The Exposure - Effect Continuum:
Emphasis on Biomonitoring
Larry L. Needham, Ph.D.
Chief, Organic Analytical Toxicology Branch
National Center for Environmental Health
Centers for Disease Control and Prevention
Atlanta, GA USA 30341
Exposure-Effect Continuum for Environmental
Chemicals
Source
Fate and Transport
RISK
MANAGEMENT
Water, Air, Food, Soil, Dust, Sediment, Surfaces, Personal
Care Products
Exposure
Inhalation
Absorption following: Ingestion
Dermal
Internal Dose
EPIDEMIOLOGICAL
STUDIES
Metabolism
Elimination
Contact
Distribution
Target
Organ
Dose
Elimination
Biologically
Effective Dose
Pharmacodynamic
Processes
Effect
Angerer et al. Tox Sci 93(1) 3-10 (2006)
RISK
ASSESSMENT
Source (Chemical plant, waste site)
Fate and Transport
Water, Air, Food, Soil, Dust, Sediment, Surfaces, Personal
Care Products
Exposure (Contact)
EXPOSURE
ANALYSIS
Absorption
Inhalation
Ingestion
Dermal Contact
Internal Dose
Target
Organ
Dose
Biologically
Effective Dose
EFFECT ANALYSIS
Adapted from: NRC 1987
Altered Structure/Function
(“omics”)
Effect
EXPOSURE
EFFECT
ANALYSIS
Biomonitoring
Assessment of human exposure to an
environmental chemical by measuring its
exposure biomarker(s): the parent
chemical (or its metabolite or reaction
product) in human blood, urine, milk,
saliva, adipose, or other tissue.
Biomonitoring for Disease Prevention
Exposure pathway
BIOMONITORING Susceptible populations
Adapted from: HESI’s Biomonitoring Technical Committee
Biomonitoring for Disease Prevention
Exposure pathway
BIOMONITORING Susceptible populations
INTERPRETATION
Adapted from: HESI’s Biomonitoring Technical Committee
Biomonitoring Hinges on the Analytical
Measurement
 All numbers are not created equally
Accuracy
 Precision
 Specificity
 Linearity & Range
 Limit of detection
 Ruggedness/Robustness

 QA/QC Program
 Interlaboratory comparison
Needham et al. J Toxicol Environ Health A 65: 1893-1908 (2002)
Choosing the Appropriate Matrix
 Chemical dependent
 Population dependent (age, race, health
status, etc.)
Selection of Biomonitoring Matrix:
Environmental Chemical Dependent
 Two primary classes of Environmental
Chemicals

