STAR Biomarkers Research Basic Sciences, Validation, and Application Kacee Deener and Nigel Fields, USEPA/ORD – National Center for Environmental Research Every day EPA makes public health decisions to manage and reduce environmental risks based on the available science. The Agency has also launched an effort to develop public health outcomes or “indicators” that can be used to assess the effectiveness and impact of risk- based regulatory decisions. In order to reduce the uncertainties in traditional risk assessment protocols and to advance the most relevant, reliable indicators, the National Center for Environmental Research (NCER), through its Science to Achieve Results (STAR) grant program, has developed a multi-year, multi-disciplinary biological markers research portfolio. Why biomarkers are important • Provide quantitative information about exposure, early biologic effect and individual susceptibility • Fill in important gaps in the exposure-to-disease continuum • Increase our understanding of chemical transport and transformation in the body • Highlight interactions at the cellular and molecular levels that lead to toxic endpoints Introduction One of the goals of biomarkers research is the development and validation of tools that can be utilized in a real world setting. It is useful to envision biomarkers research as a three step process: 1) Basic Sciences ; 2) Validation; 3) Application Through numerous Request for Applications representing a wide variety of subject areas, NCER has funded important work that represents all three research categories. Figure illustrating exposure-dose-effect continuum with opportunities for biomarker development at various points. Exposure Internal Dose Biologically Effective Dose Early Biologic Effect Altered Structure/ Function Clinical Disease Exposure and Effect Biomarkers Susceptibility Markers Adapted from National Research Council, Biologic Markers in Reproductive Toxicology. Washington: National Academy Press, 1989 Basic sciences research first identifies measurable properties that have potential to serve as biomarkers. Once exposed, a continuum of biological events occurs, beginning with exposure and ending with health effect. Events and parameters along the continuum can potentially be observed and quantified as biomarkers. Identification of biomarkers often begins with basic toxicology research, such as an animal study that investigates one or more of the stages along the exposure-dose-effect continuum or that aims to better understand disease susceptibility. Important Considerations for Basic Sciences Research • What is the distribution of the marker in human populations? • If the marker was identified in an animal model, is there an equivalent marker in humans? • Do analytical methods exist for quantifying the marker? • Are there any technological considerations? Basic Sciences Research Validation of the biomarker is extremely important if it will be used in an epidemiological study or in a clinical setting. Without proper validation, the meaning of the biomarker is ambiguous and essentially useless. Validation characterizes the relationship between the marker and a stage or stages of the exposure-to-disease continuum. For example, validation of an exposure biomarker should establish the relationship between the marker and the environmental exposure in question, while a biomarker of effect should be clearly linked to a health endpoint. Validation Important Considerations for Validation Research • What is the positive predictive value of the marker? • What are the sensitivity and specificity of the marker? • What type of validation study is most appropriate for the marker (i.e., longitudinal cohort study, case-control study)? Once developed and validated, the marker can then be applied in epidemiological studies to characterize exposure, dose, or early health effects. Historically, one of the weak