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Section D
Strategies to Alter Aflatoxin Toxicokinetics
and Toxicodynamics in Humans
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Risk Factors for Liver Cancer
! Chemicals and viruses
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Liver Cancer Etiology: A Case-Control Study in Taiwan
Hepatitis B virus surface
antigen status
Relative risk for
liver cancer
HBV antigen
negative
1.0
HBV antigen
positive
98.4
Source: Beasley et al. (1981). Lancet, 2, 1129.
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Age-Specific Male HCC Incidence Rates
! Age-specific male HCC incidence rates in populations with similar
incidence of HBV
10-fold difference
© Copyright - International Agency for Research on Cancer (IARC), 2015. All Rights Reserved.
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Aflatoxin Ingestion and Liver Cancer
! Aflatoxin ingestion and liver cancer incidence in humans
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Study of Liver Cancer Risk Factors in Shanghai
! Nested case-control study of liver cancer risk factors in Shanghai
- 18,244 urine samples collected from healthy males (ages 45–64)
during 1986–1989
- 50 liver cancers developed in this group and cases were age
matched to 267 controls
- IAC/HPLC analysis was done on the coded samples for aflatoxin
urinary biomarkers
- Hepatitis virus B antigen status was determined
Sources: Ross et al. (1992). Lancet, 339, 943–946; Qian et al. (1994). Cancer Epi,
Biomarkers, and Prevention, 3, 3–10.
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HBsAg and Urinary Aflatoxin Biomarker
! Combined effect of HBsAg and presence of urinary aflatoxin
biomarker on risk of hepatocellular carcinoma in Shanghai
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Liver Cancer (Male)
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“Geographic Pathology”
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“Geographic Pathology”
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One in Ten Adults Develops HCC
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Liver Cancer Incidence in Qidong
13
Liver Cancer Survival Rates in Qidong
14
Aflatoxin-Contaminated Staples in Qidong
! Dietary staples in Qidong consistently contaminated with aflatoxins
- Soy sauce
- Rice
- Peanuts
- Maize
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Qidong Farm
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Corn
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Corn Storage
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Corn Porridge
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Peanuts
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Peanuts
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Strategies for Prevention
Primary
! Strategies for prevention of hepatocellular carcinoma
- Immunization with HBV vaccine
- Reduced aflatoxin consumption
! Improve food storage; biocontrol
! Changes in dietary staples
22
Intervention Package in Kindia, Guinea
! Intervention villages
- Hand sorting: training in removal of groundnuts that were
visibly moldy or had the shells damaged
- Drying on mats: provision of locally produced natural fiber mats
for the sun drying process
- Sun drying: training in sun drying by shaking the kernels to
listen for the free movement of the dried nuts
- Storage in natural fiber bags: provision of natural fiber jute
bags to replace plastic or other synthetic bags
- Wooden pallets: provision of locally made wooden pallets on
which to store the bags
- Insecticide: provision of locally available insecticide (acetilite)
to sprinkle on the floor of the storage facility
! Control villages: farmers were left to follow their normal postharvest practices
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Intervention
24
Primary Prevention
! Photos courtesy of Professor Chris Wild, University of Leeds
Improved groundnut storage in
Kindia, Guinea
25
Primary Intervention and Aflatoxin Biomarker Levels
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Strategies for Prevention
Secondary
Primary
! Strategies for prevention of hepatocellular carcinoma
- Immunization with HBV vaccine
- Reduced aflatoxin consumption
! Improve food storage; biocontrol
! Changes in dietary staples
- Chemopreventive interventions
! E.g., oltipraz, broccoli sprouts, chlorophyllin,
green tea
27
Cancer Chemoprevention
! Retardation, blockade, or reversal of the process of carcinogenesis
(before malignancy) by natural or synthetic agents, e.g., drugs,
foods, supplements
28
Cancer Chemoprevention
Source: http://commons.wikimedia.org/wiki/File:Assorted_Pills_3.JPG CC BY-SA
http://commons.wikimedia.org/wiki/File:Ecologically_grown_vegetables.jpg CC BY-SA
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Chlorophyllin
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Chlorophyllin
! Semi-synthetic Na/Cu derivative of chlorophyll
! Non-prescription drug in the US
- Deodorizing activity (e.g., incontinent geriatric patients,
ileostomy/colostomy patients)
- Wound healing accelerant
! Food colorant
! Antioxidant, antimutagen and anticarcinogen in a variety of
experimental models
! Safe, inexpensive
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Aflatoxin-Chlorophyllin Interaction
32
Chlorophyllin Intervention: Qidong
PE = physical exam
U = urine sample
S = serum sample
33
Chlorophyllin and Excretion of Aflatoxin-DNA Adducts
! Effect of three months of chlorophyllin on urinary excretion of
aflatoxin-DNA adducts
Source: Egner et al. Proc Natl Acad Sci (USA). In press.
