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
The Exposure - Effect Continuum: Emphasis on Biomonitoring
Water, Air, Food, Soil, Dust, Sediment, Surfaces, Personal Care Products
Distribution
Source
Internal Dose
InhalationIngestionDermal Contact
Target Organ Dose
Biologically Effective Dose
Absorption following:
Metabolism
EliminationElimination
Effect
RISKMANAGEMENT
EPIDEMIOLOGICAL STUDIES
RISKASSESSMENT
PharmacodynamicProcesses
Exposure-Effect Continuum for Environmental Chemicals
Angerer et al. Tox Sci 93(1) 3-10 (2006)
Exposure
Fate and Transport
Water, Air, Food, Soil, Dust, Sediment, Surfaces, Personal Care Products
Source (Chemical plant, waste site)
Internal Dose
InhalationIngestionDermal Contact
Target Organ Dose
Biologically Effective Dose
Absorption
Effect
EXPOSURE ANALYSIS
EFFECT ANALYSIS
EXPOSURE EFFECT ANALYSIS
Adapted from: NRC 1987
Exposure (Contact)
Altered Structure/Function (“omics”)
Fate and Transport
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
BIOMONITORING Susceptible populations
Screening
Emerging chemicals
Sta
tus
& T
ren
dsH
igh
ly expo
sed
Exposure pathway
Clinical S
tudies
Em
erg
ency
Res
po
nse
Ep
idem
iolo
gy
Preclinical indicators
Adapted from: HESI’s Biomonitoring Technical Committee
Biomonitoring for Disease Prevention
BIOMONITORING Susceptible populations
Screening
Emerging chemicals
Sta
tus
& T
ren
dsH
igh
ly expo
sed
Exposure pathway
Clinical S
tudies
Em
erg
ency
Res
po
nse
Ep
idem
iolo
gy
Preclinical indicators
Adapted from: HESI’s Biomonitoring Technical Committee
INTERPRETATION
Biomonitoring Hinges on the Analytical Measurement
All numbers are not created equally Accuracy Precision Specificity Linearity & Range Limit of detection Ruggedness/Robustness
QA/QC ProgramInterlaboratory comparison
Needham et al. J Toxicol Environ Health A 65: 1893-1908 (2002)
Choosing the Appropriate Matrix
Chemical dependentPopulation dependent (age, race, health
status, etc.)
Selection of Biomonitoring Matrix: Environmental Chemical DependentTwo 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
Bile
Ingestion Inhalation Dermal
Gastrointestinal Tract
Lung
Blood/Lymph
PortalBlood
Kidney
Primary Deposition Sites
Soft Tissues
BoneFat
Secretory Structures
FecesBladderUrine
Liver
Secretions
Saliva Sweat Milk
TearsAlveoli
Expired Air
Needham, Barr, and Calafat. Neurotoxicology 26:547-53 (2005)
Post-Exposure Fate of a Persistent Chemical in Blood and Urine
BloodToxicant/Metabolite
DNA Adduct
Albumin Adduct
Hemoglobin Adduct
Urinary MetaboliteUrinary Adduct
1 10 100 1000
Time (Days)
Con
cent
ratio
n
Adapted from: Henderson et al. Crit Rev Toxicol 20: 65-82 (1989)
Needham and Sexton. JEAEE 10: 611-629 (2000)
Post-Exposure Fate of a Nonpersistent Chemical in Blood and Urine
Time (Days)
BloodToxicant/Metabolite
DNA Adduct
Albumin Adduct
Hemoglobin Adduct
Urinary Metabolite
Urinary Adduct
1 10 100 1000
Con
cent
ratio
n
If chemical forms an adduct: extends time window of exposure
Adapted from: Henderson et al. Crit Rev Toxicol 20: 65-82 (1989)
Needham and Sexton. JEAEE 10: 611-629 (2000)
Post-Exposure Fate of a Nonpersistent Chemical in Blood and Urine