points of epidemiological studies has been the struggle to adequately characterize exposure. Some methods traditionally used are retrospective questionnaires, environmental sampling (air, dust, etc.), and duplicate diet samples. How biomarkers can improve environmental health science • Provide quantitative measures of exposure and dose • Identify the beginnings of the disease process, allowing for intervention strategies and/or early treatment • Identify populations who are at higher risk of disease, allowing for intervention strategies Application SynthesisofN ew Esterase “Free” CPF-O xon + D egradation ofEsterase Released TC P M etabolite m olehr -1 Regeneration hr -1 B -Esterase (B -EST)Inhibition (shaded com partm ents) C PF-O xon Km 1 , Vm ax 1 Com partm entM odel Ke B-EST (A ChE,BuChE,CaE) A -EST * Km 3,4 , Vm ax 3,4 V enous B lood A rterialBlood Fat Slowly Perfused Rapid Perfused D iaphragm Brain Liver C PF O xon Qc V enous B lood Slowly Perfused Rapid Perfused Brain Liver Ca A rterialBlood Qs Qr Qd Qb Cvb Ql Cv Cvs Cvr Cvd Cvl Stom ach K aS H ydrolysis Km 2 ,Vm ax 2 D iaphragm Fat Qf Cvf Cvo Cao Qc Qfo Cvfo Q so Cvso Qro Cvro Q do Cvdo Q bo Cvbo Qlo Cvlo Intestine K sI K aI TCP Skin Q sk Cvsk G avage Exposure D erm al Exposure Kp SA * Liverand bloodonly. D ietary Exposure K zero hr -1 Inhibition uM hr -1 -1 hr -1 Fa Fa FIG URE 1. PBPK /PD m odel used to describe disposition ofC P F, C PF- oxon, TC P and B -esterase (B -E S T)inhibition in rats and hum ans. SynthesisofN ew Esterase “Free” CPF-O xon + D egradation ofEsterase Released TC P M etabolite m olehr -1 Regeneration hr -1 B -Esterase (B -EST)Inhibition (shaded com partm ents) C PF-O xon Km 1 , Vm ax 1 Com partm entM odel Ke B-EST (A ChE,BuChE,CaE) A -EST * Km 3,4 , Vm ax 3,4 V enous B lood A rterialBlood Fat Slowly Perfused Rapid Perfused D iaphragm Brain Liver C PF O xon Qc V enous B lood Slowly Perfused Rapid Perfused Brain Liver Ca A rterialBlood Qs Qr Qd Qb Cvb Ql Cv Cvs Cvr Cvd Cvl Stom ach K aS H ydrolysis Km 2 ,Vm ax 2 D iaphragm Fat Qf Cvf Cvo Cao Qc Qfo Cvfo Q so Cvso Qro Cvro Q do Cvdo Q bo Cvbo Qlo Cvlo Intestine K sI K aI TCP Skin Q sk Cvsk G avage Exposure D erm al Exposure Kp SA * Liverand bloodonly. D ietary Exposure K zero hr -1 Inhibition uM hr -1 -1 hr -1 Fa Fa SynthesisofN ew Esterase “Free” CPF-O xon + D egradation ofEsterase Released TC P M etabolite m olehr -1 Regeneration hr -1 B -Esterase (B -EST)Inhibition (shaded com partm ents) C PF-O xon Km 1 , Vm ax 1 Com partm entM odel Ke B-EST (A ChE,BuChE,CaE) A -EST * Km 3,4 , Vm ax 3,4 V enous B lood A rterialBlood Fat Slowly Perfused Rapid Perfused D iaphragm Brain Liver C PF O xon Qc V enous B lood Slowly Perfused Rapid Perfused Brain Liver Ca A rterialBlood Qs Qr Qd Qb Cvb Ql Cv Cvs Cvr Cvd Cvl Stom ach K aS H ydrolysis Km 2 ,Vm ax 2 D iaphragm Fat Qf Cvf Cvo Cao Qc Qfo Cvfo Q so Cvso Qro Cvro Q do Cvdo Q bo Cvbo Qlo Cvlo Intestine K sI K aI TCP Skin Q sk Cvsk G avage Exposure D erm al Exposure Kp SA * Liverand bloodonly. D ietary Exposure K zero hr -1 Inhibition uM hr -1 -1 hr -1 Fa Fa FIG URE 1. PBPK /PD m odel used to describe disposition ofC P F, C PF- oxon, TC P and B -esterase (B -E S T)inhibition in rats and hum ans. SynthesisofN ew Esterase “Free” CPF-O xon + D egradation ofEsterase Released TC P M etabolite m olehr -1 Regeneration hr -1 B -Esterase (B -EST)Inhibition (shaded com partm ents) C PF-O xon Km 1 , Vm ax 1 Com partm entM odel Ke B-EST (A ChE,BuChE,CaE) A -EST * Km 3,4 , Vm ax 3,4 V enous B lood A rterialBlood Fat Slowly Perfused Rapid Perfused D iaphragm Brain Liver C PF O xon Qc V enous B lood Slowly Perfused Rapid Perfused Brain Liver Ca A rterialBlood Qs Qr Qd Qb Cvb Ql Cv Cvs Cvr Cvd Cvl Stom ach K aS H ydrolysis Km 2 ,Vm ax 2 D iaphragm Fat Qf Cvf Cvo Cao Qc Qfo Cvfo Q so Cvso Qro Cvro Q do Cvdo Q bo Cvbo Qlo Cvlo Intestine K sI K aI TCP Skin Q sk Cvsk G avage Exposure D erm al Exposure Kp