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1 i.   Origins  of  this  project       Approximately  a  decade  ago,  I  was  contacted  for  the  first  time  by  the  law  offices  of   Stuart  Calwell  to  give  expert  advice  on  the  law  suit  brought  by  the  family  of  Joey  Lee   Walker  (henceforth  the  “Walker  Case”).  The  case,  to  my  recollection,  involved  the   exposure  of  Mr.  Walker  to  unregulated  levels  of  chlorpyrifos  (henceforth  “CPF”),  which   produced  both  acute  and  delayed  pathological  reactions.        The  delayed  ones  including   epileptic  seizures,  and  Mr.  Calwell  wanted  advice  as  to  how  exposure  to  CPF  and  related   organophosphates  could  give  rise  to  delayed  seizures.               Numerous  possible  mechanisms  for  this  connection  exist,  and  my  work,  initially,   consisted  of  a)  outlining  these  mechanisms;;    b)  giving  a  qualitative  assessment  of  how   well  established  they  are  in  basic  and/or  clinical  science;;  c)  outlining  alternative  routes   that  can  give  rise  to  seizure  disorders;;    d)  assessing  the  likelihood  that  those  alternative   routes  occurred  in  the  case  of  Mr.  Walker.       In  addition,  there  was  an  ancillary  issue  as  to  whether  stress  may  have   exacerbated  the  neuropathology  in  Mr.  Walker.        I  evaluated  this  possibility  as  well,  and   concluded  that  it  was  not  very  likely.     In  the  course  of  doing  this  work,  I  was  sent  a  number  of  published  papers  and   internal  reports  from  Dow  scientists  concerning  the  potential  pathological  (particularly   neuropathological)  consequences  of  CPF  exposure.  I  found  these  papers  to  be  of   remarkably  poor  quality  and,  upon  reporting  that  informally,  was  asked  to  more  formally   critique  them  as  part  of  the  Walker  report.  My  overall  assessment  was  that  the  quality  was   so  poor  that  I  would  be  skeptical  about  the  veracity  of  the  contents,  and  of  the  contents  of   any  other  work  produced  by  these  scientists  (including  both  the  direct  bench  scientists   and  the  supervisors  that  signed  off  on  the  reports).  It  should  be  noted  that,  from  the  start,   this  negative  assessment  of  the  quality  of  the  work  and  its  intrinsic  veracity  does  not  imply   any  fraudulence  on  the  part  of  these  scientists.     Similar  work  was  done  in  the  cases  of  Christina  and  Alex  Ebling  (henceforth,  the   “Ebling  Case”).  To  my  recollection,  the  case  involved  two  children  exposed  to  unregulated   levels  of  CPF  who  had  sustained  extensive  neurological  damage.  My  role  was  the  same   in  explaining  the  science  underlying  such  damage.  Again,  my  report  also  included  the   critique  I  had  made  of  the  handful  of  published  and  internal  Dow  reports  regarding  CPF,   with  a  strong  emphasis  on  their  poor  quality.     Around  the  time  of  depositions  in  the  Ebling  case,  the  idea  emerged  among  Mr.   Calwell,  Mr.  Roger  Pardieck,  Ms.  Regan  Quinn  and  myself  to  make  a  more  formal   analysis  of  all  of  the  relevant  papers  published  by  Dow  scientists,  with  the  primary  goal   being  to  determine  whether  the  poor  quality  of  the  handful  already  examined  extended  to   the  entire  body  of  work.  The  expectation  at  the  time  was  that  this  would  involve  hundreds   and  perhaps  thousands  of  papers.  