34
The Aflatoxin-DNA Adduct Is Excreted in Urine
! The aflatoxin-DNA adduct is unstable and is excreted in urine
35
Detoxication Enzymes from Vegetables
! Induction of detoxication enzymes by extracts from three families of
vegetables
36
Detoxication Enzymes from Vegetables
37
Broccoli Samples from Baltimore Area Markets
38
Protective Enzyme Inducer Potency
! Protective enzyme inducer potency: market stage broccoli versus
sprouts
39
Phase 2 Enzyme Induction Potency of Broccoli
40
Market-Stage Broccoli vs. Sprouts
41
Protection against Mammary Carcinogenesis in Rats
Source: Fahey et al. (1997). PNAS.
42
Broccoli Sprouts Intervention Trial
! Broccoli Sprouts Intervention Trial, He Zuo Township, Qidong, PRC
! Do broccoli sprouts modulate aflatoxin biomarkers?
43
Grew 200 kg Sprouts
44
Brewed 500 Liters of Sprouts Tea
! Dose = 125 ml (400 µmoles glucoraphanin)
45
Compliance Was 100%
46
Collected a “Truckload” of Urine
47
Glucosinolate Composition of Broccoli Sprouts “Tea”
48
Broccoli Sprouts Tea Intervention: He Zuo Township
! Urinary isothiocyanate/dithiocarbamate excretion
49
Urinary Excretions of Sulforaphane Metabolites
! Large INTER-individual variation in
urinary excretion of sulforaphane
metabolites
P < 0.001
50
Urinary Excretions of Sulforaphane Metabolites
! Small INTRA-individual differences in excretion of sulforaphane
metabolites in highest and lowest deciles
51
Measures of Exposure
52
Measures of Exposure
53
No Effect of Tea on Carcinogen Levels
! No effect of tea on urinary carcinogen biomarker levels based upon
“intent to treat”
AFB-N7-Guanine
fmol/mg creatinine
" Median (min, max)
Placebo
N=99
Tea
N=100
2.06 (0.12, 11.27)
1.88 (0.10, 7.75)
P-value
0.74
9%
Phenanthrene Tetraol
pmol/mg creatinine
" Median (min, max)
7.97 (0.45, 68.92)
7.20 (1.62, 28.53)
0.52
10%
Source: Kensler et al. (2005). CEBP.
54
Inverse Association
! Inverse association between urinary levels of sulforaphane
biomarker and aflatoxin-DNA adduct biomarker
55
Inverse Association
! Inverse association between urinary levels of sulforaphane
biomarker and phenanthrene tetraol (PheT) biomarker
56
The Public Health Significance of a 50% Reduction
! What might be the public health significance of a 50% reduction in
the burden of aflatoxin-DNA adducts ?
57
Age-Specific Incidence Rate of HCC
! Age-specific incidence rate of HCC: Qidong and Beijing
58
Age-Specific Incidence Rate of HCC
! Age-specific incidence rate of HCC: Qidong and Beijing
Public Health Benefit from
Intervention against Aflatoxin
Benefit from
HBV Vaccination
59
Lecture Evaluation
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