1. 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
ISEM presentation - September 2003

2. Exposure-Effect Continuum for Environmental Chemicals
Source
Fate and Transport
RISK
MANAGEMENT
Water, Air, Food, Soil, Dust, Sediment, Surfaces, Personal
Care Products
Exposure
RISK
ASSESSMENT
Inhalation
Ingestion
Dermal Contact
Absorption following:
Internal Dose
Metabolism
Distribution
EPIDEMIOLOGICAL STUDIES
Elimination
Target Organ Dose
Elimination
Biologically Effective Dose
Pharmacodynamic
Processes
Effect
Angerer et al. Tox Sci 93(1) 3-10 (2006)

3. Biologically Effective Dose
Source (Chemical plant, waste site)
Fate and Transport
Water, Air, Food, Soil, Dust, Sediment, Surfaces, Personal
Care Products
Exposure (Contact)
Inhalation
Ingestion
Dermal Contact
Absorption
EXPOSURE EFFECT ANALYSIS
EXPOSURE ANALYSIS
Internal Dose
Target Organ Dose
Biologically Effective Dose
Altered Structure/Function
(“omics”)
EFFECT ANALYSIS
Effect
Adapted from: NRC 1987

4. 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.

5. Health Effects / Risk Exposure Assessment
Biomonitoring for Disease Prevention
R e s e a r c h P u b l i c H e a l t h A c t i o n s / P o l i c y R i s k A s s e s s m e n t R e f e r e n c e / A c c e p t a b l e D o s e s
Health Effects / Risk
Exposure Assessment
Status & Trends
Highly exposed
Emerging chemicals
Screening
Exposure pathway
BIOMONITORING
Susceptible populations
Clinical Studies
Preclinical indicators
Epidemiology
Emergency Response
Adapted from: HESI’s Biomonitoring Technical Committee

6. Exposure Assessment Health Effects / Risk
Biomonitoring for Disease Prevention
R e s e a r c h P u b l i c H e a l t h A c t i o n s / P o l i c y R i s k A s s e s s m e n t R e f e r e n c e / A c c e p t a b l e D o s e s
Exposure Assessment
Health Effects / Risk
Status & Trends
Highly exposed
Emerging chemicals
Screening
Exposure pathway
BIOMONITORING
Susceptible populations
INTERPRETATION
Clinical Studies
Preclinical indicators
Epidemiology
Emergency Response
Adapted from: HESI’s Biomonitoring Technical Committee

7. 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: (2002)

8. Choosing the Appropriate Matrix
Chemical dependent
Population dependent (age, race, health status, etc.)

9. 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

10. Absorption, Distribution, and Elimination of Environmental Chemicals in the Body
Ingestion
Inhalation
Dermal
Gastrointestinal Tract
Lung
Primary Deposition Sites
Fat
Bone
Liver
Blood/Lymph
Portal
Blood
Secretory Structures
Soft Tissues
Bile
Alveoli
Kidney
Secretions
Tears
Feces
Expired Air
Urine
Saliva
Sweat
Milk
Bladder
Needham, Barr, and Calafat. Neurotoxicology 26: (2005)

11. Post-Exposure Fate of a Persistent Chemical in Blood and Urine
Toxicant/Metabolite
DNA Adduct
Albumin Adduct
Hemoglobin Adduct
Urinary Metabolite
Urinary Adduct 1 10
100
1000
Time (Days)
Concentration
Needham and Sexton. JEAEE 10: (2000)
Adapted from: Henderson et al. Crit Rev Toxicol 20: (1989)
ISEM presentation - September 2003

12. Post-Exposure Fate of a Nonpersistent Chemical in Blood and Urine
Time (Days)
Blood
Toxicant/Metabolite
DNA Adduct
Albumin Adduct
Hemoglobin Adduct
Urinary Metabolite
Urinary Adduct 1 10
100
1000
Concentration
If chemical forms an adduct: extends time window of exposure
Needham and Sexton. JEAEE 10: (2000)
Adapted from: Henderson et al. Crit Rev Toxicol 20: (1989)
ISEM presentation - September 2003

13. Post-Exposure Fate of a Nonpersistent Chemical in Blood and Urine1 10
100
1000
Time (Days)
Concentration
Blood
Toxicant/Metabolite
Urinary Metabolite
Barr et al. Environ Health Perspect 113: (2005)
Needham, Barr, and Calafat. Neurotoxicology 26: (2005)
ISEM presentation - September 2003

14. Selection of Biomonitoring Matrix: Population Dependent Life Stages of Children
Death
Young toddler
2 y
Older toddler
1 y
Infancy
3 y
Birth
Preschool
Trimesters
Embryonic (8d – 8w)
6 y
Conception
Pre High School
12 y
18-21 y
Adolescence
(High School)
Needham et al. Environ Health Perspect 113: (2005)

15. Persistent Organic Chemicals
Relative Importance of Various Biological Matrices for Measuring Exposure During the Different Life Stages
Matrices
Adult preconception
Fetal
0-1 year
2-3 years
4-11 years
1st
2nd
3rd
Persistent Organic Chemicals
Blood (whole) 1
Blood (serum)
Blood (plasma)
Urine 3
Saliva NA
Hair
Nails
Adipose Tissue
Feces
Semen
Breath
Teeth
Cord Blood
Meconium 2
Milk (maternal)
Blood (maternal)
Urine (maternal)
Hair (maternal)
Barr, Wang, and Needham. Environ Health Perspect 113: (2005)

16. 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

17. CDC’s Third National Report on Human Exposure to Environmental Chemicals (1999-2000) (2001-2002)

18. 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
Sample not selected with regard to exposure or non-exposure
ISEM presentation - September 2003

19. 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

20. 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 +

21. 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
ISEM presentation - September 2003