For  that  reason,  from  the  start,  the  idea  included   recruiting  a  team  of  experts  to  carry  out  this  analysis  under  my  supervision.  It  was   eventually  decided  that  this  project  would  be  carried  out. 2   Recruitment  and  selection  of  the  team  of  experts  to  evaluate  papers       A  team  was  recruited  with  the  following  characteristics:       A.  All  members  were  neuroscientists  with  experimental  bench  work  experience.      In   principle,  any  experimental  bench  researcher  working  in  the  life  sciences  (e.g.,  a   hematologist)  could  assess  the  quality  of  the  work,  as  the  errors  were  of  a  type   recognizable  to  any  scientist  in  that  broader  category.  However,  the  process  would  be   slower  and  more  difficult  for  non-­neuroscientists  because  of  the  unfamiliarity  with  the   scientific  content.    The  decision  was  made  not  to  restrict  the  team  to  neurotoxicologists   because  of  the  rarity  of  such  individuals  fitting  the  other  requirements;;  in  fact,  none  were   neurotoxicologists.  Despite  this,  all  neuroscientists  share  a  common  vocabulary  and  core   knowledge  base  which  allows  for  informed  reading  of  papers  in  differing  sub-­disciplines  of   neuroscience.       B.  All  members  were  affiliated  at  the  time  with  Stanford  University.  This  was  for  two   reasons.  The  first  was  because  of  the  convenience  of  working  with  people  at  the  same   institution.  The  second  was  because  of  the  quality  of  scientists,  particularly   neuroscientists,  at  Stanford.      The  team  was  made  up  of  scientists  affiliated  with  the   Neuroscience  Program  and/or  the  Biology  Department.  The  latter  was  ranked  as  the  #1   biology  department  in  the  country  by  U.S.  News  &  World  Report  for  the  majority  of   the  years  that  this  project  was  carried  out;;  this  is  considered  to  be  the  most  visible  and   influential  ranking  system  that  there  is  for  American  colleges  and  universities.  The   Neuroscience  Program  was  rated  in  the  top  5  departments  throughout  this  period,  as  well   as  by  the  Science  Citation  Index  (a  measure  of  the  impact  of  papers  in  their  field,  as   assessed  by  the  frequency  with  which  they  are  cited  subsequently  in  the  work  of  other   scientists).       C.  All  members  were  post-­doctoral  scientists.  Such  scientists  are  individuals  who   have  received  their  PhD’s  and  then  spend  approximately  2-­5  years  training  in  a  different   laboratory.  This  is  meant  to  expand  upon  their  graduate  training,  and  to  prepare  them  for   establishing  an  independent  research  career  of  their  own.  Most  such  post-­docs  occur  in   academia,  while  a  small  percentage  occur  in  industry  (i.e.,  pharmaceutical  and/or  biotech   companies  that  are  typically  large  enough  to  have  basic  science  divisions).      Following  a   successful  post-­doc,  individuals  ideally  then  obtain  a  job  in  academia  (i.e.,  a  faculty   position)  or  industry.  The  decision  was  made  to  recruit  post-­doctoral  scientists  (rather   than  graduate  students  and/or  professors)  for  two  reasons.      First,  the  quality  of  scientific   training  at  the  post-­doctoral  level  is  considerably  higher  than  at  the  graduate  student   level,  and  such  a  level  was  thought  necessary  for  this  project.        