1 10 100 1000Time (Days)
Con
cent
ratio
nBloodToxicant/Metabolite
Urinary Metabolite
Barr et al. Environ Health Perspect 113:1083-1091 (2005)Needham, Barr, and Calafat. Neurotoxicology 26:547-53 (2005)
Selection of Biomonitoring Matrix: Population DependentLife Stages of Children
Conception
Birth
Death
1 y
2 y
3 y
6 y
12 y18-21 y
InfancyYou
ng to
ddle
r
Older toddler
Preschool
Pre High School
Adolescence(High School)
TrimestersEmbryonic (8d – 8w)
Needham et al. Environ Health Perspect 113:1076-1082 (2005)
Relative Importance of Various Biological Matrices for Measuring Exposure During the Different Life StagesMatrices Adult
preconceptionFetal 0-1 year 2-3 years 4-11
years1st 2nd 3rd
Persistent Organic Chemicals
Blood (whole) 1 1 1 1Blood (serum) 1 1 1 1Blood (plasma) 1 1 1 1Urine 3 3 3 3Saliva 3 NA 3 3Hair 3 3 3 3Nails 3 3 3 3Adipose Tissue 1 NA NA NAFeces 3 3 3 3Semen 3 NA NA NABreath 3 NA 3 3Teeth NA NA NA 3Cord Blood 1 1 1 1 3 3 3Meconium 3 2 2 2 3 3 3Milk (maternal) 1 1 1 1 1 3 3Blood (maternal) 1 1 1 1 1 3 3Urine (maternal) 3 3 3 3 3 3 3Hair (maternal) 3 3 3 3 3 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, cotinine1 year 3 years +
Additional Chemicals in 3rd Report148 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 ‘03www.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” toxicityToxic effects define “Level of Concern”
0
10
20
30
40
50
60
70
1965 1970 1975 1980 1985 1990 1995
Blood lead levelsdefining lead
poisoning (g/dL)
Human studies using blood lead as the measure of exposure have found health
effects at lower and lower blood lead levels
Lead used in gasoline declined from 1976 through 1980
Year
1975 1976 1977 1978 1979 1980 1981
30
40
50
60
70
80
90
100
110
Gasoline lead
Lead
use
d In
gas
olin
e(1
000
tons
)
Environmental modeling predicted only a slight decline in blood lead levels in people
Year
1975 1976 1977 1978 1979 1980 1981
Lead used ingasoline
(thousandsof tons)
30
40
50
60
70
80
90
100
110
Mean bloodlead levels
(g/dL)
9
10
11
12
13
14
15
16
17
Gasoline lead
Predicted blood lead
Blood lead
Year
1975 1976 1977 1978 1979 1980 1981
30
40
50
60
70
80
90
100
110
9
10
11
12
13
14
15
16
17
Gasoline lead
Lead in gasoline and lead in bloodNHANES II, 1976-1980
Blo
od le
ad le
vels
(g
/dL)
Lead
use
d In
gas
olin
e(1
000
tons
)
Predicted blood lead
1974 1976 1978 1980 1982 1984 1986 1988 1990 1992
0
20
40
60
80
100
2
4
6
8
10
12
14
16
18
Blood leadGasoline lead
After NHANES II, EPA further restricted leaded gasoline and gasoline lead levels continued to decline through 1991
Year
Lead
use
d In
gas
olin
e(1
000
tons
)
Blo
od le
ad le
vels
(g
/dL)
Year
1974 1976 1978 1980 1982 1984 1986 1988 1990 1992
0
20
40
60
80
100
2
4
6
8
10
12
14
16
18
Blood leadGasoline lead
NHANES III (1988-1994) showed blood lead levels continued to decrease as gasoline levels declined
Lead
use
d In
gas
olin
e(1
000
tons
)
Blo
od le
ad le
vels
(g
/dL)
1976 1978 1980 1982 1984 1986 1988 1990 1992
2
4
6
8
10
12
14
16
Blo
od
lead
lev
els
(g
/dL
)
0
1994 1996 1998 2000
Blood lead levels in the U.S. ChildrenAges 1-5 yrs, 1976 - 2002
Year
2002