SA * Liverand bloodonly. D ietary Exposure K zero hr -1 Inhibition uM hr -1 -1 hr -1 Fa Fa SynthesisofN ew Esterase “Free” CPF-O xon + D egradation ofEsterase Released TC P M etabolite m olehr -1 Regeneration hr -1 hr -1 B -Esterase (B -EST)Inhibition (shaded com partm ents) B -Esterase (B -EST)Inhibition (shaded com partm ents) C PF-O xon Km 1 , Vm ax 1 Com partm entM odel Ke B-EST (A ChE,BuChE,CaE) A -EST * Km 3,4 , Vm ax 3,4 V enous B lood A rterialBlood Fat Slowly Perfused Rapid Perfused D iaphragm Brain Liver C PF O xon Qc V enous B lood Slowly Perfused Rapid Perfused Brain Liver Ca A rterialBlood Qs Qr Qd Qb Cvb Ql Cv Cvs Cvr Cvd Cvl Stom ach K aS H ydrolysis Km 2 ,Vm ax 2 H ydrolysis Km 2 ,Vm ax 2 D iaphragm Fat Qf Cvf Fat Qf Cvf Cvo Cao Qc Qfo Cvfo Q so Cvso Qro Cvro Q do Cvdo Q bo Cvbo Qlo Cvlo Intestine Intestine K sI K aI TCP Skin Q sk Cvsk Skin Q sk Cvsk G avage Exposure D erm al Exposure Kp SA * Liverand bloodonly. D ietary Exposure K zero hr -1 hr -1 Inhibition uM hr -1 -1 Inhibition uM hr -1 -1 hr -1 hr -1 Fa Fa FIG URE 1. PBPK /PD m odel used to describe disposition ofC P F, C PF- oxon, TC P and B -esterase (B -E S T)inhibition in rats and hum ans. SynthesisofN ew Esterase “Free” CPF-O xon + D egradation ofEsterase Released TC P M etabolite m olehr -1 Regeneration hr -1 B -Esterase (B -EST)Inhibition (shaded com partm ents) C PF-O xon Km 1 , Vm ax 1 Com partm entM odel Ke B-EST (A ChE,BuChE,CaE) A -EST * Km 3,4 , Vm ax 3,4 V enous B lood A rterialBlood Fat Slowly Perfused Rapid Perfused D iaphragm Brain Liver C PF O xon Qc V enous B lood Slowly Perfused Rapid Perfused Brain Liver Ca A rterialBlood Qs Qr Qd Qb Cvb Ql Cv Cvs Cvr Cvd Cvl Stom ach K aS H ydrolysis Km 2 ,Vm ax 2 D iaphragm Fat Qf Cvf Cvo Cao Qc Qfo Cvfo Q so Cvso Qro Cvro Q do Cvdo Q bo Cvbo Qlo Cvlo Intestine K sI K aI TCP Skin Q sk Cvsk G avage Exposure D erm al Exposure Kp SA * Liverand bloodonly. D ietary Exposure K zero hr -1 Inhibition uM hr -1 -1 hr -1 Fa Fa Free Esterase O xon-Esterase A gedC om plex SynthesisofN ew Esterase “Free” CPF-O xon + D egradation ofEsterase Released TC P M etabolite m olehr -1 Regeneration hr -1 hr -1 B -Esterase (B -EST)Inhibition (shaded com partm ents) B -Esterase (B -EST)Inhibition (shaded com partm ents) C PF-O xon Km 1 , Vm ax 1 Com partm entM odel Ke B-EST (A ChE,BuChE,CaE) A -EST * Km 3,4 , Vm ax 3,4 Blood V enous B lood A rterialBlood Fat Slowly Perfused Rapid Perfused D iaphragm Brain Liver C PF O xon Qc V enous B lood Slowly Perfused Rapid Perfused Brain Liver Ca A rterialBlood Qs Qr Qd Qb Cvb Ql Cv Cvs Cvr Cvd Cvl Stom ach K aS H ydrolysis Km 2 ,Vm ax 2 H ydrolysis Km 2 ,Vm ax 2 D iaphragm Fat Qf Cvf Fat Qf Cvf Cvo Cao Qc Qfo Cvfo Q so Cvso Qro Cvro Q do Cvdo Q bo Cvbo Qlo Cvlo Intestine Intestine K sI K aI TCP Skin Q sk Cvsk Skin Q sk Cvsk G avage Exposure D erm al Exposure Kp SA * Liverand bloodonly. D ietary Exposure K zero hr -1 hr -1 Inhibition uM hr -1 -1 Inhibition uM hr -1 -1 hr -1 hr -1 Fa Fa STAR Basic Sciences Research • Identification of a genetic susceptibility factor in mice that will likely lead to identification of equivalent gene in humans - Miller, Wake Forest University • Investigation of a potential suite of biomarkers to predict future asthmatics who may have been exposed to tobacco smoke in utero or during early childhood - Klonoff- Cohen, University of California, San Diego • Investigation of effects of mixtures of bromoform, chloroform and PCE on perturbations of p53 expression and protein synthesis during different developmental stages – Reinisch, Marine Biological Lab STAR Validation Research • Validation of meconium as a biomarker of cumulative prenatal exposure to pesticides - Whyatt, Columbia University • Validation of saliva as a biomarker of exposure to pesticides with simultaneous development and validation of a physiologically-based pharmacokinetic model - Timchalk, Battelle Pacific Northwest