Historical Considerations on the Potential Risks of Nitrite and Nitrate to Humans

1. Historical Considerations on the Potential
Risks of Nitrite and Nitrate to Humans
James R. Coughlin, PhD CFS
President, Coughlin & Associates
Aliso Viejo, California USA
jrcoughlin@cox.net
www.linkedin.com/in/jamescoughlin
23rd International Conference and
Expo on Functional Foods
San Diego, CA
April 24, 2018

2. Presentation Outline
Nitrite/Nitrate/N-Nitrosamines, Processed Meats and Cancer
 N-nitroso compounds as carcinogens (1956 - )
 Nitrite per se as a possible carcinogen (1978 - )
 California Proposition 65 Battles over Nitrite & Processed Meats (1998 - )
 IARC classified red meat & nitrite-processed meat as human carcinogens
(October 2015)
 U.S. National Toxicology Program – NTP Report on Carcinogens considering
addition of meats (Sept 2016 - )
 WCRF/AICR – Meats and Human Colorectal Cancer (2007 - )
 Acceptable Daily Intake (ADI) for Nitrate…is it too low?
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3. Remembering My “Roots” at the University of
California, Davis

4. Safety and Regulatory History of Nitrite / Nitrate -
Methemoglobenimia (MHG)
 Mechanism:
 ~ 5% of ingested nitrate is converted to nitrite in vivo
 Nitrite can bind to ferrous (Fe++) hemoglobin to form ferric (Fe+++)
hemoglobin (methemoglobin) and nitric oxide
 Because methemoglobin cannot transport oxygen, normal oxygen
transport can be altered, resulting in toxicity
 Data from the 1920’s-1950’s document that high doses of nitrate, usually in
well water, were associated with occurrence of MHG in infants & very young
children
 More recent studies have lessened this concern, because the earlier
studies were confounded by gastroenteritis and altered pharmacokinetics
in infants
 Studies support the absence of MHG in older children and adults, but
some sensitive infants may still be of concern.
ATSDR, 2015
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5. N-Nitrosamine Carcinogenicity Concerns
Began with Rodents in 1956
~
My PhD/Post-doc research on N-Nitrosamines in the
“Maillard Browning Reaction” began in 1974 at
UC Davis
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13. International Agency for Research on Cancer (IARC)
Evaluation of Meat and Cancer, October 2015
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15. IARC and Red & Processed Meat
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16. IARC: Red & Processed Meat Decisions (Oct. 2015)
 22 invited scientists on Working Group; 8 global meat industry Observers were
silenced!; 8 days of deliberations; global written submissions not shared with WG;
conclusions published two weeks later in Lancet Oncology (Oct. 2015)
 RED MEAT: [No “Sufficient Evidence = No Calif. Prop 65 listing]
 Group 2A, “Probable Human Carcinogen”
 “Limited Evidence” in humans, colorectal cancer only
 “Inadequate Evidence” in animals
 Mechanistic considerations made classification go from Group 3 to Group 2A
 PROCESSED MEAT: [Will eventually be listed by Calif. Prop 65]
 Group 1, “Human Carcinogen”
 “Sufficient Evidence” in humans for colorectal cancer only; Relative Risk
=1.18; barely statistically significant, translates to 18% increase in risk; fuller
published meta-analysis showed no increased risk; IARC excluded some epi
studies
 “Inadequate Evidence” in animals
 Mechanistic considerations made classification go from Group 2B to Group 1.
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18. ~ NTP’s ROC Nominated Red & Processed Meats
in September 2016
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19. California Proposition 65
~
Nitrite “Battles” raging since 1998
- Carcinogenicity
- Reproductive/Developmental Toxicity
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20. Sodium Nitrite DART Listing Challenge
 April - June 1998 – OEHHA requested information on 15 chemicals,
including nitrite, for potential listing as developmental toxicants under the
AB mechanism, based on EPA’s Toxic Release Inventory; American Meat
Institute (AMI) submitted written comments to OEHHA
 December 1998 – OEHHA published “Notice of Intent to List” Nitrite
 February - May 1999 – AMI coalition submitted comments objecting to
nitrite’s listing on scientific grounds, and OEHHA agreed that the