Second,  in  contrast  to   most  faculty  members,  post-­doctoral  scientists  are  still  predominately  doing  bench  work   (i.e.,  carrying  out  experiments  on  their  own),  rather  than  supervising  the  work  of  others,   and  this  generally  gives  more  insight  into  small  details  of  scientific  papers.             Individuals  meeting  the  criteria  above  were  excluded  from  the  project  if  a)  they   knew  any  of  the  scientists  whose  papers  were  to  be  critiqued;;  b)  any  laboratory  that  they   had  worked  in  had  been  supported  by  funds  from  Dow  Chemical  or  from  an  affiliate  of   Dow  Chemical;;  c)  if  they  or  family  members  had  any  stocks  in  Dow  Chemical  or  its 3 affiliates;;  d)  if  they  had  been  involved  in  any  related  legal  cases,  including  as  an  expert   witness.         Team  members  were  recruited  in  early  2006  by  sending  an  announcement  through   an  email  list  of  post  doctoral  scientists  at  Stanford.  The  project  was  described  as  involving   critiquing  a  body  of  published  neuroscience  research.  The  announcement  did  not  make   mention  of  Dow,  CPF,  or  organophosphate  pesticides.  The  announcement  did  make   mention  that  this  was  related  to  a  legal  project;;  no  indication  was  made  whether  the  work   would  be  done  for  a  plaintiff  or  a  defendant.      The  announcement  indicated  that  pay  would   be  $50/hour.     Ten  individuals  applied;;  one  was  excluded  because  of  family  investments  in  Dow   Chemical.      In  late  2007,  a  second  team  was  recruited.      This  was  because  of  a  certain   degree  of  attrition  of  the  original  team,  either  because  the  individual,  a)  no  longer  had   time  to  work  on  the  project,  or  b)  had  left  Stanford  to  a  position  elsewhere.      Six   individuals  applied;;  one  was  excluded  because  of  a  history  of  working  in  a  lab  receiving   funding  from  Dow.          A  few  months  later,  an  additional  person  was  added  on  to  pick  up   the  pace  of  the  work.     Appendix  I  consists  of  the  CV’s  of  these  15  individuals  at  the  time  of  their   recruitment.    Individuals  had  degrees  from  universities  such  as  Cornell,  Harvard,   Stanford,  U.C.  Berkeley,  U.  Pennsylvania  and  Yale.    Collectively,  team  members  had   published  more  than  100  papers  reporting  experimental  research  in  peer-­reviewed   English  language  scientific  journals  (excluding  book  chapters  and  reviews);;  this   represents  a  high  level  of  productivity  for  neuroscientists  at  this  stage  of  training. 4   Establishing  quality  control  prior  to  data  generation       The  broad  goal  was  for  the  team  to  read  and  critique  papers  by  Dow  scientists   concerning  CPF,  along  with  a  number  of  types  of  control  papers  (described  below).         Quality  control  was  established  before  analysis  began  (with  additional  features  added   once  data  were  generated).      These  included:       a.  Each  paper  was  to  be  analyzed  by  two  members  of  the  team.       b.  Members  were  instructed  not  to  discuss  papers  with  any  other  team  members.       c.  The  data  base  of  evaluations  was  not  accessible  to  any  team  members  (i.e.,   they  could  input  data  but  could  not  see  reports  of  other  individuals).       An  extensive  section  after  the  Results  discusses  additional  quality  controls  in  this   study. 5   Identification  of  the  chlorpyrifos  papers  by  Dow  scientists  to  be  analyzed        Relevant  papers  were  searched  for  on  “PubMed,”  which  is  the  most  commonly   used  search  engine  for  biomedical  and  life  science  papers  published  in  professional   journals,  with  more  than  10  million  papers  accessible  from  it.  