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 Director,  Western  States  Pediatric  Environmental  Health  Specialty  Unit    

 University  of  California  San  Francisco*    

Director,  CA  EPA  Program  for  Children’s  Environmental  Health  (Comments  do  not  represent  state  of  California)  

 Director  COTC,  Center  for  IntegraJve  Research  on  Childhood  Leukemia  and  Environment    

University  of  California  Berkeley  

Pediatric  Environmental  Illness:    The  Canary  in  the  Coal  Mine  

 

*Funded by Agency for Toxic Substances Disease Registry and US EPA through ACMT

Mark  Miller  MD,  MPH    

San  Francisco,  March  2016  

 

No  disclosures  

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Pediatric  Environmental  Health  Specialty  Units  

Western  States  PEHSU    hTp://coeh.berkeley.edu/ucpehsu/  

1-­‐866-­‐827-­‐3478  NaJonal  PEHSU  System  

www.pehsu.net    888-­‐347-­‐2632    

Library  of  Congress  –  Public  Domain    digital  ID  hhh.co0168    

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.

• Breathing rates calculated from inhalation rates (m3/kg-day) and body weights reported in Layton (1993); original data from NFCS (1977-78).

Breathing Rates by Age Group

0100200300400500600700

<1 1-­‐2 3-­‐5 6-­‐8  9-­‐11

12-­‐18

19-­‐74 75

+

Age Group (years)

L/k

g-d

ay

0

50

100

150

200

250

300

<1

1 to

2

3 to

5

6 to

11

12 to

19

20 -

39

40 -

69

70+

age in years

meatdairyeggsfish

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Case      

•  Female  infant  •  breas^ed  with  formula  supplement  •  normal  1  month  checkup  (mother  notes  acrocyanosis  at  2  weeks)  

•  At  2  months  pharmacist  comments  on  cyanoJc  color  

•  Given  progressively  more  formula  made  with  well  water  

•  At  2  months  develops  vomiJng  and  severe  diarrhea  

•  Rushed  to  physician  -­‐  cyanosis  doesn’t  respond  to  oxygen  /  full  arrest  

•  Chocolate-­‐brown  blood  •  Well  water  150mg/L  

nitrates  By Mike Blyth (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html). Commons

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Nitrates    

•  Preventable  cause  of  methemoglobinemia  in  infants  

•  Over  2,000  cases  reported  with  case  fatality  rate  of  10%  

•  EPA  drinking  water  standards                                                                nitrates  <  10mg/L  (10ppm)  

•  4.5  million  people  served  >  EPA  standard  •  65,000  infants    •  117,000  children  via  public  systems  

Infant  Under  4  Months  

Methemoglobin

Single food source High fluid

intake

Hemoglobin F dominant – more readily oxidized

Methemoglobin reductase activity low

↑ Gastric pH ( ↑ bacteria that convert nitrate to nitrites)

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EXPOSURES  DURING  DEVELOPMENTAL  PERIODS  AND  AT  DOSES  NOT  ASSOCIATED  WITH  ADULT  TOXICITY  MAY  RESULT  IN  IMPACTS  UNEXPECTED  BY  ADULT  

EXPOSURE  

Rauh  et  al.  Pediatrics  20  06  

Rauh  et  al.,  EHP  2011    

Chlorpyrifos  Impacts  Neurodevelopment  

•  Detected in >64% of maternal and newborn blood samples •  Follow up at 3 yrs. for 189 children

•  Highly exposed –  Delays in psychomotor and mental developmental

indexes (Bayley) •  PDI delays 5 times as great (MDI 2.4 times)

•  Symptoms ADHD and PDD significantly more likely (child behavior checklist)

•  Declines in working memory and full scale IQ at age 7

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Chlorpyrifos  has  Measurable  Impact  on  Brain  Structure  (non-­‐occupaJonal)  

Brain  anomalies  in  children  exposed  prenatally  to  a  common  organophosphate  pesJcide,  Rauh  et  al.,  PNAS  2012  (copyrighted)  

Regional  enlargements  of  the  cerebral  surface  (primarily  underlying  white  maTer)  

•  Posterior  middle  temporal,  inferior  postcentral  gyri  bilaterally  –   ATenJon  and  recepJve  language  

•   Superior  frontal  gyrus,  superior  temporal  gyrus,  cuneus,  and  precuneus  –  Social  cogniJon  