scientific criteria for listing had not been met; but OEHHA passed the
listing decision to the DART Identification Committee (8 scientists)
 July - Sept 1999 – AMI coalition submitted written comments to DART
Committee objecting to listing
 June 2000 – DART Committee voted NOT to list sodium nitrite as a
reproductive or developmental toxicant
 Listing could have meant birth defects warnings on packages of bacon,
ham, hot dogs, etc.
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21. Meat Industry Wins Federal Preemption
 In 1987, the USDA Secretary wrote to the Governor expressing USDA’s view
that the Federal Meat Inspection Act of 1906 preempted Prop 65; essentially,
USDA “owns the label”
 In Nov. 2004, “60-Day Notices” were filed by Dr. Whitney Leeman against
grocery retailers and meat companies, for not providing label warnings
about dioxins (carcinogens) and PCBs (carcinogens & DARTs) in ground
beef and beef liver
 American Meat Institute and National Meat Assn. sued Leeman before she
could sue (May 2005); the “twist” here was that industry initiated the
litigation themselves rather than raising preemption as a defense
 In December 2009, a California Court of Appeal granted a victory to the meat
industry, declaring there is an express Federal Preemption for package
labeling at point of sale, so no warning label requirement is permitted.
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22. IARC and “Endogenous Nitrosation” in the
Human Stomach
Monograph Working Group [June 2006]
~
Group 2A – “Probable Human Carcinogen”
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24. “Nitrite in Combination with Amines or Amides” –
Proposition 65 Carcinogen Listing Challenge
 IARC Monograph No. 94 (2010) on “Ingested Nitrite and Nitrate”
classified as Group 2A “probably carcinogenic” due to Endogenous
Nitrosation
 “Nitrite in Combination with Amines or Amides” – the only
“sufficient evidence” finding
 American Meat Institute and Grocery Manufacturers Association
submitted comments objecting to this “Authoritative Bodies” listing in
May 2014
 After consideration of our comments, the state 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 for listing
 The CIC voted unanimously November 2016 not to list, agreeing with
our industry comments, another victory.
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25. American Institute for Cancer Research / World Cancer
Research Foundation – Processed Meats and Colorectal Cancer
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27. Using a “Benefit-Risk” Approach for
Nitrite-Processed & Red Meat …
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29. Acceptable Daily Intake for Nitrate (ADI)
WHO/FAO JECFA -
 ADI of 0-3.7 mg nitrate/kg bw for nitrate set in 1974, reconfirmed in
1995 & 2002, based on studies of sodium nitrate fed orally to rats &
two dogs
 Concluded that public health risk is negligible when intake is below
this ADI
 ADI is equivalent to ~ 222 mg nitrate ion/day for a 60 kg individual
USEPA Reference Dose (RfD) -
 Chose a different data set to estimate the RfD
 Used very old human case studies of methemoglobinemia in infants
and young children, poor anecdotal studies, confounders
 Established chronic oral RfD for noncarcinogenic effects of 1.6 mg
nitrate-nitrogen/kg bw-day, or 7 mg nitrate/kg bw-day, in 1991 and
has not revised the RfD, but it is now under review.
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30. Summary and Conclusions
 Potential hazards of Nitrite and Nitrate exposure have been extensively
evaluated by many regulatory agencies and public health bodies for decades
 Nitrate is not a carcinogen and is associated with an overall low level of
toxicity…it’s been Nitrite that has gotten all the attention
 Nitrite per se is not a carcinogen in animals or man
 Yes, nitrite does react to form carcinogenic N-nitroso compounds in foods and
in the human body, but at levels much to low to induce cancer risk
 Processed meats have been tortured with barely-statistical epidemiologic
findings [colorectal cancer only] and unproven mechanistic hypotheses
Must use Benefit-Risk Evaluation…
”Turning Toxicants into Nutrients”!!!
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32. Thank You!
~
Questions?
James R. Coughlin, PhD CFS
jrcoughlin@cox.net
949-916-6217