Nitrite in combination with amines and amides - OEHHA · PDF file15-11-2016 ·...
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Transcript of Nitrite in combination with amines and amides - OEHHA · PDF file15-11-2016 ·...
Evidence on the Carcinogenicity of Nitrite in Combination with
Amines or Amides
Jennifer C.Y. Hsieh, PhD Amy J. Dunn, MPH
Carcinogen Identification Committee Meeting November 15, 2016
Cancer Toxicology and Epidemiology Section Reproductive and Cancer Hazard Assessment Branch
1
Overview
Chemical Identity Occurrence and Use Evidence from Studies in Humans Evidence from Studies in Animals Mechanistic Evidence and Other Relevant Data, Including Genotoxicity Studies
2
Chemical Identity
Nitrite: can form salts with sodium and potassium ions
Amines Primary Secondary
Tertiary
R'''
R'' N R
R'
Quaternary
Cyclic Aromatic
3
Chemical Identity (contd)
Amides Primary O Ureas (diamides)
R NH2
Secondary Carbamates (esteramides)O O
R N R' NH H
Sulfonamides (with an isosteric SO2 ) O
Tertiary S
O O N R'O
R R''
R N R' Guanidine (carbamidine, iminourea) N
R''
4
Occurrence and Use
Nitrite Part of the nitrogen cycle, present in water, soil,
organisms Dynamic interchange of nitrite with nitrate Industrial Uses Nitrous acid production Chemical synthesis (e.g., saccharin, caffeine, pharmaceuticals, pesticides) Polymerization inhibitor Removal of hydrogen sulfide from natural gas
Occurrence in foods Low levels in vegetables, grains, and fish Used as a preservative (e.g., curing of meats and fish)
5
Occurrence and Use (contd) Amines Widespread occurrence in biological systems All amino acids, biogenic amines (e.g., histamine, tyramine, dopamine)
Occur as food constituents (e.g., meat, fish, beer, wine, coffee, cheese, milk, ground pepper) Formed during hightemperature cooking (e.g., PhIP, MeIQ, MeIQx) Present in tobacco smoke Used In rubber, dye and nylon production As coloring/filling agents, pesticides and pharmaceuticals
(also formed as metabolites of drugs) Other industrial uses
6
Occurrence and Use (contd)
Amides Widespread occurrence in biological systems The key linking moiety (peptide bond) in proteins
Occur as food constituents (e.g., beef, fish, evaporated milk) Formed during hightemperature cooking (e.g., acrylamide) Formed endogenously (methylguanidine) Used As pharmaceuticals, pesticides, research chemicals In synthetic fiber production (e.g., nylon)
7
Occurrence and Use (contd)
Nitrite in combination with amines or amides Used in occupational settings, e.g., azo dye production Occurs in foods, such as plantbased foods (e.g., some vegetables, grains and fruits) and processed meats and fish Present in tobacco
8
Evidence from Studies in Humans
Presented by Amy J. Dunn, MPH
9
Sources of Human Evidence of Carcinogenicity
IARCs 2006 review Studies of ingested nitrite (IARC, 2010)
Other reviews Epidemiologic studies published since IARCs 2006 review
10
Nitrite Exposure Evaluated in Human Studies
Majority of studies estimated dietary intake of nitrite Food frequency questionnaires Estimated levels of nitrite in foods eaten
Most drew from the literature A few measured nitrite Variation across time not always factored in
Some studies only reported nitrate + nitrite exposure levels Human diet includes amines and amides
Levels of nitrite in urine one study of gastric cancer Occupational exposure two studies
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Endpoints of Interest in Human Studies
12
Endpoints of Interest in Human Studies
13
Colorectal Cancer IARC 2010 IARC (2010) Two studies One casecontrol study
Increased risk of colon cancer Increased risk of rectal cancer
One cohort study No association
Did not consider studies that looked only at processed meat exposure Focused on studies that estimated nitrite exposure Because many, but not all, cured meats contain nitrite and because otherfoods can also be important sources of nitrite
14
Colorectal Cancer
Other reviews IARC 2015 Working Group on Red and Processed Meats Classified consumption of processed meat as carcinogenic to humans (Group 1)
The basis was sufficient evidence for colorectal cancer (Bouvard et al. 2015)
An IARC Monograph describing the evidence has not yet been published
15
Studies since IARC (2010): Colon cancer casecontrol studies
16