•  Gyrus  rectus  (related  orbitofrontal  regions)  –  Reward,  emoJon,  and  inhibitory  control  

•  L  superior  frontal    gyrus  (dorsal  and  mesial  surfaces)  

– ExecuJve  funcJon  

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From Minamata Eugene and Aileen Smith H,R,W 1975

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Time Lines of Developmental Processes in Humans

                         Prenatal Period (Months) Postnatal Period (Years) 0 1 2 3 4 5 6 7 8 9 Birth 1 2 3 4 5 6 7 8

9 10 Cell radial glia,neurons glia Proliferation Migration brain, spinal cord ext. granular layer cerebellum of Neurons Subplate Neurons

Synapse mz sp hp rf visual cortex association cortex Formation Myelination                                                                                                                                                                      Key:  mz  –  marginal  zone;  sp  –  subplate;  hp  –  hippocampus;  rf  –  reJcular  formaJon  

Specific processes disrupted by neurodevelopmental toxicants

proliferation radiation, ethanol, mercury, cholinesterase inhibitors

migration radiation, mercury, ethanol

differentiation ethanol, nicotine, mercury, lead

synaptogenesis radiation, ethanol, lead, triethyl tin, parathion, PCBs

gliogenesis & thyroid, ethanol, lead myelinization

apoptosis ethanol, lead, mercury signaling ethanol, cholinesterase inhibitors,

mercury, lead, PCBs

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Takeuchi:  From  Minamata  Eugene  and  Aileen  Smith  H,R,W  1975  

Cohort  studies  find  lower  dose  effects:    loss  of  IQ  points,    decreased  performance:  memory,  aQenRon,  language,  and  spaRal  cogniRon      

Grandjean  P,  et  al.  Neurotoxicol  Teratol  1997;19:417-­‐28.      

 Who  is  the  canary?      

ü  A  day  laborer  goes  to  the  ER  for  a  work  related  injury.    ü Working  on  demolishing  a  firing  range  -­‐  lead  level  is  74  mcg/dl  amer  

3  days  on  this  job.  ü  Four  other  workers  tested  between  57  and  98    (all  worked  less                than  2  ½  weeks).  ü  None  had  previously  worked  with  lead.  

Hipkins  KL,  Materna  BL,  Payne  SF,  Kirsch  LC.,  Clin  Pediatri  2004  

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What  should  be  done  next?  

1.  Perform  X-­‐ray  fluorescence  (XFR)  on  workers  to  evaluate  cumulaJve  exposure?  

2.  Inquire  about  use  of  tradiJonal  medicine?  3.  Check  for  use  of  imported  poTery.  4.  Test  the  worker’s  families  for  lead  poisoning?  

 

Pediatric  Environmental  Health  Toolkit  2006  

Greater  Boston  and  San  Francisco  Bay  Area  Physicians  for  Social  Responsibility,  UCSF  Pediatric  Environmental  Health  Specialty  Unit  

 OccupaJonal/Take  Home  Exposures  

ü  9  children  of  three  workers  tested    between  13  and  34  mcg/dl.  (highest  18  month  old)  

ü Wife  of  one  with  symptoms  and  Pb  level  of  36  mcg/dl.  

ü Workers  may  bring  home  hazards  on  clothing,  shoes,  and  body.  

ü  In  2001-­‐2002  year,  22%  of  California  childhood  lead  poisoning  cases  had  potenJal  contribuJon  from  occupaJonal  sources.  

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Early  Life  Lead  Exposure  and  Alzheimer’s  Disease?  (Barker’s  Hypothesis)  

•  Plaque  and  neurofibrillary  tangles  •  B  amyloid  and  APP    make  up  plaques  •  Expression  of  genes  related  to  these  upregulated  by  lead  exposure  in  early  childhood  (10mcg/dl)  

•  MethylaJon  paTerns  altered  •  Monkeys  exposed  to  lead    in  early  life  develop  plaque  and  NFTs  in  old  age  

Wu  et  al.,  J  Neuroscience  08  

Wikipedia  comons  

   Transient  Hypertonia  in  an  Infant  

ü  7lbs.  14  oz.  term  female,  jaundice  peak  bili  12.6  ü  Nl.  PE  at  12  weeks  except  lower  extremity                        

hypertonicity  ü  Pediatric  consult  at  16  weeks  -­‐  upper  and  lower  extremity  

hypertonicity,  ankle  clonus  with  Dx  of  cerebral  palsy  ü  Physical  therapy  begun  ü  No  environmental  hx  was  taken  