A  search  was  carried  out   with  the  search  terms  “Dow”  and  “chlorpyrifos.”  A  total  of  46  papers  were  identified.  Six   were  eliminated,  as  they  turned  out  not  to  be  by  Dow  authors.     An  additional  21  papers  were  eliminated  as  they  were  not  relevant  to  the  analysis.         This  was  because  they  were  a)  purely  methodological  in  nature;;  b)  about  non-­mammalian   species;;  c)  about  agricultural  issues,  such  as  levels  of  chlorpyrifos  residues  in  soil  or  food;;   d)  merely  an  abstract.  These  21  were:       a.   A  total  of  11  papers  were  eliminated  because  they  were  purely   methodological  (e.g.,  describing  an  improved  or  less  expensive  technique  for  measuring   chlorpyrifos  breakdown  products  in  the  urine,  a  new  statistical  method  for  analyzing   epidemiological  data,  a  way  of  assessing  the  accuracy  of  estimates  of  occupational   pesticide  exposure,  a  theoretical  model  for  analyzing  exposure  to  a  pesticide).      Neither   the  content  nor  the  quality  of  such  papers  would  be  directly  relevant  to  issues  of  the   extent  of  CPF  neurotoxicity.          These  papers  were:       Aggregate  exposures  under  the  Food  Quality  Protection  Act:  An  approach  using   chlorpyrifos.  Shurdut  BA,  Barraj  L,  Francis  M.  Regul  Toxicol  Pharmacol.  1998   Oct;;28(2):165-­77.  Review.  PMID:  9927565  [PubMed  -­  indexed  for  MEDLINE]   Analysis  of  3,5,6-­trichloropyridinol  in  human  urine  using  negative-­ion  chemical   ionization  gas  chromatography-­mass  spectrometry.  Bartels  MJ,  Kastl  PE.  J  Chromatogr.   1992  Mar  13;;575(1):69-­74.  PMID:  1517302  [PubMed  -­  indexed  for  MEDLINE]   On-­line  coupling  of  supercritical  fluid  extraction  with  multidimensional  microcolumn   liquid  chromatography/gas  chromatography.  Cortes  HJ,  Green  LS,  Campbell  RM.  Anal   Chem.  1991  Dec  1;;63(23):2719-­24.  PMID:  1722652  [PubMed  -­  indexed  for  MEDLINE]   Semiautomated  preparation  of  3,5,6-­trichloro-­2-­pyridinol  in  human  urine  using  a   Zymate  XP  laboratory  robot  with  quantitative  determination  by  gas  chromatography-­ negative-­ion  chemical  ionization  mass  spectrometry.  Ormand  JR,  McNett  DA,  Bartels  MJ.   J  Anal  Toxicol.  1999  Jan-­Feb;;23(1):35-­40.  PMID:  10022207  [PubMed  -­  indexed  for   MEDLINE]   Exposure  endpoint  selection  in  acute  dietary  risk  assessment.  Wolt  JD.  Regul   Toxicol  Pharmacol.  1999  Jun;;29(3):279-­86.  PMID:  10388613  [PubMed  -­  indexed  for   MEDLINE]   Practical  immunochemical  method  for  determination  of  3,5,  6-­trichloro-­2-­pyridinol   in  human  urine:  applications  and  considerations  for  exposure  assessment.  Shackelford   DD,  Young  DL,  Mihaliak  CA,  Shurdut  BA,  Itak  JA.  J  Agric  Food  Chem.  1999   Jan;;47(1):177-­82.  PMID:  10563869  [PubMed  -­  indexed  for  MEDLINE]   Refinements  in  acute  dietary  exposure  assessments  for  chlorpyrifos.  Wright  JP,   Shaw  MC,  Keeler  LC.  J  Agric  Food  Chem.  2002  Jan  2;;50(1):235-­41.  PMID:  11754574   [PubMed  -­  indexed  for  MEDLINE] 6 Strategies  to  assess  systemic  exposure  of  chemicals  in  subchronic/chronic  diet   and  drinking  water  studies.  Saghir  SA,  Mendrala  AL,  Bartels  MJ,  Day  SJ,  Hansen  SC,   Sushynski  JM,  Bus  JS.  Toxicol  Appl  Pharmacol.  2006  Mar  15;;211(3):245-­60.  