Division • Validation of meconium as a biomarker of fetal exposure to heavy metals and pesticides - Ostrea, Wayne State University • Evaluation of biomarkers of effect and susceptibility for studying cancer risk in pediatric populations •Validation of biomarkers of chromium exposure and effect in Chinese occupational population- Qu, New York University •PBPK model to evaluate age and gender dependent differences in detoxifying enzymes for biomarkers of susceptibility and effect- Olson, State University of New York at Buffalo STAR Research Applies Biomarkers • Application of urinary biomarkers to assess exposure to organophosphate pesticides - Eskenazi, University of California, Berkeley • Application of various biomarkers to assess exposure, susceptibility and risk from several environmental toxicants - Perera, Columbia University •Application of biomarkers of susceptibility, exposure and effect in Azerbaijan and Chinese populations with high rates of neural tube defects – Donnelly, Texas A& M University • Potential application of STAR-funded biomarkers research to national-scale studies such as the National Children’s Study Bar graph showing interaction effect of BAP-DNA and ETS on A) birth weight and B) head circumference Perera et al, 2004 Allergens Exposure Biomarkers of Exposure Outcomes Assessment Effect/Susceptibility Growth & Neurodevelopment Persistent Wheeze / Asthma (Cancer Risk) PAH-DNA Adducts Pesticides Cotinine, 4-ABP-Hb Immune changes (lymphocyte prolif., IgE, cytokines) Lead, mercury Vitamins A,C,E Susceptibility Factors Nutritional deficits Genetic polymorphisms Social stressors PAH, PM 2.5 , DEP Pesticides ETS Metals Biomonitoring scheme for STAR-funded longitudinal cohort study at Columbia Center for Children’s Environmental Health, Perera et al, 2004 Important Biomarker Issues Biomarkers hold much promise for improving environmental health science and human health risk assessment. However, there are important issues that surround the development, validation, and application of these tools. • Treatment of values that fall below the analytical detection level • Continuity of databases to facilitate meta-analysis • Development of biorepositories for future research • Ethical issues – biomarker interpretation; communication to study participants; susceptibility markers and social stigma and employability • Intra- and inter-individual variability References National Research Council, Biologic Markers in Reproductive Toxicology, National Academy Press, 1989. Perera, Frederica P., Rauh, Virginia, Whyatt, Robin M., Tsai, Wei-Yann, Bernert, John T., Tu, Yi-Hsuan, Andrews, Howard, Ramirez, Judyth, Qu, Lirong, Tang, Deliang; Molecular Evidence of an Interaction Between Prenatal Environmental Exposures and Birth Outcomes in a Multiethnic Population , Environmental Health Perspectives April 2004 112(5):626-630. Timchalk C, Nolan RJ, Mendrala AL, Dittenber DA, Brzak KA, Mattsson JL; A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate insecticide chlorpyrifos in rats and humans, Toxicol Sci 2002 March 66(1):34-53.
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STAR Biomarkers ResearchBasic Sciences, Validation, and Application
Kacee Deener and Nigel Fields, USEPA/ORD – National Center for Environmental Research
Every day EPA makes public health decisions to manage and reduce environmental risks based on the available science. The Agency has also launched an effort to develop public health outcomes or “indicators” that can be used to assess the effectiveness and impact of risk-based regulatory decisions. In order to reduce the uncertainties in traditional risk assessment protocols and to advance the most relevant, reliable indicators, the National Center for Environmental Research (NCER), through its Science to Achieve Results (STAR) grant program, has developed a multi-year, multi-disciplinary biological markers research portfolio.
