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Section A
Biomarkers of Exposure
Traditional Epidemiology
Exposure
Disease
Traditional Toxicology
Exposure
Disease
4
The Problem
To identify the role of specific risk factors,
some of which may interact with host
susceptibility factors, in the causation of
environmentally-induced disease
Multiple exposures, multiple agents
Low levels of exposure
Wide range of susceptibility mechanisms
Long latency periods
6
Definitions
Biomarkers: Molecular, biochemical or
cellular alterations that are measurable in
biological media, such as human tissues,
cells, or fluids
Molecular epidemiology: Incorporation of
biomarkers into analytic, epidemiologic
research
Fundamental Principles
of Toxicology
Principle I
The toxic action of a substance is a
consequence of the physical/chemical
interaction of the active form of that
substance with a molecular target within
the living organism
Continued
Fundamental Principles
of Toxicology
Principle II
The magnitude of the toxic effect will be
a function of the concentration of
altered molecular targets, which in turn
is related to the concentration of the
active form of the toxicant at the site
where the molecular targets are located
10
11
Biomarkers of Exposure
12
13
14
Examples of Biomarkers of
Internal Dose
15
16
Markers of Biologically-Effective
Dose
Urine: E.g., aflatoxin-N7 guanine
adducts in urine of individuals
consuming AFB1; oxidized DNA bases in
urine following radiation and other
forms of oxidative stress
Continued
17
Markers of Biologically-Effective
Dose
Protein adducts
Hemoglobin: Ethylene oxide, aromatic
amines, tobacco-specific nitrosamines,
cisplatinum
Albumin: Aflatoxin B1
18
Examples of Assays
19
Examples of Assays
20
21
23
24
Section B
Biomarkers of Risk
27
Reporter genes
HPRT, Glycophorin A
Oncogenes and suppressor genes
Gatekeepers: Control net cellular
proliferation, e.g., APC, K-ras, p53
Caretakers: Maintain genomic integrity,
e.g., hMSH2, hMLH1
28
29
Brain
273
Liver
249
30
Esophagus: Barretts
Prostate: PIN
Cervix: CIN
32
Early Detection/Prognostic
Biomarkers: Altered Cell Structure
Most common intermediate endpoint
currently in use in chemoprevention trials
Detection: histopathological, quantitative
computer-assisted image nuclear
morphometry
33
Cross-sectional study of
biomarker levels in
exposed humans
Longitudinal study of
biomarkers in humans
Validated exposure marker
Modulation of biomarker
and disease in animal
chemoprevention studies
Case-control studies
Cohort studies
Clinical trials
Validated risk marker
35
Section C
Susceptibility Factors: Overview
37
38
Inverse Correlation
Adapted from Hussain and Harris, Cancer Research 58: 4023-4037, 1998
40
Susceptibility Factors
Assessing inter-individual variability in
Biotransformation: Phase I and Phase II enzymes
Phenotypic
Direct in vitro determination of enzyme content and
activity in biopsy specimens
Assay substrate/metabolite levels and/or kinetics (t
1/2s) in blood, urine, feces, saliva, milk, breath
Genotypic
Genetic polymorphisms, RFLPs
DNA repair: repair proficiency by plasmid-host cell
reactivating assay
41
42
43
44
Adapted from Wei et al. Cancer Epi. Biomarkers & Prev. 5:199-204 (1995)
45
Adapted from Wei et al., Proc. Natl Acad. Sci. 90:1614-1618 (1993)
46
47
Susceptibility Factors
Assessing inter-individual variability in
Biotransformation: Phase I and Phase II enzymes
Phenotypic
Direct in vitro determination of enzyme content and
activity in biopsy specimens
Assay substrate/metabolite levels and/or kinetics (t
1/2s) in blood, urine, feces, saliva, milk, breath
Genotypic
Genetic polymorphisms, RFLPs
DNA repair: repair proficiency by plasmid-host cell
reactivating assay
48
Examples of Procarcinogens
49
Heterocyclic Amines
50
70
% Rapid Phenotype
60
50
40
30
20
10
0
Acetylation
CYP1A2
51
Slow/Rapid
Slow/Slow
Rapid/Rapid
Rapid/Slow
Colon
Slow/Rapid
Slow/Slow
Rapid/Rapid
Rapid/Slow
Polyp
Slow/Rapid
Slow/Slow
Rapid/Rapid
Rapid/Slow
Controls
Slow/Rapid
Slow/Slow
0
10
15
20
25
% of Population
30
35
40
45
52
Cases
Controls
OR (95%) CI
12 (24%)
33 (34%)
1.0 (ref.)
15 (30%)
44 (46%)
0.9 (0.42.5)
Well done
23 (46%)
18 (20%)
3.5 (1.39.6)
Total
50 (100%)
95 (100%)
53
Meat Cooking
Preference
Slow-slow
Rapid-slow
Odds Ratio
1.00
Rare/medium
0.91
Slow-rapid
1.39
Rapid-rapid
3.13
Slow-slow
2.06
Rapid-slow
1.87
Well done
Slow-rapid
2.86
Rapid-rapid
6.45
Source: adapted by CTLT from Lang et al. (1994). Cancer Epi Biomarkers & Prevention 3:675682.
54
Activation
Deactivation
High
DNA
Repair
Adduct
Level
Low
High
High
High
Low
Low
High
Low
High
High
Low
Low
Low
Low
High
55
Key Points
Continued
56
Key Points
57