Biomonitoring of Exposure to Environmental Chemicals:

Complexities in Interpreting Data

Dana Boyd Barr, Ph.D.

Professor, Exposure Science and Environmental Health

01/07/2011 1CA Biomonitoring Workshop -- March 2011

01/07/2011 CA Biomonitoring Workshop -- March 2011 2

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

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

01/07/2011 CA Biomonitoring Workshop -- March 2011 3

Bruegel’s “Little” Tower of Babel, ca. 1563

Interpretation complicated by incongruent views of “exposure”

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

01/07/2011 CA Biomonitoring Workshop -- March 2011 4

Exposure --- Disease

X

?

Biomonitoring Data are Not Created Equally

Analytical methodology

Biologic Variability

Chosen biomarker

Preanalytic Considerations

Inherent Characteristics ofExposure Scenario Study design

01/07/2011 5CA Biomonitoring Workshop -- March 2011

Comorbidity

Coexposures

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

01/07/2011 CA Biomonitoring Workshop -- March 2011 66

DACT77%

DIA6%

DEA15%

AM2%

Env’l exposures

DIA1.7%

DEA33%

AM5.57

DACT27.6%

Low level acute exposures

Cl

N

N

N

HN NH

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

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 ….

01/07/2011 CA Biomonitoring Workshop -- March 2011 8

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

01/07/2011 CA Biomonitoring Workshop -- March 2011 9

Biomonitoring Hinges onBiomarker Specificity

• Is the biomarker selective for the chemical/agent it represents?

• Likely differs based upon the exposure scenario

01/07/2011 CA Biomonitoring Workshop -- March 2011 10

O C N H C H 3

O

Carbaryl

OH

OH

Naphthalene

1-Naphthol 2-Naphthol

X

The Chlorpyrifos Story….

01/07/2011 CA Biomonitoring Workshop -- March 2011 11

+ +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

Biomonitoring Hinges onBiomarker Specificity

• Is the matrix appropriate?– PAHs in blood?

– Urinary benzene?

– Urinary B[a]P?

– Salivary cotinine?

– nPOPs in lipid-rich matrices?

01/07/2011 CA Biomonitoring Workshop -- March 2011 12

0.11.0101001000

0.1 1.0 10 100 1000Serum Cotinine, ng/mL

Saliv

ary

Coti

nine

, ng/

mL

UrineFeces

Hydroxylatedmetabolites

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

01/07/2011 13CA Biomonitoring Workshop -- March 2011

Biomonitoring Hinges on Biomarker Specificity

• Chemicals in a single class may have different metabolism and bioaccumulation characteristics– PAHs

– Phthalates

– Even PCBs!

01/07/2011 CA Biomonitoring Workshop -- March 2011 14

Phthalate Metabolism and Excretion

050

100150200250300350400450

Conc

entr

atio

n (n

g/m

L)

95th

90th

75th

50th

01/07/2011 CA Biomonitoring Workshop -- March 2011 15

UrinaryExcretion

OR

OH

O

O

OR

OR’

O

O

O

O(R/R1)

O

O

COOH

OHO

OHOH

Oxidation/elimination products

Hydrolysis

Glucuronidation

Biological Persistence is a Key Factor for Consideration

01/07/2011 16CA Biomonitoring Workshop -- March 2011

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

Curve Ball …..

• Not all POPs persist biologically

• Not all nPOPs fail to bioaccumulate

• Varies not only among persons but also within persons

01/07/2011 CA Biomonitoring Workshop -- March 2011 17

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.

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

To Adjust or Not ?

• Is creatinine adjustment appropriate?

• Should nPOPs be lipid-adjusted?

• Should we strive to collect more integrated samples?

01/07/2011 CA Biomonitoring Workshop -- March 2011 19

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

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?

01/07/2011 CA Biomonitoring Workshop -- March 2011 20

Contextual Parameters for Exposure

• Position in overall distribution

• Reference Ranges

• Provide context related to common exposures and biological measurements– Caffeine

– Acetaminophen

– Aspirin

01/07/2011 CA Biomonitoring Workshop -- March 2011 21

Units mg/L

http://proceedings.live-record.de/proceedings_12_pdf/12_27.pdf

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

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

01/07/2011 CA Biomonitoring Workshop -- March 2011 23

The Unexplored Territory: Mixtures

01/07/2011 CA Biomonitoring Workshop -- March 2011 24

Continuing to avoid addressingthem does not mean they willDisappear.

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

01/07/2011 CA Biomonitoring Workshop -- March 2011 25

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

01/07/2011 CA Biomonitoring Workshop -- March 2011 26

Environmental Science Leaders Recognition of Utility of Paradigm Shift

01/07/2011 CA Biomonitoring Workshop -- March 2011 27

Linda Birnbaum, NIEHS Director, “decade of the epigenome” …

Paul Anastas, EPA “seismic shift” for the agency

The New Dilemma?

01/07/2011 28CA Biomonitoring Workshop -- March 2011

01/07/2011 CA Biomonitoring Workshop -- March 2011 29

Life is a consequenceof and adaptationto the exposome

~ Matti Jantunen

01/07/2011 CA Biomonitoring Workshop -- March 2011 30

In loving memory of Dr. Larry L. Needham

Biomonitoring guruBroad thinking scientist

Beloved mentorDear friend