Wagner  SL,  Orwick  DL.,  Pediatrics  1994

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Parents  Ask  if  Symptoms  Could  be  Related  to  PesJcide  Spray?  I  Would  Say:  

1.  Yes  2.  No  3.  Maybe  (I  have  no  idea)  4.  Let’s  call  the  NaJonal  PesJcide  

TelecommunicaJons  Network  (800.858.7378)  

•  Diazinon  1%  sprayed  by  unlicensed  pesJcide  applicator  

•  Levels  sJll  high  six  months  amer  spraying    •  Serum  cholinesterase  normal  •  Urine  metabolites  high  –    similar  to  post-­‐shim  urine  of  applicators  

•  Six  weeks  amer  removal  from  house  muscle            tone  returned  to  normal  

 

 Transient  Hypertonia  in  an  Infant  

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Children  aren’t  liTle  adults?  

Developmental  origins  of    health  and  adult  disease  (DOHAD)  

•  Under-­‐nutriJon  in  utero  and  infancy  resulted  in  changes  in  organ  structure,  funcJon,  and  metabolism  that  were  permanent    

•  adult  lipid  profiles  linked  to  high  cholesterol  and  hypertension  

•  Impaired  glucose  regula7on  (insulin  resistance)  

•  Metabolic  syndrome  

Life  course  approach  

Wikipedia  commons  

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Morris  Water  Maze  •  Test  of  memory  and  spaJal  

learning  (adults)  •  LG  babies  do  beTer    

–  Non-­‐LG  babies  raised  by  LG  mom’s  do  beTer  

•  Adults  born  to  mothers  with  prenatal  stress  but  same  post-­‐natal  environment  do  worse  

It  is  a  combinaJon  of  geneJcs  and  pre  /  postnatal    environment  that  determines  funcJon  into  adulthood  

Wikipedia  commons  

low LG and low LG mothers low LG and high LG mothers

Fearful offspring with brisk HPA stress response Less fearful offspring with more modest HPA stress response

EFFECTS OF CROSS-FOSTERING

Slide  courtesy  of  Bob  Wright  –  Mt.  Sinai  NYC  

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GeneJcs  =  Gene  +  Expression  

Wikipedia  commons  

EpigeneRcs  

pup  

DemethylaRon    of  GR  exon  1  

DeacetylaRon  of  histones  around  GR  

Permanent  increase  in  GR  expression  in  hippocampus        

Increased  NGF1-­‐A  acRvity  

hippocampus  

Increased    Serotonin  

tone  

Mother  high  licker  groomer  

Adult     High  hippocampal  GR  levels    

High  licker  groomer  behavior  

exploratory,  less  fearful  and    stress  reacJve  more    cogniJvely  intact  in  old  age.    

Champagne  and  Meany,  Behavioral  Neuroscience  2007  Champagne  et  al.,  Journal  Neuroscience  2008  Zhang  et  al,  Journal  Neuroscience  Sept.  2010  

 

less  methylaJon  GAD1    

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Hippocampus  

Hypothalamus  

Pituitary  

Adrenals  

CRF  

ACTH  

GlucocorJcoids  

GlucocorRcoid  Receptor  

Hippocampus  

Hypothalamus  

Pituitary  

Adrenals  

GlucocorRcoids  

GR  

Impacts  on  HPA  System  Non-­‐licker  groomer          Licker  groomer  

Prenatal  Stress  –  Effects  in  Adult  Female  Offspring  

•  Exposures  – RelaJonship  hardship  (eg.  Divorce)  – Death/severe  illness  of  someone  close  – Severe  financial,  car  accident,  refugee  

•  Impacts  – Altered  HPA  axis  response  (Trier  Social  Stress  and  ACTH  sJmulaJon)  

– Bias  to  Th2,  IL-­‐4,  IFN  –gamma,  IL6,  IL10  producJon  

Entringer  et  al  Dev  Psychobiol    2008  Entringer  et  al  Hormones  and  Behavior,  2009  

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Allostasis  –  acJve  process  for  adaptaJon  (brain  –  body)  

Neuroendocrine  Immune  

Autonomic    biomediators  

Allostasis  

AdaptaRon  

AllostaJc    load  

Costs:  metabolic,  cardiovascular,  immune,  behavioral  dysregulaJon  

Adapted  from  McEwen  and  Gianaros,  2010    

Limbic  PlasJcity  effected  by  •  Parental  resources  •  EducaJon  •  Exposures/nurturance  