Why biomarkers are important
• Provide quantitative information about exposure, early biologic effect and individual susceptibility
• Fill in important gaps in the exposure-to-disease continuum
• Increase our understanding of chemical transport and transformation in the body
• Highlight interactions at the cellular and molecular levels that lead to toxic endpoints
Introduction
One of the goals of biomarkers research is the development and validation of tools that can be utilized in a real world setting. It is useful to envision biomarkers research as a three step process:
1) Basic Sciences ; 2) Validation; 3) Application
Through numerous Request for Applications representing a wide variety of subject areas, NCER has funded important work that represents all three research categories.
Figure illustrating exposure-dose-effect continuum with opportunities for biomarker development at various points.
Exposure InternalDose
Biologically Effective
Dose
EarlyBiologic
Effect
AlteredStructure/Function
ClinicalDisease
Exposure and Effect Biomarkers
Susceptibility Markers
Adapted from National Research Council, Biologic Markers in Reproductive Toxicology. Washington: National Academy Press, 1989
Basic sciences research first identifies measurable properties that have potential to serve as biomarkers. Once exposed, a continuum of biological events occurs, beginning with exposure and ending with health effect. Events and parameters along the continuum can potentially be observed and quantified as biomarkers. Identification of biomarkers often begins with basic toxicology research, such as an animal study that investigates one or more of the stages along the exposure-dose-effect continuum or that aims to better understand disease susceptibility.
Important Considerations for Basic Sciences Research
• What is the distribution of the marker in human populations?
• If the marker was identified in an animal model, is there an equivalent marker in humans?
• Do analytical methods exist for quantifying the marker?
• Are there any technological considerations?
Basic Sciences Research
Validation of the biomarker is extremely important if it will be used in an epidemiological study or in a clinical setting. Without proper validation, the meaning of the biomarker is ambiguous and essentially useless. Validation characterizes the relationship between the marker and a stage or stages of the exposure-to-disease continuum. For example, validation of an exposure biomarker should establish the relationship between the marker and the environmental exposure in question, while a biomarker of effect should be clearly linked to a health endpoint.
Validation
Important Considerations for Validation Research
• What is the positive predictive value of the marker?
• What are the sensitivity and specificity of the marker?
• What type of validation study is most appropriate for the marker (i.e., longitudinal cohort study, case-control study)?
Once developed and validated, the marker can then be applied in epidemiological studies to characterize exposure, dose, or early health effects. Historically, one of the weak points of epidemiological studies has been the struggle to adequately characterize exposure. Some methods traditionally used are retrospective questionnaires, environmental sampling (air, dust, etc.), and duplicate diet samples.
How biomarkers can improve environmental health science
• Provide quantitative measures of exposure and dose
• Identify the beginnings of the disease process, allowing for intervention strategies and/or early treatment
• Identify populations who are at higher risk of disease, allowing for intervention strategies
Application
Free Esterase Oxon-Esterase Aged Complex
Synthesis of New Esterase
“Free”CPF-Oxon +
Degradation of Esterase Released TCP Metabolite
mole hr-1
Regeneration
hr -1
B-Esterase (B-EST) Inhibition(shaded compartments)
CPF-Oxon
Km1,Vmax1
Compartment Model
Ke B-EST (AChE, BuChE, CaE)
A-EST* Km3,4, Vmax3,4
Blood
Ven
ous
Blo
od
Art
eria
l Blo
od
Fat
Slowly Perfused
Rapid Perfused
Diaphragm
Brain
Liver
CPF
Oxon
Qc
Ven
ous
Blo
od
Slowly Perfused
Rapid Perfused
Brain
Liver
Ca
Art
eria
l Blo
od
Qs
Qr
Qd
Qb Cvb
Ql
Cv
Cvs
Cvr
Cvd
Cvl
Stomach
KaS HydrolysisKm2, Vmax2
Diaphragm
FatQf Cvf CvoCao
Qc
Qfo Cvfo
Qso Cvso
Qro Cvro
Qdo Cvdo
Qbo Cvbo
Qlo Cvlo
Intest ine
KsI
KaI
TCP
SkinQsk Cvsk
GavageExposure
DermalExposure
Kp
SA
* Liver and blood only.
Dietary Exposure
Kzero
hr -1
InhibitionuM hr-1 -1
hr -1
Fa Fa
FIGURE 1. PBPK/PD model used to describe disposition of CPF, CPF-oxon, TCP and B-esterase (B-EST) inhibition in rats and humans.
