1 / 70

Exposure Assessment Studies at CDC of Potential Use in National Children’s Study

Exposure Assessment Studies at CDC of Potential Use in National Children’s Study. Larry L. Needham, Ph.D. Chief, Toxicology Branch National Center for Environmental Health Centers for Disease Control and Prevention Atlanta, GA USA 30341. Definitions.

sari
Download Presentation

Exposure Assessment Studies at CDC of Potential Use in National Children’s Study

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Exposure Assessment Studies at CDC of Potential Use in National Children’s Study Larry L. Needham, Ph.D. Chief, Toxicology Branch National Center for Environmental Health Centers for Disease Control and Prevention Atlanta, GA USA 30341

  2. Definitions • Environmental chemical: a chemical compound or element present in air, water, food, soil, dust or other environmental media • Biomonitoring: assessment of human exposure to chemicals by measuring the chemical, its metabolites, or reaction products (adducts) in human specimens, such as blood or urine

  3. Human Exposure Effect Paradigm Source of Chemical Environmental Matrix Biological Matrix Contact Fate & Transport Exposure Environmental Matrix Biological Matrix Contact Exposure

  4. Adult/Child Exposure Effect Paradigm Dose Differences Physiological Differences Pharmacokinetics (ADME) Exposure Assessment Pharmacodynamics Windows of Vulnerability Effect Assessment

  5. Human Exposure Adverse Health Outcomes

  6. Life Cycle Death 2 y Young toddler Older toddler 1 y 3 y Infancy Birth Preschool Trimesters Embryonic (8d – 8w) 6 y Conception Pre High School 12 y 18-21 y Adolescence

  7. Assessing Human Exposure at All Life Cycle Stages • Questionnaire/Historical Information (includes GIS + video) • Environmental monitoring • Biomonitoring • Combine these 3 approaches with calibrated and validated models

  8. National Children’s Study Follow 100,000 children prospectively for 20 years Primary health outcomes: Asthma, Neurodevelopment Goal: Be in the field by January, 2005

  9. Two Primary “Studies” • National Health and Examination Survey (NHANES) • Focused studies, such as National Children’s Centers

  10. History of NHANESAdministered by National Center for Health Statistics (NCHS), CDC

  11. NHANES III • 30,000 participants from 1988-1994 • Stratified, complex, multistage probability sample of the civilian, noninstitutionalized U.S. population • Estimates are probability based for this U.S. population • Detailed history, physical, and laboratory exam

  12. NHANES 1999-2000: Additional Features • About 5000 participants annually from 15 locations • Continuous annual survey • Includes home interview • Oversampled African Americans, Mexican Americans, adolescents (12-19 years), older Americans ( 60 years); pregnant women. In 2000 also low income whites • More information: www.cdc.gov/nchs/nhanes/htm

  13. NHANES 1999-2000: Assessment of Exposure to Following Chemical Classes, ages • PCDDs/PCDFs/PCBs/OC pesticides, ages  12 years • Phthalates, ages  6 years • Phytoestrogens, ages  6 years • Polyaromatic Hydrocarbons (2,3,4-ringed), ages  6 years • Nonpersistent Pesticides, ages 6-59 years • Metals • Lead, cadmium, ages  1 year; mercury, ages 1-5 years, females 16-49 years • 11 urinary metals, ages  6 years • Nicotine (cotinine), ages  3 years Web site: www.cdc.gov/exposurereport

  14. National Report on Human Exposureto Environmental Chemicals What it is: An ongoing (every 2 years) biomonitoring assessment of the exposure of the U.S. population to environmental chemicals. Biological Matrices monitored: Urine; blood and its components; Hair (Hg)

  15. Major findings: U.S. population-based reference ranges • Geometric means • 10th, 25th, 50th, 75th, 90th, and 95th percentiles • Age, sex, race/ethnicity breakout

  16. Public Health Uses of the Report • Identifies environmental chemicals in U.S. population • Provides reference range for selected chemicals in U.S. population • Identifies exposure status of individuals • Identifies prevalence of persons with elevated levels • May Identify population groups with elevated levels • Monitors changes in exposure over time of U.S. population • Assesses effectiveness of public health efforts to reduce exposures • Aggregates exposure from all sources and routes • May identify potential sources/routes of exposure • Provides exposure data for risk assessment • Helps set priorities for human health effects research