Persistent (half-lives in years); PCDDs,
PCBs, PBDEs, PFCs, OCs, Pb

Non Persistent (half-lives in
minutes/hours); phthalates, pesticides
(OPs, carbamates, pyrethroids), VOCs
Absorption, Distribution, and Elimination of
Environmental Chemicals in the Body
Ingestion
Gastrointestinal
Tract
Liver
Inhalation
Primary Deposition Sites
Lung
Portal Blood/
Blood Lymph
Bile
Kidney
Feces
Urine
Dermal
Bladder
Fat
Secretory
Structures
Bone
Soft
Tissues
Alveoli
Secretions
Expired
Air
Saliva
Needham, Barr, and Calafat. Neurotoxicology 26:547-53 (2005)
Sweat
Tears
Milk
Post-Exposure Fate of a Persistent Chemical
in Blood and Urine
Blood
Toxicant/Metabolite
Hemoglobin Adduct
Albumin Adduct
DNA Adduct
Urinary Adduct
Urinary Metabolite
1
10
100
Time (Days)
Needham and Sexton. JEAEE 10: 611-629 (2000)
Adapted from: Henderson et al. Crit Rev Toxicol 20: 65-82 (1989)
1000
Post-Exposure Fate of a Nonpersistent
Chemical in Blood and Urine
Blood
Toxicant/Metabolite
Urinary Metabolite
Albumin Adduct
Hemoglobin Adduct
DNA Adduct
If chemical forms an
adduct: extends time
window of exposure
Urinary Adduct
1
10
100
Time (Days)
Needham and Sexton. JEAEE 10: 611-629 (2000)
Adapted from: Henderson et al. Crit Rev Toxicol 20: 65-82 (1989)
1000
Post-Exposure Fate of a Nonpersistent
Chemical in Blood and Urine
Blood
Toxicant/Metabolite
Urinary Metabolite
1
10
100
Time (Days)
Barr et al. Environ Health Perspect 113:1083-1091 (2005)
Needham, Barr, and Calafat. Neurotoxicology 26:547-53 (2005)
1000
Selection of Biomonitoring Matrix: Population Dependent
Life Stages of Children
Death
2y
1y
3y
Birth
Preschool
Trimesters
6y
Embryonic (8d – 8w)
Conception
Pre High
School
12 y
18-21 y
Adolescence
(High School)
Needham et al. Environ Health Perspect 113:1076-1082 (2005)
Relative Importance of Various Biological Matrices for
Measuring Exposure During the Different Life Stages
Matrices
Adult
preconception
1st
Fetal
2nd
0-1 year
2-3 years
4-11
years
1
1
1
3
3
3
3
NA
3
NA
3
NA
3
3
3
3
3
3
1
1
1
3
3
3
3
NA
3
NA
3
3
3
3
3
3
3
3
3rd
Persistent Organic Chemicals
Blood (whole)
Blood (serum)
Blood (plasma)
Urine
Saliva
Hair
Nails
Adipose Tissue
Feces
Semen
Breath
Teeth
Cord Blood
Meconium
Milk (maternal)
Blood (maternal)
Urine (maternal)
Hair (maternal)
1
1
1
3
3
3
3
1
3
3
3
NA
1
3
1
1
3
3
1
2
1
1
3
3
1
2
1
1
3
3
1
2
1
1
3
3
1
1
1
3
NA
3
3
NA
3
NA
NA
NA
3
3
1
1
3
3
Barr, Wang, and Needham. Environ Health Perspect 113:1083-91 (2005)
Exposure Assessment Approaches
 Questionnaire/Historical
Information (includes
GIS + video)
 Environmental
monitoring (Air, Water,
Food, Soil)
 Biomonitoring
 Combine these 3
approaches with
calibrated and validated
models
CDC’s Third National Report on Human
Exposure to Environmental Chemicals
(1999-2000) (2001-2002)
www.cdc.gov/exposurereport
Caveats About the Report
 The presence of a chemical does not
imply disease
 Cannot provide estimates for:
States, cities, special localities
 Groups with special exposures

 Analysis of trends for many chemicals
awaits future data
NHANES
 National Health and Nutrition Examination
Survey (administered by NCHS)



Stratified, multistage, national probability sample
of the civilian, noninstitutionalized population
Data released every 2 years
30 localities via mobile trailers
 Data collected




Extensive questionnaire on demographics and
health behaviors
Physical exam
Medical and nutritional lab tests
Drinking water sampled
CDC’s National Report on Human
Exposure to Environmental Chemicals
Urine Specimens
Ages  6
Blood Specimens
Ages  12
Exceptions: Pb, Cd, Hg, cotinine
1 year
3 years +
Additional Chemicals in 3rd Report
148 chemicals
Exposure biomarkers for:
 Metals
 Polychlorinated biphenyls, dioxins and furans
 Organochlorine pesticides
 Carbamate pesticides
 Organophosphorous pesticides
 Pyrethroid pesticides
 Herbicides
 Polycyclic aromatic hydrocarbons
 Phthalates
 Phytoestrogens
 Pest repellants
 Cotinine
*
Perfluorinated chemicals
*
BFRs
*
VOCs
*
Perchlorate
*
Bisphenol A
*
Sunscreen agent
*
Triclosan
*
Acrylamide
* Starting in ‘03
www.cdc.gov/exposurereport
National Exposure Report
 Descriptive presentation
Geometric means, percentiles and
confidence intervals
 Demographic group comparisons
 No health outcomes analysis

 General text on:
Uses, sources, biologic fate, health
effects
 Comparisons to other biomonitoring
studies