Free Esterase Oxon-Esterase Aged Complex
Synthesis of New Esterase
“Free”CPF-Oxon +
Degradation of Esterase Released TCP Metabolite
mole hr-1
Regeneration
hr -1
B-Esterase (B-EST) Inhibition(shaded compartments)
CPF-Oxon
Km1,Vmax1
Compartment Model
Ke B-EST (AChE, BuChE, CaE)
A-EST* Km3,4, Vmax3,4
Blood
Ven
ous
Blo
od
Art
eria
l Blo
od
Fat
Slowly Perfused
Rapid Perfused
Diaphragm
Brain
Liver
CPF
Oxon
Qc
Ven
ous
Blo
od
Slowly Perfused
Rapid Perfused
Brain
Liver
Ca
Art
eria
l Blo
od
Qs
Qr
Qd
Qb Cvb
Ql
Cv
Cvs
Cvr
Cvd
Cvl
Stomach
KaS HydrolysisKm2, Vmax2
Diaphragm
FatQf Cvf CvoCao
Qc
Qfo Cvfo
Qso Cvso
Qro Cvro
Qdo Cvdo
Qbo Cvbo
Qlo Cvlo
Intest ine
KsI
KaI
TCP
SkinQsk Cvsk
GavageExposure
DermalExposure
Kp
SA
* Liver and blood only.
Dietary Exposure
Kzero
hr -1
InhibitionuM hr-1 -1
hr -1
Fa Fa
Free Esterase Oxon-Esterase Aged Complex
Synthesis of New Esterase
“Free”CPF-Oxon +
Degradation of Esterase Released TCP Metabolite
mole hr-1
Regeneration
hr -1
B-Esterase (B-EST) Inhibition(shaded compartments)
CPF-Oxon
Km1,Vmax1
Compartment Model
Ke B-EST (AChE, BuChE, CaE)
A-EST* Km3,4, Vmax3,4
Blood
Ven
ous
Blo
od
Art
eria
l Blo
od
Fat
Slowly Perfused
Rapid Perfused
Diaphragm
Brain
Liver
CPF
Oxon
Qc
Ven
ous
Blo
od
Slowly Perfused
Rapid Perfused
Brain
Liver
Ca
Art
eria
l Blo
od
Qs
Qr
Qd
Qb Cvb
Ql
Cv
Cvs
Cvr
Cvd
Cvl
Stomach
KaS HydrolysisKm2, Vmax2
Diaphragm
FatQf Cvf CvoCao
Qc
Qfo Cvfo
Qso Cvso
Qro Cvro
Qdo Cvdo
Qbo Cvbo
Qlo Cvlo
Intest ine
KsI
KaI
TCP
SkinQsk Cvsk
GavageExposure
DermalExposure
Kp
SA
* Liver and blood only.
Dietary Exposure
Kzero
hr -1
InhibitionuM hr-1 -1
hr -1
Fa Fa
FIGURE 1. PBPK/PD model used to describe disposition of CPF, CPF-oxon, TCP and B-esterase (B-EST) inhibition in rats and humans.
Free Esterase Oxon-Esterase Aged Complex
Synthesis of New Esterase
“Free”CPF-Oxon +
Degradation of Esterase Released TCP Metabolite
mole hr-1
Regeneration
hr -1
B-Esterase (B-EST) Inhibition(shaded compartments)
CPF-Oxon
Km1,Vmax1
Compartment Model
Ke B-EST (AChE, BuChE, CaE)
A-EST* Km3,4, Vmax3,4
Blood
Ven
ous
Blo
od
Art
eria
l Blo
od
Fat
Slowly Perfused
Rapid Perfused
Diaphragm
Brain
Liver
CPF
Oxon
Qc
Ven
ous
Blo
od
Slowly Perfused
Rapid Perfused
Brain
Liver
Ca
Art
eria
l Blo
od
Qs
Qr
Qd
Qb Cvb
Ql
Cv
Cvs
Cvr
Cvd
Cvl
Stomach
KaS HydrolysisKm2, Vmax2
Diaphragm
FatQf Cvf CvoCao
Qc
Qfo Cvfo
Qso Cvso
Qro Cvro
Qdo Cvdo
Qbo Cvbo
Qlo Cvlo
Intest ine
KsI
KaI
TCP
SkinQsk Cvsk
GavageExposure
DermalExposure
Kp
SA
* Liver and blood only.