  17. Disadvantages of Biomonitoring • Requires human specimen (invasive) • Usually does not identify source/pathway for the chemical • Analyte (e.g., metabolite) may not be specific for parent compound (for 2 reasons) • May require knowledge of when sample was collected post-exposure • Requires knowledge of pharmacokinetics (ADME) of chemical and effects of individual differences on ADME

  18. Interpreting Data in the Report • Just because a chemical can be measured in blood or urine, does not mean it causes disease • For many of these chemicals, more research is needed to interpret these levels • Provides new exposure data – does not identify new levels that cause disease (those studies done separately)

  19. Longevity of Chemicals in the Body Exposure Absorption  Distribution  Metabolism  Elimination Nonpersistent chemicals: “pass through” ADME quickly generally measured in urine (as metabolite) Persistent chemicals: metabolize and eliminate slowly distribute among tissues; tissue concentrations in equilibrium with blood concentrations

  20. Post-exposure Fate of a Persistent Toxicant in Blood and Urine Blood Toxicant/Metabolite Hemoglobin Adduct Concentration Albumin Adduct DNA Adduct Urinary Adduct Urinary Metabolite 1 10 100 1000 Time (Days)

  21. Post-exposure Fate of a Nonpersistent Toxicant in Blood and Urine Blood Toxicant/Metabolite Urinary Metabolite Albumin Adduct Concentration Hemoglobin Adduct DNA Adduct Urinary Adduct 1 10 100 1000 Time (Days) Needham and Sexton, JEAEE 10:611-629 (2000)

  22. Concentration 1 10 100 1000 Time (Days) Post-exposure Fate of a Nonpersistent Toxicant in Blood and Urine – Chronic Exposure Blood Toxicant/Metabolite Urinary Metabolite Needham and Sexton, JEAEE 10:611-629 (2000)

  23. Matrix Two primary matrices used for NHANES biomonitoring are blood (or its components) and urine. Limited amount of blood is available. Age (years) Blood (mL) 1-2 9 3-5 22 6-11 38 12+ 89-92

  24. Neurotoxic Environmental Chemicals

  25. Analytical Chemistry Methods Organic compounds – either high resolution mass spectrometry or tandem mass spectrometry (MS/MS) and isotope dilution technique for quantification Elements – atomic absorption spectroscopy or inductively coupled argon plasma spectroscopy

  26. Lead Blood lead levels (BLLs) 1 year of age and greater

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

  28. Predicted blood lead changes with decreasing gasoline lead 110 17 Predicted blood lead 100 16 90 15 14 80 Lead used in Gasoline lead gasoline Mean blood 13 70 lead levels (thousands (  g/dL) 12 of tons) 60 11 50 10 40 9 30 1975 1976 1977 1978 1979 1980 1981 Year

  29. NHANES II blood lead measurements found a substantial decline in blood lead levels, 10 times more than predicted from environmental modeling 110 17 Predicted blood lead 100 16 90 15 14 80 Lead used in Gasoline lead gasoline Mean blood 13 70 lead levels (thousands (  g/dL) 12 of tons) 60 11 50 Observed blood lead 10 40 9 30 1975 1976 1977 1978 1979 1980 1981 Year

  30. 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 10 Blood lead levels (mg/dL) Gasoline lead 40 8 6 20 4 0 2 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 Year

  31. NHANES III (1988-1994) showed blood lead levels continued to decrease as gasoline levels declined 18 100 16 14 80 12 60 Blood lead Lead used In gasoline (1000 tons) 10 Blood lead levels (mg/dL) Gasoline lead 40 8 6 20 4 0 2 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 Year

  32. Blood lead levels in the U.S. population 1976 -2000 NHANES II, III, 1999-2000 18 16 14 12 10 Blood lead levels (mg/dL) 8 6 4 2 0 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 Year

