Biomonitoring of Exposure to Environmental Chemicals ...to the exposome ~ Matti Jantunen. 01/07/2011...
Transcript of Biomonitoring of Exposure to Environmental Chemicals ...to the exposome ~ Matti Jantunen. 01/07/2011...
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Biomonitoring of Exposure to Environmental Chemicals:
Complexities in Interpreting Data
Dana Boyd Barr, Ph.D.
Professor, Exposure Science and Environmental Health
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SourceWater, Air, Food, Soil, Dust, Sediment, Personal Care Products
Internal Dose
InhalationIngestionDermal Contact
Target Organ Dose
Biological Effective Dose
Absorption following:
DistributionMetabolism
Elimination
Elimination
Effect
External DoseEXPOSURE
Body Burden
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The Exposure Conundrum
• Exposure = contact of a chemical or agent at biological interface
• Body burden = amount of a chemical/agent residing in body (including deposition matrices)
• Biomonitoring = measurement of chemical/metabolite/rxnproduct in biomatrix
• Body burden ≠ biomonitoringmeasurement
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Bruegel’s “Little” Tower of Babel, ca. 1563
Interpretation complicated by incongruent views of “exposure”
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Why are we biomonitoring?
• Assess exposure• See what chemicals
people may be exposed to
• Follow temporal trends• Evaluate regulatory
interventions• Evaluate risk
management• Elucidate role of exposure
in disease
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Exposure --- Disease
X
?
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Biomonitoring Data are Not Created Equally
Analytical methodology
Biologic Variability
Chosen biomarker
Preanalytic Considerations
Inherent Characteristics ofExposure Scenario Study design
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Comorbidity
Coexposures
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Biomonitoring Hinges on the Inherent Characteristics of the Exposure Scenario
• High level exposures ≠ low level exposures– e.g., lead
• Chemical or agent exposed/measured may differ by scenario– Urinary benzene
– Atrazine
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DACT77%
DIA6%
DEA15%
AM2%
Env’l exposures
DIA1.7%
DEA33%
AM5.57
DACT27.6%
Low level acute exposures
Cl
N
N
N
HN NH
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Biomonitoring Hinges on theStudy Design
• Exposure is dynamic
• Predicting exposure becomes difficult unless repeated empirical data are available
01/07/2011 7CA Biomonitoring Workshop -- March 2011The New Game of Human Life: John Wallis, 1790
Exposure
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Biomonitoring Hinges on Preanalytic Characteristics
• Were the samples collected properly?
• Was contamination properly avoided?
• Was the integrity of the sample maintained?
• Were the samples stored appropriately?
• Sometimes these variables are a luxury ….
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Biomonitoring Hinges on theAnalytical Measurement
• All numbers are not created equally– Analytic techniques– Credible validation– Achievable limits of detection
• Analytical ability to differentiate between two similar chemicals
• Method characteristics and measured values are not static
• “Quality“ includes recognizing the limitations of the data
• Interlaboratory comparisons needed: not single lab qualifying
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Biomonitoring Hinges onBiomarker Specificity
• Is the biomarker selective for the chemical/agent it represents?
• Likely differs based upon the exposure scenario
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O C N H C H 3
O
Carbaryl
OH
OH
Naphthalene
1-Naphthol 2-Naphthol
X
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The Chlorpyrifos Story….
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+ +N OH
ClCl
Cl
N O
ClCl
Cl P
O
OCH2CH3
OCH2CH3N O
ClCl
Cl P
S
OCH2CH3
OCH2CH3
HO P
S
OCH2CH3
OCH2CH3 HO P
O
OCH2CH3
OCH2CH3
Dialkyl Phosphates in urine
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Biomonitoring Hinges onBiomarker Specificity
• Is the matrix appropriate?– PAHs in blood?
– Urinary benzene?
– Urinary B[a]P?
– Salivary cotinine?
– nPOPs in lipid-rich matrices?
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0.11.0101001000
0.1 1.0 10 100 1000Serum Cotinine, ng/mL
Saliv
ary
Coti
nine
, ng/
mL
UrineFeces
Hydroxylatedmetabolites
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Biomonitoring Hinges on Biologic Variability, Coexposures, and Comorbidity
• Pollution-related exposures result in blood concentrations in the fM-nM range
• Dietary and endogenous exposure result in blood concentrations in the nM-mMrange– Lipid peroxidation products– ROS, quinones, carbonyls from
diet and stress• Exposure to exogenous and
endogenous chemicals vary greatly (10-10,000 fold) within and among people
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Biomonitoring Hinges on Biomarker Specificity
• Chemicals in a single class may have different metabolism and bioaccumulation characteristics– PAHs
– Phthalates
– Even PCBs!