Lead
 A chemical with “known” toxicity
 Toxic effects define “Level of Concern”
Human studies using blood lead as the
measure of exposure have found health
effects at lower and lower blood lead levels
70
60
Blood lead levels
defining lead
poisoning (g/dL)
50
40
30
20
10
0
1965
1970
1975
1980
1985
1990
1995
Lead used in gasoline declined from 1976 through 1980
110
Lead used In gasoline
(1000 tons)
100
90
80
Gasoline lead
70
60
50
40
30
1975
1976
1977
1978
Year
1979
1980
1981
Environmental modeling predicted only a slight decline
in blood lead levels in people
110
17
Predicted blood lead
100
Lead used in
gasoline
90
15
80
14
Gasoline lead
13
70
(thousands
of tons)
16
12
60
11
50
10
40
9
30
1975
1976
1977
1978
Year
1979
1980
1981
Mean blood
lead levels
(g/dL)
Lead in gasoline and lead in blood
NHANES II, 1976-1980
110
17
Lead used In gasoline
(1000 tons)
16
90
15
80
14
Gasoline lead
70
13
12
60
11
50
Blood lead
10
40
9
30
1975
1976
1977
1978
Year
1979
1980
1981
Blood lead levels (g/dL)
Predicted blood lead
100
After NHANES II, EPA further restricted leaded gasoline and
gasoline lead levels continued to decline through 1991
100
16
80
14
12
60
Blood lead
Gasoline lead
40
10
8
6
20
4
0
2
1974 1976 1978 1980 1982 1984 1986 1988 1990
Year
1992
Blood lead levels (g/dL)
Lead used In gasoline
(1000 tons)
18
NHANES III (1988-1994) showed blood lead levels
continued to decrease as gasoline levels declined
100
16
80
14
12
60
Blood lead
Gasoline lead
40
10
8
6
20
4
0
2
1974 1976 1978 1980 1982 1984 1986 1988 1990
Year
1992
Blood lead levels (g/dL)
Lead used In gasoline
(1000 tons)
18
Blood lead levels in the U.S. Children
Blood lead levels (g/dL)
16
Ages 1-5 yrs, 1976 - 2002
14
12
10
8
6
4
2
0
1976 1978 1980 1982 1984 1986 1988 1990 1992
Year
1994 1996 1998
2000 2002
Percentage of children 1-5 years old in the U.S. population
with elevated blood lead levels ( 10 g/dL)
100
88.2
Percent
80
60
40
20
8.6
4.4
1.6
1991-1994
1999-2002
0
1976-1980
1988-1991
Cotinine
 Nicotine metabolite
that tracks exposure
to tobacco smoke
 For nonsmokers,
tracks exposure to
secondhand smoke
N
CH3
N
O
Exposure of the U.S. Population to Tobacco
Smoke: Serum Cotinine Levels
(NHANES III, 1988-1991)
Percentage of the population
5
ETS exposure
(nonsmokers)
4
Smokers
3
2
1
0
0.1
1.0
10
100
Serum cotinine (ng/mL)
1000
Environmental Tobacco Smoke
 Monitored as serum cotinine
 Comparing NHANES III (1988-91) to NHANES
99-02, median levels in non-smokers have
fallen:



68% in children
69% in adolescents
About 75% in adults
 Higher in non-Hispanic blacks than Mexican
Americans or non-Hispanic whites
Serum Cotinine Levels: Tracking Exposure to
Secondhand Smoke in the Non-smoking U.S.
Population
1988-1991
1999-2002
Serum cotinine (ng/mL)
0.3
0.2
68%
69%
75%
0.1
0
4-11
12-19
Age (years)
20-74
Working Backwards on Pathway:
Example Dioxin
Effect
Based on human studies or
animal studies
Internal Dose
Based on human studies
and animal studies
Exposure
Water, Air, *Food, Soil, Dust, Sediment
* ~ 95% of exposure via food chain; mitigation: regulate levels in food
Question
 Two examples (lead and cotinine) “levels
of concern” are based on “known” human
toxicity.
 Should we have similar or different
“levels of concern” for other chemicals,
for which we have limited toxicity data,
but base these “concern levels” on
biomonitoring data? AK Department of
Health is basing fishing advisories on
biomonitoring data (Arnold et al. AJPH 95
393-7 (2005))
NHANES Serum Pools
 2001-2002:
12 years of age and older
3 - 5 years: planned
6 - 11 years: planned
Serum Pools: NHANES 2001/2002
 Used for estimates of the “means”
 34 People per pool (Total 1,734 people; 51 pools)
 0.75mL Serum per person
 25.5 g Serum per pool
 2 g BFRs/PCBs/Persistent Pesticides
 22 g PCDDs/PCDFs/cPCBs
 0.5 g Total Lipids
 0.4 g Perfluorinated chemicals
NHANES 2001-2002 Pools
Race/Ethnicity
Non-Hispanic
White
Non-Hispanic
Black
MexicanAmerican
Age Group (years)
Number of Pools
Gender
12-19
20-39
40-59
60+
M
2 (3)
3
3
3 (4)
F
M
2 (3)
3
4
1
3
1
4
1
F
3
1
1
1
M
F
3
4
2
2
1
1
1
1
( ) for perfluorinated chemicals
Geometric Mean & 95% Adjusted CI of TEQs (PCDDs, PCDFs,
dioxin-like PCBs) by Age, Group, Race & Sex (using 2005 TEFs)
60
50
Total TEQ
40
30
20
10
0
M
F
M
12-19
F
20-39
M
F
M
40-59
Mexican-American
F
60+
M
F
12-19
M
F
20-39
M
F
M
40-59
F
60+
M
F
12-19
Non-Hispanic Black
Race/Ethnicity, Age, & Gender
M
F
20-39
M
F
M
40-59
Non-Hispanic White
F
60+
What is a Flame Retardant?
 Flame Retardants (FRs) are a diverse group
of chemicals that are added to materials such
as plastics, rubber, textiles and construction
materials to reduce their flammability.

Annual World production of FRs estimated
to 600,000 metric tons

25% of world production of FRs were
bromine containing chemicals

5-30% of flame retarded polymeric materials
consist of FRs

Inorganic compounds often used in
combination with brominated and/or
phosphorus containing FRs.
Mean and Range of BDE-47 by Age
Group, Race and Sex
200
180
160
ng/g lipid
140
120
100
80
60
40
20
0
M
F
12-19
M
F
20-39
M
F
M
40-59
Mexican-American
F
60+
M
F
12-19
M
F
20-39
M
F
40-59
M
F
60+
M
F
12-19
Non-Hispanic Black
Race/Ethnicity, Age, & Gender
M
F
20-39
M
F
40-59
M
F
60+
Non-Hispanic White
Perfluorochemicals (PFCs) in the
Environment
 Produced since 1950's for use in:



Surface treatments: soil and stain
resistant coatings on textiles, carpet,
leather
Paper protection: provides oil, grease
and water resistance on paper
products including those for food use
Performance chemicals including
insecticide, fire fighting foams,
industrial surfactants, acid mist
suppression
 3M phased out its
fluorooctanylchemistry in May 2000
Mean and Range of PFOS by Age
Group, Race and Sex
45.0
40.0
ng/mL
35.0
30.0
25.0
20.0
15.0
10.0
5.0
M F M F M F M F M F M F M F M F M F M F M F M F
(3) (4) (2) (2) (1) (1) (1) (1) (3) (3) (1) (1) (1) (1) (1) (1) (3) (3) (3) (4) (3) (3) (4) (4)
12-19
20-39
40-59
Mexican-American
60+
12-19
20-39
40-59
60+
Non-Hispanic Black
Race/Ethnicity, Age, & Gender
12-19
20-39
40-59
Non-Hispanic White
60+
Mean and Range of PFOA by Age
Group, Race and Sex
10.0
9.0
8.0
ng/mL
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
M F M F M F M F M F M F M F M F M F M F M F M F
(3) (4) (2) (2) (1) (1) (1) (1) (3) (3) (1) (1) (1) (1) (1) (1) (3) (3) (3) (4) (3) (3) (4) (4)
12-19
20-39
40-59
Mexican-American
60+
12-19
20-39
40-59
60+
Non-Hispanic Black
Race/Ethnicity, Age, & Gender
12-19
20-39
40-59
Non-Hispanic White
60+
Biomonitoring for Disease Prevention
Exposure pathway
BIOMONITORING Susceptible populations
Adapted from: HESI’s Biomonitoring Technical Committee
Exposure Analysis for Disease Prevention
Exposure pathway
Exposure
Analysis
Adapted from: HESI’s Biomonitoring Technical Committee
Susceptible populations