Proposition 65 Scientific Issues and Challenges, Invited Presentation in California Proposition 65 session

1. Scientific Issues and Challenges
James R. Coughlin, Ph.D. CFS
President, Coughlin & Associates:
Food/Nutritional/Chemical Toxicology & Safety
Aliso Viejo, California USA
jrcoughlin@cox.net
www.linkedin.com/in/jamescoughlin
GMA Science Forum
Proposition 65 – Current and
Emerging Issues
March 28, 2018

2. Presentation Outline
 Focus on the International Agency for Research on Cancer (IARC)
and U.S. National Toxicology Program (NTP) listings of chemicals
under Prop 65 (Authoritative Bodies and Labor Code)
 NTP & IARC - historical coordination on herbals/supplements
 Controversies over recent IARC classifications strongly impact
Prop 65 listings
o Glyphosate / 2,4-D / Red & Processed Meats
o “Nitrite combined with amines or amides”
 IARC’s “Future Priorities” for evaluation will impact Prop 65;
IARC’s methods of operation are justifiably under assault globally
 Maillard Browning Reaction carcinogens (acrylamide, 4-MEI,
furfuryl alcohol and beyond)
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3. NTP Bioassays – Food & Supplement Ingredients
Substance Levels of Evidence
(Clear, Some,
Equivocal, No)
Already Listed
(Likely to be?)
Remarks
(NTP Tech. Report)
Chromium Picolinate
Ginseng αβ-Thujone
Milk Thistle Extract
NOT SUFFICIENT NO All Final Technical Reports
Goldenseal Root Powder C – C – S – N YES Dec. 2015 TR 562
(2010)
Ginkgo Biloba Extract S – S – C – C (Maybe)
IARC 2B (2016)
TR 578
(2013)
Aloe Vera Non-decolorized Whole
Leaf Extract
C – C – N – N YES Dec. 2015 TR 577
(2013)
Kava Kava Extract E – N – C – S (Maybe)
IARC 2B (2016)
TR 571
(2012)
Isoeugenol
[Methyleugenol listed 2001]
E – N – C – E (Maybe) TR 551
(2010)
Pulegone (mint oils) N – C – C – C YES Apr. 2014 TR 563
(2010)
β-Myrcene (citrus, other oils) C – E – C – E YES Mar. 2015 TR 557
(2010) 3

4. IARC’s Recent Classifications
~
Coffee, Glyphosate, 2,4-D, Red and
Processed Meat
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5. IARC vs. “Agriculture and Foods” (2015-2016) -
Monograph Meetings
 March 2015 – Glyphosate (“Roundup” herbicide for GMOs)
 Group 2A, “Probable Human Carcinogen”
 “Sufficient evidence” in animals, “Limited” epi evidence (non-Hodgkin
lymphoma) + Mechanisms (genotoxicity & oxidative stress)
 June 2015 – 2,4-Dichlorophenoxyacetic acid (2,4-D) (pesticide):
 Group 2B, “Possibly Carcinogenic”
 First agency in the world to call the animal studies even “Limited
evidence”; but oxidative stress mechanism raised the call above the
Group 3 “not classifiable” category
 October 2015 – Red and Processed Meat: [see following slides]
 Coffee – Monograph meeting May 2016, Group 3 “not classifiable”
 Improved from Group 2B/bladder (1991); should have gotten “Group 5”!
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6. IARC: Red & Processed Meat Decisions (Oct. 2015)
 22 invited scientists on Working Group (WG); 8 global meat industry Observers
were silenced!; 8 days of deliberations; conclusions published two weeks later in
Lancet Oncology; huge negative media storm! Credit Red Flag Consulting’s
efforts to get WHO to tame down the IARC conclusions within two weeks. NTP
Report on Carcinogens proposed meat for inclusion in Fall 2016
 RED MEAT: [No “Sufficient Evidence” = No Prop 65 listing]
 Group 2A, “Probable Human Carcinogen”
 “Limited Evidence” in humans, colorectal cancer only
 “Inadequate Evidence” in animals
 Mechanistic considerations raised the classification; the IARC WG members
were not shown the 18 written submissions by the global meat industry
 PROCESSED MEAT: [Will be listed by Prop 65 when Monograph appears]
 Group 1, “Human Carcinogen”
 “Sufficient Evidence” in humans, colorectal cancer only, Relative Risk =1.18;
barely statistically significant; IARC did not review all the epi studies
 “Inadequate Evidence” in animals
 Mechanistic considerations also raised the classification
 CSPI petitioned USDA for cancer warning labels in Dec 2015
 PCRM (pro-vegan) seeks to ban processed meat from southern California
school cafeterias.