Neural  Mediators  of  Resilience  

•  Brain  Derived  Neurotrophic  Factor  (BDNF)  – Necessary  factor  in  plasJcity  – BDNF  low  in  depression  – Elevated  by  fluoxeJne,  regular  physical  acJvity  •  Reopen  windows  of  plasJcity  (stroke  and  depression)  

–  Combined  with  intensive  physiotherapy  or  behavioral  therapy    

Karatsoreos  and  McEwen,  Resilience  and  Vulnerability:  A  neurobiological  perspecJve  F1000  Prime  Reports  2013  hTp://f1000.com/prime/reports/b/5/13    

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Lead/Stress  Act  by  Similar  Mechanisms  effects  addiJve  

•  Learning  and  memory  in  hippocampus  dependant  on  acJvaJon  of  NMDA  glutamate  receptors  

 •  Stress  or  an  environmental  

chemical  (lead)  impact  same  mechanism  

•  Both  lead  and  stress  impact  HPA  axis  

Lead  &  Stress    Potent  inhibitors    

X  

Wikipedia  creaJve  commons/public  domain  Delldot  

Social  Environment  /  chemical  interacRon  

Guilarte    Ann  Neurology  2003  Neal  Neurotoxicology  2011  

Environmental  enrichment  enhances    memory  and  learning  /plasJcity  

•  Early  lead  exposure  results  in  decrease  in  learning,  memory,  NMDA  r  acJvity  (BDNF)  

•  Enriched  environment  reduces  leads  cogniJve  impacts  and  normalizes  NMDA  r  acJvity  (  BDNF)  Guilarte  T,  Ann  Neurology,  2003  

Social  environment,  exploraRon,  play,    spaRal  learning  

Public  domain  wikipedia  

Social  environment  

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“Well,  your  nose  feels  cold”  

Environmental  enrichment  effecJve  in  amelioraJng  neuro-­‐cogniJve  effects  

•  Lead  –  associaJon  cogniJve  deficit  <10mcg/dl  only  in  “less  advantaged”,  >10mcg/dl                  effect  aTenuated  for  “advantaged”*  

•  PCBs  –  (prenatal)  negaJve  effect  only  in  “less  opJmal”  parenJng  and  home  characterisJcs  .  Breas^eeding  protecJve  of  aTenJon  at  school  age.  

•  ETS  –  greatest  cogniJve  effect  in  those  with  “unmet  basic  needs  in  the  areas  of  food,  housing,  and  clothing”    

 Weiss  and  Bellinger,  2006  Rauh  et  al.,  Neurotox  Teratol,  2004  Vreugdenhil  et  al.  EHP  2002  Bellinger,  Neurotox  Teratol,  1988*,  Miranda  et  al.  2008**    Jacobson  and  Jacobson,  2003    

Social  environment  

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AAP  Grand  Rounds  6:16-­‐17  (2001)  ©  2001  American  Academy  of  Pediatrics    

EPIDEMIOLOGY      

Oral  Succimer  for  Lead  ChelaRon  Does  Not  Lead  to  BeQer  

Neuropsychological  Outcomes    (children  with  20  –  45  mcg/dl)  

SOCIAL  ENVIRONMENT  /  CHEMICAL  ENVIRONMENT  INTERACTION  

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Ozone  -­‐  postnatal  exposure  (+/-­‐HDMA)  

•  Results  permanently  alters  bronchioles  (monkeys)  – Fewer  branches  – Longer  – Smaller  diameter  – Altered  muscle      bundle  orientaJon  – Change  in            innervaJon  Plopper  et  al.  2007  

 Community/Home  Violence      Link  to  Decrease  in  Lung      FuncJon  

•  Girls  with  home  conflict    (highest  terJle)  had  >5%  decrease    in  FEV1  and  FVC  (smaller  decrease  in  boys)  •  Boys  with  exposure  to  community  violence  (highest  terJle)  had  >5%  decrease  in  FEV1  and  FVC  –  Independent  of  SES,  SHS,  birth  wt.,  respiratory  illness  history  

Suglia  et  al  2007  PsychosomaJc  Med  

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Asthma  –    neurobiology  underlying  stress  vulnerability  

•  Early  life  adversity  (chronic  stress)  linked  to:  – Disturbed  regulaJon  of  endocrine  and  autonomic  processes  •  HPA  axis;  sympatheJc  adrenal  medulllary  system  

– May  permanently  program  for  exaggerated  stress  reponse  

•  AlteraJons  in  Th1/Th2  balance  •  AlteraJons  in  inflammatory    cytokines,  IgE  

RJ  Wright  Biological  Psychology  2010  Perinatal  stress  and  early  life  programming    of    lung  structure  and  funcJon  

Stress  and  Asthma  Cohort  Study  on  IPV  

•  3,116  parJcipants  enrolled  at  birth  •  Assess  inJmate  partner  violence  impact  on  asthma  Dx  by  36  mos.  