Dietary Exposure
Kzero
hr -1
InhibitionuM hr-1 -1
hr -1
Fa Fa
Free Esterase Oxon-Esterase Aged Complex
Synthesis of New Esterase
“Free”CPF-Oxon +
Degradation of Esterase Released TCP Metabolite
mole hr-1
Regeneration
hr -1hr -1
B-Esterase (B-EST) Inhibition(shaded compartments)
B-Esterase (B-EST) Inhibition(shaded compartments)
CPF-Oxon
Km1,Vmax1
Compartment Model
Ke B-EST (AChE, BuChE, CaE)
A-EST* Km3,4, Vmax3,4
Blood
Ven
ous
Blo
od
Art
eria
l Blo
od
Fat
Slowly Perfused
Rapid Perfused
Diaphragm
Brain
Liver
CPF
Oxon
Qc
Ven
ous
Blo
od
Slowly Perfused
Rapid Perfused
Brain
Liver
Ca
Art
eria
l Blo
od
Qs
Qr
Qd
Qb Cvb
Ql
Cv
Cvs
Cvr
Cvd
Cvl
Stomach
KaS HydrolysisKm2, Vmax2
HydrolysisKm2, Vmax2
Diaphragm
FatQf CvfFatQf Cvf CvoCao
Qc
Qfo Cvfo
Qso Cvso
Qro Cvro
Qdo Cvdo
Qbo Cvbo
Qlo Cvlo
Intest ineIntest ine
KsI
KaI
TCP
SkinQsk CvskSkinQsk Cvsk
GavageExposure
DermalExposure
Kp
SA
* Liver and blood only.
Dietary Exposure
Kzero
hr -1hr -1
InhibitionuM hr-1 -1InhibitionuM hr-1 -1
hr -1hr -1
Fa Fa
FIGURE 1. PBPK/PD model used to describe disposition of CPF, CPF-oxon, TCP and B-esterase (B-EST) inhibition in rats and humans.
Free Esterase Oxon-Esterase Aged Complex
Synthesis of New Esterase
“Free”CPF-Oxon +
Degradation of Esterase Released TCP Metabolite
mole hr-1
Regeneration
hr -1
B-Esterase (B-EST) Inhibition(shaded compartments)
CPF-Oxon
Km1,Vmax1
Compartment Model
Ke B-EST (AChE, BuChE, CaE)
A-EST* Km3,4, Vmax3,4
Blood
Ven
ous
Blo
od
Art
eria
l Blo
od
Fat
Slowly Perfused
Rapid Perfused
Diaphragm
Brain
Liver
CPF
Oxon
Qc
Ven
ous
Blo
od
Slowly Perfused
Rapid Perfused
Brain
Liver
Ca
Art
eria
l Blo
od
Qs
Qr
Qd
Qb Cvb
Ql
Cv
Cvs
Cvr
Cvd
Cvl
Stomach
KaS HydrolysisKm2, Vmax2
Diaphragm
FatQf Cvf CvoCao
Qc
Qfo Cvfo
Qso Cvso
Qro Cvro
Qdo Cvdo
Qbo Cvbo
Qlo Cvlo
Intest ine
KsI
KaI
TCP
SkinQsk Cvsk
GavageExposure
DermalExposure
Kp
SA
* Liver and blood only.
Dietary Exposure
Kzero
hr -1
InhibitionuM hr-1 -1
hr -1
Fa Fa
Free Esterase Oxon-Esterase Aged Complex
Synthesis of New Esterase
“Free”CPF-Oxon +
Degradation of Esterase Released TCP Metabolite
mole hr-1
Regeneration
hr -1hr -1
B-Esterase (B-EST) Inhibition(shaded compartments)
B-Esterase (B-EST) Inhibition(shaded compartments)
CPF-Oxon
Km1,Vmax1
Compartment Model
Ke B-EST (AChE, BuChE, CaE)
A-EST* Km3,4, Vmax3,4
Blood
Ven
ous
Blo
od
Art
eria
l Blo
od
Fat
Slowly Perfused
Rapid Perfused
Diaphragm
Brain
Liver
CPF
Oxon
Qc
Ven
ous
Blo
od
Slowly Perfused
Rapid Perfused
Brain
Liver
Ca
Art
eria
l Blo
od
Qs
Qr
Qd
Qb Cvb
Ql
Cv
Cvs
Cvr
Cvd
Cvl
Stomach
KaS HydrolysisKm2, Vmax2
HydrolysisKm2, Vmax2
Diaphragm
FatQf CvfFatQf Cvf CvoCao
Qc
Qfo Cvfo
Qso Cvso
Qro Cvro
Qdo Cvdo
Qbo Cvbo
Qlo Cvlo
Intest ineIntest ine
KsI
KaI
TCP
SkinQsk CvskSkinQsk Cvsk
GavageExposure
DermalExposure
Kp
SA
* Liver and blood only.