Percentage of children 1-5 years old in the U.S. populationwith elevated blood lead levels ( 10 g/dL)
0
20
40
60
80
100
1976-1980 1988-1991 1991-1994 1999-2002
Per
cent
88.2
8.64.4 1.6
Cotinine
Nicotine metabolite that tracks exposure to tobacco smoke
For nonsmokers, tracks exposure to secondhand smoke
N
N
CH3
O
Serum cotinine (ng/mL)
Per
cent
age
of t
he p
opul
atio
n
0
1
2
3
4
5
0.1 1.0 10 100 1000
ETS exposure (nonsmokers)
Smokers
Exposure of the U.S. Population to Tobacco Smoke: Serum Cotinine Levels
(NHANES III, 1988-1991)
Environmental Tobacco Smoke
Monitored as serum cotinineComparing 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
0
0.1
0.2
0.3
4-11 12-19 20-74
Age (years)
Se
rum
co
tinin
e (n
g/m
L)
68%
75%
69%
1988-19911999-2002
Working Backwards on Pathway: Example Dioxin
Internal Dose
Effect
Water, Air, Food, Soil, Dust, Sediment
Based on human studies or animal studies
Exposure
Based on human studies and animal studies
* ~ 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 Gender
Age Group (years)
Number of Pools12-19 20-39 40-59 60+
Non-Hispanic
White
M 2 (3) 3 3 3 (4)
F 2 (3) 4 3 4
Non-Hispanic
Black
M 3 1 1 1
F 3 1 1 1
Mexican-American
M 3 2 1 1
F 4 2 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)
0
10
20
30
40
50
60
M F M F M F M F M F M F M F M F M F M F M F M F
12-19 20-39 40-59 60+ 12-19 20-39 40-59 60+ 12-19 20-39 40-59 60+
Mexican-American Non-Hispanic Black Non-Hispanic White
Race/Ethnicity, Age, & Gender
To
tal
TE
Q
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
0
20
40
60
80
100
120
140
160
180
200
M F M F M F M F M F M F M F M F M F M F M F M F
12-19 20-39 40-59 60+ 12-19 20-39 40-59 60+ 12-19 20-39 40-59 60+
Mexican-American Non-Hispanic Black Non-Hispanic White
Race/Ethnicity, Age, & Gender
ng
/g l
ipid
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
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
45.0
M(3)
F(4)
M(2)
F(2)
M(1)
F(1)
M(1)
F(1)
M(3)
F(3)
M(1)
F(1)
M(1)
F(1)
M(1)
F(1)
M(3)
F(3)
M(3)
F(4)
M(3)
F(3)
M(4)
F(4)
12-19 20-39 40-59 60+ 12-19 20-39 40-59 60+ 12-19 20-39 40-59 60+
Mexican-American Non-Hispanic Black Non-Hispanic White
Race/Ethnicity, Age, & Gender
ng/m
L
Mean and Range of PFOA by Age Group, Race and Sex
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
M(3)
F(4)
M(2)
F(2)
M(1)
F(1)
M(1)
F(1)
M(3)
F(3)
M(1)
F(1)
M(1)
F(1)
M(1)
F(1)
M(3)
F(3)
M(3)
F(4)
M(3)
F(3)
M(4)
F(4)
12-19 20-39 40-59 60+ 12-19 20-39 40-59 60+ 12-19 20-39 40-59 60+
Mexican-American Non-Hispanic Black Non-Hispanic White
Race/Ethnicity, Age, & Gender
ng/m
L
Biomonitoring for Disease Prevention
BIOMONITORING Susceptible populations
Screening
Emerging chemicals
Sta
tus
& T
ren
dsH
igh
ly expo
sed
Exposure pathway
Clinical S
tudies
Em
erg
ency
Res
po
nse
Ep
idem
iolo
gy
Preclinical indicators
Adapted from: HESI’s Biomonitoring Technical Committee
Exposure Analysis for Disease Prevention
ExposureAnalysis
Susceptible populations
Screening
Emerging chemicals
Sta
tus
& T
ren
dsH
igh
ly expo
sed
Exposure pathway
Clinical S
tudies
Em
erg
ency
Res
po
nse
Ep
idem
iolo
gy
Preclinical indicators
Adapted from: HESI’s Biomonitoring Technical Committee