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Phthalate Metabolism and Excretion
050
100150200250300350400450
Conc
entr
atio
n (n
g/m
L)
95th
90th
75th
50th
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UrinaryExcretion
OR
OH
O
O
OR
OR’
O
O
O
O(R/R1)
O
O
COOH
OHO
OHOH
Oxidation/elimination products
Hydrolysis
Glucuronidation
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Biological Persistence is a Key Factor for Consideration
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1 10 100 1000Time (Days)
Needham and Sexton, JEAEE 10:611-629 (2000)
1 10 100 1000Time (Days)
POPs
nPOPs
Red = blood chemical/metaboliteGreen = urinary metabolite
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Curve Ball …..
• Not all POPs persist biologically
• Not all nPOPs fail to bioaccumulate
• Varies not only among persons but also within persons
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Needham LL. Assessing exposure to organophosphorus pesticides by biomonitoring in epidemiologic studies of birth outcomes. Environ Health Perspect. 2005;113(4):494-8
Barr DB, Weihe P, Davis MD, Needham LL, Grandjean P. Serum polychlorinated biphenyl and organochlorine insecticide concentrations in a Faroese birth cohort.Chemosphere. 2006;62(7):1167-82.
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1 10 100 1000Time (Days)
BloodToxicant/Metabolite
Urinary Metabolite
Chronic Exposure: A different story
Barr, Wang, and Needham. Environ. Health Perspect 113(8):1083-1091 (2005)
Needham, Barr, and Calafat. Neurotoxicology 26:547-53(2005)01/07/2011 18CA Biomonitoring Workshop -- March 2011
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To Adjust or Not ?
• Is creatinine adjustment appropriate?
• Should nPOPs be lipid-adjusted?
• Should we strive to collect more integrated samples?
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80
100
120
140
160
180
200
6-11 12-19 20-29 30-39 40-49 50-59 60-69 70+
Age Group (yrs)
Uri
nary
Cre
atin
ine
(mg/
dL)
All
Male
Female
white
black
ma
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Population versus Individual Scale
• Most current studies designed to inform population level exposures/risks
• Participant wants to know THEIR exposures and risks
• How can we provide a contextual framework given our current knowledge?
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Contextual Parameters for Exposure
• Position in overall distribution
• Reference Ranges
• Provide context related to common exposures and biological measurements– Caffeine
– Acetaminophen
– Aspirin
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Units mg/L
http://proceedings.live-record.de/proceedings_12_pdf/12_27.pdf
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Biomonitoring Hinges on Our Ability to Meaningfully Interpret Data with Respect to Exposure or Disease
• Timing of exposure
• Typically requires PK information
• May require uptake information
• Likely many epidemiologic studies
Source Disease
Exposure Dose01/07/2011 22CA Biomonitoring Workshop -- March 2011
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Questions and Answers?QUESTION CROSS-
SECTIONAL BIOMARKERDATA
LONGITUDINALDATA
ENVIRONMENTAL DATA
DATA GAPS
Temporaltrends in exposure
Probably Better Bonus Selectivity of biomarker
Risk Helpful More helpful Helpful Hazard information
Exposure Helpful Helpful Needed Bioavailabilityand uptake
Risk mitigation strategies
Limited utility Limited utility Needed Estimated uptake info
Effectiveness of risk mitigation
Probably Probably Helpful Route specificinfo
Disease Limited ability Better Better Coexposures/comorbidity
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The Unexplored Territory: Mixtures
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Continuing to avoid addressingthem does not mean they willDisappear.
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Successes and Pitfalls
• We’ve come a long way, baby!– Understand more now
than ever– Idea of what we do not
know– Biomonitoring successes
• Too narrowly focusing our efforts can be our demise
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The Unconventional Approach
• Biomonitoring in isolation is not sufficient
• Coexposures and co-morbidity should be addressed
• Advocate studies with holistic approaches to exposure science
• Non-hypothesis driven exploration BUT link it to toxicological relevance
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Environmental Science Leaders Recognition of Utility of Paradigm Shift
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Linda Birnbaum, NIEHS Director, “decade of the epigenome” …
Paul Anastas, EPA “seismic shift” for the agency
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The New Dilemma?
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Life is a consequenceof and adaptationto the exposome
~ Matti Jantunen
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In loving memory of Dr. Larry L. Needham
Biomonitoring guruBroad thinking scientist
Beloved mentorDear friend