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7. Sodium Nitrite – IARC Carcinogen Listing Challenged
 IARC Monograph No. 94 (July 2010) –
 10-day meeting held June 2006; over 20 experts; I was Observer for
American Meat Institute Foundation (AMIF)
 “Ingested nitrate or nitrite under conditions that result in endogenous
nitrosation is probably carcinogenic to humans (Group 2A)”
 Limited evidence in humans for nitrite in food (stomach cancer)
 Limited evidence in animals for nitrite per se (there is no evidence!)
 Mechanistic information raised classification to Group 2A, double abuse of
“mechanism” since this is first mechanism ever evaluated
 No “Sufficient Evidence” found for any effect, should be Group 3!
 AMIF – sponsored a 1.5-year effort to scientifically dispute IARC’s classification
– publication and letter to IARC Director Wild:
 Bryan, Alexander, Coughlin, Milkowski and Boffetta. 2012. “Ingested nitrate
and nitrite and stomach cancer risk: An updated review.” Food Chem.
Toxicol. 50: 3646-3665.
 Absolutely no response from IARC to date, except Processed meat now a
Group 1 human carcinogen.
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8. “Nitrite in Combination with Amines or Amides” –
Carcinogen Listing Challenged [“Sufficient Evidence”]
 Cited in IARC Monograph No. 94 (2010) on “Ingested Nitrite and
Nitrate” classified as Group 2A “probably carcinogenic”
 AMI and GMA submitted comments objecting to this “Authoritative
Bodies” listing in May 2014; would impact processed meats and all
natural products containing nitrite and amines/amides
 After consideration of our comments, OEHHA determined that the
regulatory criteria for automatic listing had not been met
 But the state notified us in May 2015 that they would ask the
Carcinogen Identification Committee (CIC) to consider this listing
 The CIC evaluated our comments on November 15, 2016 and voted
unanimously not to list, agreeing with our arguments.
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9. Future HIGH Priorities for IARC Monographs
 Acrylamide, furan and 5-(hydroxymethyl) furfural - commonly found in
cooked foods; cancer bioassay data are available
 Aspartame and sucralose - widespread use and concern about their potential
carcinogenicity; Aspartame also Prop 65 CIC Med/High Priority (Nov 2016)
 Beta-carotene - chemoprevention trials provide data on cancer incidence in
high-risk groups (cigarette smokers and asbestos exposed workers) who
were exposed to high doses
 Bisphenol A - widely used in epoxy resins and plastics; ongoing cancer
bioassays of perinatal exposure
 Iron (in food and as supplements) - daily iron intake exceeds recommended
levels in many women; epidemiological studies of heme iron intake and
colon and other cancers are available
 Obesity and being overweight - high and increasing prevalence; many
epidemiological studies of several cancer types are available
Lancet Oncology 15: 683-684 (June 2014)
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10. IARC Controversies are Raging in the Media,
Industry Fighting Hard, and even Battles
within and amongst Public Health &
Regulatory Bodies [Glyphosate!]
~ ~ ~
Mainly from Classifications for Agriculture
and Food Substances
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15. Boobis et al. - Concluding Paragraph on the IARC
Monographs Program
 It’s time that the global scientific, regulatory and political community
assess the value of continuing the IARC monograph program, and
openly – with complete transparency — examine the legitimate
questions that have been raised concerning the organization’s
conflicts of interest, scientific rigor and evidential standards.
 The IARC monograph program needs to be fundamentally reformed to
reflect advances in knowledge of mechanisms of chemical
carcinogenicity and other areas of biology if it is to provide value.
 If that reform can’t be accomplished, it should be relegated to the
regulatory museum where it belongs, along with other historical
artifacts like the Model T Ford, the biplane, and the rotary dial
telephone that no longer serve an important function in our society
today.