Dietary Exposure
Kzero
hr -1hr -1
InhibitionuM hr-1 -1InhibitionuM hr-1 -1
hr -1hr -1
Fa Fa
STAR Basic Sciences Research• Identification of a genetic susceptibility factor in mice that will likely lead to identification of equivalent gene in humans - Miller, Wake Forest University
• Investigation of a potential suite of biomarkers to predict future asthmatics who may have been exposed to tobacco smoke in utero or during early childhood - Klonoff-Cohen, University of California, San Diego
• Investigation of effects of mixtures of bromoform, chloroform and PCE on perturbations of p53 expression and protein synthesis during different developmental stages – Reinisch, Marine Biological Lab
STAR Validation Research• Validation of meconium as a biomarker of cumulative prenatal exposure to pesticides - Whyatt, Columbia University
• Validation of saliva as a biomarker of exposure to pesticides with simultaneous development and validation of a physiologically-based pharmacokinetic model - Timchalk, Battelle Pacific Northwest Division
• Validation of meconium as a biomarker of fetal exposure to heavy metals and pesticides - Ostrea, Wayne State University
• Evaluation of biomarkers of effect and susceptibility for studying cancer risk in pediatric populations
•Validation of biomarkers of chromium exposure and effect in Chinese occupational population- Qu, New York University
•PBPK model to evaluate age and gender dependent differences in detoxifying enzymes for biomarkers of susceptibility and effect- Olson, State University of New York at Buffalo
STAR Research Applies Biomarkers• Application of urinary biomarkers to assess exposure to organophosphate pesticides - Eskenazi, University of California, Berkeley
• Application of various biomarkers to assess exposure, susceptibility and risk from several environmental toxicants - Perera, Columbia University
•Application of biomarkers of susceptibility, exposure and effect in Azerbaijan and Chinese populations with high rates of neural tube defects – Donnelly, Texas A& M University
• Potential application of STAR-funded biomarkers research to national-scale studies such as the National Children’s Study
Bar graph showing interaction effect of BAP-DNA and ETS on A) birth weight and B) head circumference Perera et al, 2004
Allergens
Exposure Biomarkers of Exposure Outcomes Assessment Effect/Susceptibility
Growth & Neurodevelopment
Persistent Wheeze / Asthma
(Cancer Risk)
PAH-DNA AdductsPesticidesCotinine, 4-ABP-Hb
Immune changes (lymphocyte prolif., IgE, cytokines)Lead, mercury
Vitamins A,C,E
Susceptibility Factors
Nutritional deficits Genetic polymorphisms Social stressors
PAH, PM2.5, DEP Pesticides ETS
Metals
Biomonitoring scheme for STAR-funded longitudinal cohort study at Columbia Center for Children’s Environmental Health, Perera et al, 2004
Important Biomarker IssuesBiomarkers hold much promise for improving environmental health science and human health risk assessment. However, there are important issues that surround the development, validation, and application of these tools.
• Treatment of values that fall below the analytical detection level
• Continuity of databases to facilitate meta-analysis
• Development of biorepositories for future research
• Ethical issues – biomarker interpretation; communication to study participants; susceptibility markers and social stigma and employability
• Intra- and inter-individual variability
References
National Research Council, Biologic Markers in Reproductive Toxicology, National Academy Press, 1989.
Perera, Frederica P., Rauh, Virginia, Whyatt, Robin M., Tsai, Wei-Yann, Bernert, John T., Tu, Yi-Hsuan, Andrews, Howard, Ramirez, Judyth, Qu, Lirong, Tang, Deliang; Molecular Evidence of an Interaction Between Prenatal Environmental Exposures and Birth Outcomes in a Multiethnic Population, Environmental Health Perspectives April 2004 112(5):626-630.
Timchalk C, Nolan RJ, Mendrala AL, Dittenber DA, Brzak KA, Mattsson JL; A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate insecticide chlorpyrifos in rats and humans, Toxicol Sci 2002 March 66(1):34-53.
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