•  IPV  2  fold  increase  •  Maternal  child    acJvity  protects  –  IPV  +  housing    hardship/disarray  addiJve  

0  

0.5  

1  

1.5  

2  

2.5  

3  

RR  asthma  IPV  

overall  IPV  

IPV  +  high  mother-­‐child  acJvity  

IPV  +  low  mother-­‐child  acJvity2  

Suglia  SF  et  al.  Arch  Pediatr  Adolesc  Med.  2009;  Suglia  et  al.  JECM  2009  

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Air  PolluJon  and  Exposure  to  Violence  SynergisJc  Effects  

•  Birth  cohort  N=417  •  NO2  measured      

•  LifeJme  exposure  to  violence  surveyed  – AssociaJon  between  air  polluJon  and  asthma  only  in  those  with  above  median  ETV  

– For  lifeJme  residents  (most  accurate  exposure)      asthma  OR    2.4  (1.48-­‐3.88)  for    higher  air  polluJon  +  ETV  

Clougherty  et  al  EHP  2007:    Shankardas  et  al  PNAS  2009  

Days  exceeding  CA  standards  for  Ozone    (1  hr)  and  PM10  (24  hr)  (South  Coast  air  basin  Data  California  Air  

resources  Board  )  

0  

50  

100  

150  

200  

250  

300  

1990   2000   2010  

Ozone  

PM  10  

6.3%  low  lung  

funcJon   3.6%  low  lung  funcJon  

Gauderman WJ et al. N Engl J Med 2015;372:905-913 USC Children’s Health Study

 

7.8%  low  lung  

funcJon  

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QuarJles  infant  Vmax  at  funcJonal  residual  capacity  

Up  to  14%  of  adult  lung  funcRon  predicted  by  lung  funcRon  at  2-­‐3  mos  Stern  2007  

FEV1/FVC  raRo  

FEF25-­‐75  

FEV1  

A  porJon  of  adult  lung  funcJon  is  set  by  infancy  

Funding  EPA,  ATSDR    

This  material  was  supported  by  the  American  College  of  Medical  Toxicology  (ACMT)  and  funded  (in  part)  by  the  coopera7ve  agreement  FAIN:  U61TS000238  from  the  Agency  for  Toxic  Substances  and  Disease  Registry  (ATSDR).        Acknowledgement:  The  U.S.  Environmental  Protec7on  Agency  (EPA)  supports  the  PEHSU  by  providing  par7al  funding  to  ATSDR  under  Inter-­‐Agency  Agreement  number  DW-­‐75-­‐92301301.  Neither  EPA  nor  ATSDR  endorse  the  purchase  of  any  commercial  products  or  services  men7oned  in  PEHSU  publica7ons  

Western  States  Pediatric  Environmental  Health  Specialty  Unit  

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Children  may  be  canaries  due  to:  

1.  Exposures  may  be  different  or  greater  2.  Physiologic  differences  (pharmacokineJcs)  3.  SensiJve  developmental  windows  

(pharmacodynamics)  4.  All  of  the  above  

Lung  FuncJon  

1.  In  middle  age  is  predicted  in  part  by  childhood  lung  funcJon  

2.  In  adults  is  not  impacted  by  early  life  events  3.  In  children  is  reduced  as  a  result  of  exposure  

to  violence  4.  Exposure  to  stress  plus  air  pollutants  are  

addiJve  factors  for  asthma  risk  in  children  5.  1,3,4  

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CriJcal  Windows  of  Development  Include:  

1.  Time  periods  of  rapid  growth  and  development  such  as  fetus,  infancy,  and  adolescence.  

2.  Periods  in  which  structure  and  funcJon  may  be  programmed  and  impact  adult  disease.  

3.  Times  when  programming  can  result  in  reduced  risks.  

4.  All  of  the  above.