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16. Concentration Range of Food Contaminants
< 500,000
ppb
< 1,000 ppb
< 100 ppb
< 1ppb
• Furfuryl Alcohol
• Acrylamide - 2002
• Mycotoxins, PAHs
• Nitrosamines, HCAs
• Pb, As, Cd, Hg
• Dioxins
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17. “Maillard Browning Reaction”
Listed Carcinogens
~
Acrylamide
4-Methylimidazole
Furfuryl Alcohol
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18. Ammonia
Alkyl amines
Amino acids
Proteins
Phospholipids
Aldehydes
Ketones
Sugars
Carbohydrates
Lipids
Carbonyls
Esters
Amides (Acrylamide)
Heterocyclic Compounds
Amine
Carbonyl
Amino-Carbonyl
Interaction
(Amadori Products)
HEATHEAT
Furans Oxazoles
Pyrroles Imidazoles
Thiophenes Pyridines
Thiazoles Pyrazines
Melanoidins
(pigments)
Volatile Compounds
(aroma chemicals)
General Scheme of Maillard Browning Reaction

19. N-Nitrosamine Carcinogenicity Concerns
Began with Rodents in 1956
~
My PhD lab research on N-nitrosamines in the “Maillard
Browning Reaction” began in 1974 at UC Davis
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20. Acrylamide
Listed as a Carcinogen
~
A Huge Battleground Since 2002
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21. Acrylamide Snapshot: Chemistry and Toxicology
 Occupational neurotoxin in humans, genotoxic/mutagenic in cell cultures
 Known rat carcinogen, IARC classified as “probable human carcinogen”
 Metabolized to glycidamide (an epoxide), also an animal carcinogen
 Acrylamide & glycidamide can bind to DNA, amino acids and proteins
 DNA adducts  carcinogenic potential
 Blood hemoglobin adducts  biomarker of exposure (and a “sink”)
 Dietary proteins may reduce acrylamide uptake in humans (a “sink”)
 Human protective enzymes can detoxify acrylamide and glycidamide
 NTP Acrylamide Bioassay in rats and mice (2012) – “Clear Evidence of
Carcinogenicity” for both species and both sexes
 Discovered by the Swedes in 2002 in hundreds of heat-processed food products,
making up about 40% of our total daily calories.
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22. 4-Methylimidazole Listed as a Carcinogen
~
Cola / Caramel Formulations Modified at Great Cost
to Get Lower Concentrations
Also in Coffee and Other Heated Food/Beverage
Products
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23. Furfuryl Alcohol
Listed as a Carcinogen in Sept. 2016 Based
on U.S. EPA (AB)
~
60-Day Notices have Begun Appearing Since
Fall 2017
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25. Six 60-Day Notices (since Fall 2016) for
FURFURYL ALCOHOL - Failure to Warn
 Pretzels
 Potato Bread
 Baked Potato or Sweet Potato-Based Snack
Foods
 Most filed by Center for Environmental Health
(CEH)
 Reminder from chart above…occurs in
foods/beverages at levels 500-1000 times greater
than acrylamide!
 We are in for a WILD RIDE!!!
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26. Furfuryl Alcohol ~ IARC Working Group Meeting for
Monograph No. 119 (June 2017)
 IARC reviewed Furfuryl Alcohol (FFA) as one of several chemicals in food and
consumer products at its June 6-13 WG meeting; Group 2B “possible”
 U.S. National Toxicology Program cancer bioassay (1999) found it to be a
carcinogen via inhalation:
 Male rats – weak nasal carcinogen
 Male mice – weak kidney carcinogen
 Females – not carcinogenic in any organ
 COFFEE is by far…
 the #1 source of FFA in the total diet of coffee drinkers
 levels in roasted coffee reported to be ~ 100 - 500 ppm
 this is over a thousand times higher than acrylamide levels in coffee
 Many other heated foods and beverages also contain high FFA levels.
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32. Lessons to be Learned to Minimize the
Threats of Prop 65 Listings…
1. Know everything going on with the all 5 Authoritative Bodies,
especially IARC and NTP, and early enough to try to prevent
their worst classifications or decisions, or at least to minimize
their damage to anything less than “sufficient evidence”
2. Submit written scientific comments in response to OEHHA’s AB-
based proposals to list; comment and testify to the CIC and
DARTIC in order to prevent their listings outright, or at least to
achieve “qualified” less-damaging listings
 e.g., “Furfuryl Alcohol (by inhalation only)” would have been a
great victory for food and beverage products
3. HOWEVER…THE VERY BEST OUTCOME IS TO PREVENT your
chemical or substance of interest from EVER being listed by
Prop 65 in the first place!!!
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33. Thank You!
~
Questions?
James R. Coughlin, PhD CFS
jrcoughlin@cox.net
949-916-6217