Exposure (To Stressors) Autism Spectrum Disorders

Transcription

1 Exposure (To Stressors) Autism Spectrum Disorders Larry L. Needham, Ph.D. Chief, Organic Analytical Toxicology Branch National Center for Environmental Health Centers for Disease Control and Prevention Atlanta, GA USA 04

2 Exposure-Effect Continuum for Environmental Chemicals RISK MANAGEMENT Source Fate and Transport Water, Air, Food, Soil, Dust, Sediment, Surfaces, Personal Care Products EPIDEMIOLOGICAL STUDIES Metabolism Elimination Exposure Internal Dose Target Organ Dose Absorption following: Distribution Elimination Inhalation Ingestion Dermal Contact RISK ASSESSMENT Biologically Effective Dose Pharmacodynamic Processes Effect Needham in Angerer et al. Tox Sci 9() -0 (2006)

3 Environmental Stressors Chemicals Environmental Occupational Pharmaceuticals Personal Care Products Diet Household Products Infectious Agents Social Built Environment

4 Individual Stressors Genetics Personal Characteristics Age Nutritional Status Health Status Sex

5 Environmental Stressors Individual Stressors Pregnant Woman/Fetus Infant Pharmacodynamic Processes ASD Effect Markers? No ASD ASD No ASD

6 Effects of Multiple Stressors 0 L filtered tap water Tadpoles Add to experimental tub. Water control with and without predator 2. Acetone control with and without predator. Carbaryl (varying concentrations in acetone) with and without predator Relyea and Mills. PNAS 98: (200)

7 Survival Results Relyea and Mills. PNAS 98: (200)

8 Environmental Stressors Chemicals Infectious Agents Social

9 Chemical Exposures Environmental Occupational Medications Personal Care Products Diet

10 Number of Chemicals in Commerce -USA "industrial", ~82,000 (~40% polymers) Food additives, ~8600 Cosmetic ingredients, ~400 Pharmaceuticals, ~800 Pesticides (active), ~000 Muir and Howard. ES&T 40: (2006)

11 Chemical Exposure Assessment Where do we start? What s available for monitoring?

12 Exposure Assessment Approaches Questionnaire/Historical Information (includes GIS + video) Environmental monitoring (Air, Water, Food, Soil, Personal) Biomonitoring Combine these approaches with calibrated and validated models

13 Chemicals in 4 th Report ~265 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 & Alkylated phenols Triclosan Sunscreen agent Speciated arsenic Acrylamide Parabens

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

15 Selection of Biomonitoring Matrix: Environmental Chemical Dependent Two primary classes of Environmental Chemicals u Persistent (half-lives in years); PCDDs, PCBs, PBDEs, PFCs, OCs, Pb u Non Persistent (half-lives in minutes/hours); phthalates, pesticides (OPs, carbamates, pyrethroids), VOCs

16 So where do we start?

17 Selection of BiomonitoringMatrix: Population Dependent Life Stages of Children y Preschool 6 y Older toddler 2 y y Young toddler Trimesters Infancy Death Birth Embryonic (8d 8w) Conception Pre High School 2 y Adolescence (High School) 8-2 y Needham et al. Environ Health Perspect : (2005)

18 Relative Importance of Various Biological Matrices for Measuring Exposure During the Different Life Stages Matrices 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) Adult preconception NA st 2 Fetal 2nd Persistent Organic Chemicals 2 rd 2 0- year NA NA NA NA NA 2- years Barr, Wang, and Needham. Environ Health Perspect :08-9 (2005) NA NA NA 4- years NA NA

19 So where do we start? Number of Chemicals in Commerce - USA "industrial", ~82,000 (~40% polymers) Food additives, ~8600 Cosmetic ingredients, ~400 Pharmaceuticals, ~800 Pesticides (active), ~000 Muir and Howard. ES&T 40: (2006)

20 Which chemicals are absorbed? Which chemicals are increasing in environment? People? Which chemicals are neuroactive? Cause oxidative stress? Which chemicals have structures similar to chemicals linked to ASD?

21 Chemicals Linked to ASD O Pb CH CH 2 OH N N O Lead Ethanol O H Thalidomide CH CH CH O C OH O CH CH 2 CH 2 CH C OH CH CH Retinoids Valproic Acid CH 2 CH 2 CH COONa SHgCH 2 CH Thimerosal

22 What information can be gained from nested case-control studies? sibling and twin studies? National Children s study? National Children s Centers? These will require casting a wide net analytically or better information to select the analytes.

23 Wider net includes Time of flight mass spectrometry/2d GC Biosensors Working backwards

24 Environmental Stressors Individual Stressors Pregnant Woman/Fetus Infant Pharmacodynamic Processes ASD Effect Markers? No ASD ASD No ASD

25 How do concentrations in particular matrix reflect body burden?

26 Absorption, Distribution, and Elimination of Environmental Chemicals in the Body Ingestion Inhalation Dermal Gastrointestinal Tract Feces Liver Bile Urine Portal Blood Kidney Bladder Lung Blood/ Lymph Alveoli Expired Air Primary Deposition Sites Secretory Structures Secretions Fat Bone Soft Tissues Tears Saliva Sweat Milk Needham, Barr, and Calafat. Neurotoxicology 26:547-5 (2005)

27 Fetal Period/Fetal Environment Maternal Blood Ingestion Dermal Inhalation Lung Cord Blood GI Tract Liver Bile Portal Blood Kidney Fetal Blood Primary Deposition Sites Secretory Structures Fat Soft Tissues Bone Meconium Fetal Urine Amniotic Fluid Brain Placenta

28 Biomonitoring for Disease Prevention Emerging chemicals Highly exposed Status & Trends Screening Exposure pathway BIOMONITORING Susceptible populations Clinical Studies Emergency Response Epidemiology Preclinical indicators Needham et al. International J Hygiene and Environ Health