  33. 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 40 defining lead poisoning (g/dL) 30 20 10 0 1965 1970 1975 1980 1985 1990 1995

  34. Major findings: Decline in blood lead levels among children For children 1 through 5 years old • NHANES III (1991-94) • Geometric mean BLL 2.7 g/dL • 4.4% had BLLs  10 g/dL • NHANES 1999-2000 • Geometric mean BLL 2.23 g/dL • 2.2% had BLLs  10 g/dL • Higher prevalence of BLLs in U.S. children occur in urban settings, lower SES, immigrants and refugees (Geltman et al., 2001)

  35. Geometric Mean BLLs • Age groups (relative order of decreasing concentrations): 1-5 years > 6-11 years > 20+ years > 12-19 years • Gender: Males > Females • Race/ethnicity: Non-Hispanic Black ~ Mexican American > Non-Hispanic White

  36. Mercury (g/L)50th, 75th, 90th, and 95th percentiles 0.900 2.00 4.9 7.10 16-49 years 0.300 0.500 1.40 2.30 1-5 years

  37. Mercury Blood Mercury (primarily organic – primarily methyl)

  38. Hg Questions Answered • Who is exposed? >95% maternal age females • To how much? Most less than 6 g/L. Mostly organic (<10% is inorganic). • Who is at risk? All are below the lowest concentration (58 g/L) causing a 5% increase prevalence in abnormal developmental test scores for children exposed in utero. • MOS = 5-10 fold

  39. Polychlorinated Biphenyls (PCBs) 25 Non-coplanar congeners in serum/lipid basis 12 years + Bottom Line: General population levels have decreased remarkably

  40. Organohalogen Compounds in Breast Milk in Sweden Hooper and She, EHP 111(1): 109-114 (2003). Data from Noren and Mieronyte, 1998 and Guvenius and Noren, 2001

  41. Second Report results • DDT banned in U.S. in 1973 • Pesticide DDE is 3 times higher in Mexican-Americans • Also measurable in 12-19 year olds (born after ban) • May be persisting in environment or from imported food

  42. Food Quality Protection Act of 1996 • EPA mandate to implement • Exposure component with focus on children • Aggregate and cumulative exposures • Aggregate – multiple route exposures • Cumulative – 2 or more chemicals with same mechanism of action • Organophosphate insecticides • Safety factor ( 10 fold) for children • Most reevaluated • Chlorpyrifos, diazinon use restricted • Evaluate efficacy of implementation with NHANES III, NHANES 99+, and beyond

  43. Organophosphate (OP) Pesticides Metabolites in Urine 6+ years

  44. Cl Cl Cl Cl S O Cl Cl O O P P OR’ OR’ N N OR’ OR’ Cl Cl Cl OH N S O HO HO P P OR’ OR’ OR’ OR’ Chlorpyrifos (R’=ethyl) and Chlorpyrifos-methyl (R’=methyl) Metabolism + + 3,5,6-TCPy 3,5,6-TCPy is “specific” metabolite Dialkyl phosphates are “nonspecific” metabolites

  45. Organophosphate Pesticide Nonspecific Metabolites

  46. OP Pesticide - Metabolism Of 39 EPA-registered OP pesticides, 28 metabolize to 6 dialkyl phosphates; DMP, DMTP, DMDTP, DEP, DETP, DEDTP These 6 dialkyl phosphates are nonspecific for identifying parent OP Useful for tracking reduction of OP pesticide use Little differences observed among age groups, race/ethnicity, or gender

  47. “Specific” Metabolites of OP Pesticdes OP Pesticides: Malathion, Diazinon, Chlorpyrifos, Parathion • Malathion and Diazinon – mostly < LOD • Parathion • Due to nonspecificity, difficult to interpret • Mexican-Americans highest levels • Chlorpyrifos • Most prevalent (91% > LOD) • 6-11 years age group 2x higher levels than adults

  48. Asthma • Environmental chemical link???? Cockroach allergen Particulate matter Diesel exhaust Mold Environmental tobacco smoke Phthalates?

  49. O O C C OR OH C C OR OR O O Phthalate Metabolism Monoester Metabolite Phthalates

More Related