice and rice product samples to cause any immediate or short-term adverse health effects.”

ü Next steps –ü Exposure and risk assessments for long-term exposure to very low

amounts of iAs (cancer endpoints)ü Release sometime in 2014 for public commentsü Will eventually decide if further actions are required (i.e., action levels)

ü Current FDA advice:ü Eat a well-balanced diet for good nutrition and to minimize potential

adverse consequences; follow AAP guidance for infants/toddlers.44

Benefit-Risk Evaluation –

The “Holistic Approach”

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“Benefit-Risk Evaluation” to Assess the Safety of Foods Containing Toxicants and Carcinogens

ü I believe we’ve been doing it the WRONG WAY for decades, by simply evaluating the risk of individualchemicals one by one in a food

üGoing forward, I believe the RIGHT WAY is to evaluate the safety of the whole food by comparing its risks vs. benefits using the “Holistic Approach”

üVarious “Benefit-Risk Evaluations” and regulatory guidance documents have recently been published in the U.S. [FDA’s “Mercury in Fish” evaluation] and Europe [EFSA, ILSI Europe].

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