22. 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

24. Lead A chemical with “known” toxicity
Toxic effects define “Level of Concern”

25. Human studies using blood lead as the measure of exposure have found health effects at lower and lower blood lead levels 70 60 50
Blood lead levels
defining lead
poisoning (g/dL) 40 30 20 10
1965
1970
1975
1980
1985
1990
1995
ISEM presentation - September 2003

26. Lead used in gasoline declined from 1976 through 1980
110
100 90 80
Lead used In gasoline
(1000 tons)
Gasoline lead 70 60 50 40 30
1975
1976
1977
1978
1979
1980
1981
Year
ISEM presentation - September 2003

27. Environmental modeling predicted only a slight decline
in blood lead levels in people
110 17
100
Predicted blood lead 16 90 15 80 14
Lead used in
Gasoline lead
gasoline 13
Mean blood 70
lead levels
(thousands ( m
g/dL)
of tons) 12 60 11 50 10 40 9 30
1975
1976
1977
1978
1979
1980
1981
Year
ISEM presentation - September 2003

28. Lead in gasoline and lead in blood
NHANES II,
110 17
100
Predicted blood lead 16 90 15 80 14
Lead used In gasoline
(1000 tons)
Gasoline lead 13 70
Blood lead levels (mg/dL) 12 60 11 50
Blood lead 10 40 9 30
1975
1976
1977
1978
1979
1980
1981
Year
ISEM presentation - September 2003

29. After NHANES II, EPA further restricted leaded gasoline and
gasoline lead levels continued to decline through 1991 18
100 16 14 80 12 60
Lead used In gasoline
(1000 tons)
Blood lead
Gasoline lead
Blood lead levels (mg/dL) 10 40 8 20 6 4 2
1974
1976
1978
1980
1982
1984
1986
1988
1990
1992
Year
ISEM presentation - September 2003

30. NHANES III (1988-1994) showed blood lead levels
continued to decrease as gasoline levels declined 18
100 16 14 80 12 60
Lead used In gasoline
(1000 tons)
Blood lead
Gasoline lead
Blood lead levels (mg/dL) 10 40 8 20 6 4 2
1974
1976
1978
1980
1982
1984
1986
1988
1990
1992
Year
ISEM presentation - September 2003

31. Blood lead levels in the U.S. Children Blood lead levels (mg/dL)
Ages 1-5 yrs, 16 14 12 10
Blood lead levels (mg/dL) 8 6 4 2
1976
1978
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
Year
ISEM presentation - September 2003

32. Percentage of children 1-5 years old in the U.S. population
with elevated blood lead levels ( 10 g/dL)
100
88.2 80 60
Percent 40 20
8.6
4.4
1.6
ISEM presentation - September 2003

33. Cotinine Nicotine metabolite that tracks exposure to tobacco smoke O
For nonsmokers, tracks exposure to secondhand smoke N
CH3 O
ISEM presentation - September 2003

34. Exposure of the U.S. Population to Tobacco Smoke: Serum Cotinine Levels (NHANES III, 1988-1991)1 2 3 4 5
0.1
1.0 10
100
1000
ETS exposure
(nonsmokers)
Smokers
Percentage of the population
Serum cotinine (ng/mL)
ISEM presentation - September 2003

35. Environmental Tobacco Smoke
Monitored as serum cotinine
Comparing NHANES III ( ) 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
Exclude PK, new targets
ISEM presentation - September 2003

36. Serum Cotinine Levels: Tracking Exposure to
Secondhand Smoke in the Non-smoking U.S. Population
0.3
0.2
68%
69%
Serum cotinine (ng/mL)
75%
0.1
4-11
12-19
20-74
Age (years)
ISEM presentation - September 2003

37. 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

38. 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 (2005))

39. NHANES Serum Pools 2001-2002: 12 years of age and older
3 - 5 years: planned
years: planned
ISEM presentation - September 2003

40. 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

41. NHANES 2001-2002 Pools Race/Ethnicity Gender Age Group (years)
Number of Pools
12-19
20-39
40-59
60+
Non-Hispanic
White M
2 (3) 3
3 (4) F 4
Black 1
Mexican-American 2
( ) for perfluorinated chemicals

42. Geometric Mean & 95% Adjusted CI of TEQs (PCDDs, PCDFs, dioxin-like PCBs) by Age, Group, Race & Sex (using 2005 TEFs)

43. 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.

44. Mean and Range of BDE-47 by Age Group, Race and Sex

45. 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

46. Mean and Range of PFOS by Age Group, Race and Sex

47. Mean and Range of PFOA by Age Group, Race and Sex

48. Health Effects / Risk Exposure Assessment
Biomonitoring for Disease Prevention
R e s e a r c h P u b l i c H e a l t h A c t i o n s / P o l i c y R i s k A s s e s s m e n t R e f e r e n c e / A c c e p t a b l e D o s e s
Health Effects / Risk
Exposure Assessment
Status & Trends
Highly exposed
Emerging chemicals
Screening
Exposure pathway
BIOMONITORING
Susceptible populations
Clinical Studies
Preclinical indicators
Epidemiology
Emergency Response
Adapted from: HESI’s Biomonitoring Technical Committee

49. Health Effects / Risk Exposure Assessment
Exposure Analysis for Disease Prevention
R e s e a r c h P u b l i c H e a l t h A c t i o n s / P o l i c y R i s k A s s e s s m e n t R e f e r e n c e / A c c e p t a b l e D o s e s
Health Effects / Risk
Exposure Assessment
Status & Trends
Highly exposed
Emerging chemicals
Screening
Exposure
Analysis
Exposure pathway
Susceptible populations
Clinical Studies
Preclinical indicators
Epidemiology
Emergency Response
Adapted from: HESI’s Biomonitoring Technical Committee