Studies since IARC (2010): Colon cancer cohort studies
17
Studies since IARC (2010): Rectal cancer casecontrol studies
18
Studies since IARC (2010): Rectal cancer cohort studies
19
Studies since IARC (2010): Colorectal cancer casecontrol studies
20
Studies since IARC (2010): Colorectal cancer cohort studies
21
Endpoints of Interest in Human Studies
22
Esophageal Cancer
IARC (2010) Two casecontrol studies
Both had a positive nonsignificant association
Other reviews Jakszyn and Gonzalez (2006) examined two studies
Considered the data insufficient
23
Studies since IARC (2010):
Esophageal cancer cohort studies
24
Esophageal cancer casecontrol studies
Studies since IARC (2010):
Esophageal adenocarcinoma (EAC) cohort studies
25
Studies since IARC (2010): Esophageal squamous cell carcinoma (ESCC) cohort studies
26
Endpoints of Interest in Human Studies
27
Stomach Cancer IARC (2010)
IARC (2010) Six of seven casecontrol studies found a positive association
Significant in four Two cohort studies
Finnish study no association Dutch study Significant increase in risk for highest intake
Nonsignificant after adjustment for potential confounders
Concluded: Nitrite in food is associated with increased incidence of stomach cancer
Classified the overall human evidence as limited
28
Stomach Cancer Other Reviews and Metaanalyses
Other reviews and metaanalyses of ingested nitrite Jakszyn and Gonzalez (2006) Evidence supports a positive association with gastric cancer Pooled relative risks Song et al. (2015) 18 studies: RR=1.31, 95% CI, 1.131.52 Xie et al. (2016) 51 studies: RR = 1.21, 95% CI, 0.991.47 IARC 2015 Working Group on Red and Processed Meats Summarizing the findings, Bouvard et al. (2015) noted:
a positive association with the consumption of processed meat was found for stomach cancer
29
http:0.99-1.47http:1.131.52
Studies since IARC (2010): Gastric cancer cohort study
30
Studies since IARC (2010): Gastric cancer casecontrol studies
31
Studies since IARC (2010): Gastric cardia adenocarcinoma Cohort studies
32
Studies since IARC (2010): Gastric noncardia adenocarcinoma Cohort studies
33
Endpoints of Interest in Human Studies
34
NonHodgkin Lymphoma (NHL) IARC 2010 & Other Reviews
IARC (2010) One of two casecontrol studies found increase in risk with increasing quartiles of nitrite intake
When plant and animal sources of dietary nitrite were evaluated separately, the positive association was observed only for plant sources.
Metaanalysis: Xie et al. (2016) 4 casecontrol studies Highest vs lowest nitrite intake, RR = 1.54 (95% CI = 0.98 2.41)
35
http:0.98-2.41
Studies since IARC (2010): Lymphoma casecontrol studies, Part A
36
Studies since IARC (2010): Lymphoma casecontrol
studies, Part B: NHL, FL and
DLBCL
37
Studies since IARC (2010): Lymphoma casecontrol
studies, Part B: CLL/SLL, MZBL
and TCL
38
Endpoints of Interest in Human Studies
39
Brain Cancer IARC (2010)
Childhood brain cancer 12 case control studies Maternal diet: children born to mothers who had the highest category of intake of nitrite specifically from cured meat had an almost twofold increased risk for brain tumours.
Drinkingwater Nitrite measured in homes where pregnancies occurred A twofold increase in risk for brain tumours in the offspring
Stronger among women who did not rely on bottled water
Astroglial tumors
Dietary nitrite and adult brain tumors Seven studies No significant associations over all dietary sources
The largest study (conducted in CA) observed a twofold increase in risk among men who consumed levels of nitrite above the median and levels of vitamin C below the median
Two small studies a positive association with intake of nitrite from cured meat
A larger casecontrol study A threefold increase among those with high consumption of nitrite from plant sources
40
Brain Cancer Studies Since IARC (2010)
Two large cohort studies Michaud et al. (2009) Elevated but not statistically significant risks with total nitrite Dubrow et al. (2010) Significantly elevated risks with nitrite from plant sources, driven by an effect seen in men
Mens highest intake level: HR= 2.04 (1.462.87), ptrend= 0.0026 Dietary nitrate plus nitrite intake from processed meat at age 12 and 13, diet estimated retrospectively
Risks were elevated for fourth quintile, but no significant trend Metaanalysis: Xie et a