Epub  2005   Jul  22.  PMID:  16040073  [PubMed  -­  indexed  for  MEDLINE]   Human  red  blood  cell  acetylcholinesterase  inhibition  as  the  appropriate  and   conservative  surrogate  endpoint  for  establishing  chlorpyrifos  reference  dose.    Chen  WL,   Sheets  JJ,  Nolan  RJ,  Mattsson  JL.      Regul  Toxicol  Pharmacol.  1999  Feb;;29(1):15-­22.   Review.    PMID:  10051415  [PubMed  -­  indexed  for  MEDLINE]   The  effect  of  route,  vehicle,  and  divided  doses  on  the  pharmacokinetics  of   chlorpyrifos  and  its  metabolite  trichloropyridinol  in  neonatal  Sprague-­Dawley  rats.  Marty   MS,  Domoradzki  JY,  Hansen  SC,  Timchalk  C,  Bartels  MJ,  Mattsson  JL.  Toxicol  Sci.  2007   Dec;;100(2):360-­73.  Epub  2007  Oct  10.  PMID:  17928393  [PubMed  -­  indexed  for   MEDLINE]   Chlorpyrifos  exposure  and  biological  monitoring  among  manufacturing  workers.   Burns  CJ,  Garabrant  D,  Albers  JW,  Berent  S,  Giordani  B,  Haidar  S,  Garrison  R,   Richardson  RJ.  Occup  Environ  Med.  2006  Mar;;63(3):218-­20.  PMID:  16497866  [PubMed  -­   indexed  for  MEDLINE]     b.  A  total  of  five  papers  were  eliminated  because  they  were  concerned  with   chlorpyrifos  effects  on  non-­mammalian  species  (fish,  insects  or  shellfish).      While  such   studies  are  of  relevance  to  issues  of  agriculture  and  aquaculture,  they  are  only  distantly   related  to  the  core  issues  of  CPF  effects  on  mammalian  physiology.      These  papers  were:     Evidence  for  negative  cross  resistance  to  insecticides  in  field  collected  Spodoptera   littoralis  (Boisd.)  from  Lebanon  in  laboratory  bioassays.  Miles  M,  Lysandrou  M.  Meded   Rijksuniv  Gent  Fak  Landbouwkd  Toegep  Biol  Wet.  2002;;67(3):665-­9.  PMID:  12696435   [PubMed  -­  indexed  for  MEDLINE]   The  bioconcentration  and  metabolism  of  chlorpyrifos  by  the  eastern  oyster,   Crassostrea  virginica.  Woodburn  KB,  Hansen  SC,  Roth  GA,  Strauss  K.  Environ  Toxicol   Chem.  2003  Feb;;22(2):276-­84.  PMID:  12558158  [PubMed  -­  indexed  for  MEDLINE]   An  ecological  risk  assessment  for  chlorpyrifos  in  an  agriculturally  dominated   tributary  of  the  San  Joaquin  River.  Poletika  NN,  Woodburn  KB,  Henry  KS.  Risk  Anal.   2002  Apr;;22(2):291-­308.  PMID:  12022677  [PubMed  -­  indexed  for  MEDLINE]   Hansen  SC,  Roth  GA,  Strauss  K.  The  bioconcentration  and  metabolism  of   chlorpyrifos  by  the  eastern  oyster,  Crassostrea  virginica.    Environ  Toxicol  Chem.  2003   Feb;;22(2):276-­84.      PMID:  12558158  [PubMed     Barron  MG,  Plakas  SM,  Wilga  PC.    Chlorpyrifos  pharmacokinetics  and  metabolism   following  intravascular  and  dietary  administration  in  channel  catfish.    Toxicol  Appl   Pharmacol.  1991  May;;108(3):474-­82.    PMID:  1708533  [PubMed  –  indexedkljlkj\     c.  One  paper  was  eliminated  because  it  was  merely  an  abstract  (i.e.,  not  a  full-­ length,  peer-­reviewed  paper).      The  paper  was:     Chlorpyrifos  (Dursban)  and  Dow  employees.  Sherman  JD.  Environ  Health   Perspect.  1999  Mar;;107(3):A132-­4.  No  abstract  available.  PMID:  10391732  [PubMed  -­   indexed  for  MEDLINE] 7   d.  Four  papers  were  eliminated  because  they  focused  on  quantities  of  CPF  residue   in  soil  or  food,  or  the  effects  of  food  processing  techniques  on  quantities  of  residues.       Such  studies  would  be  pertinent  to  determining  the  amount  of  CPF  people  might  be   exposed  to  from  particular  food  sources,  but  are  not  relevant  to  issues  of  the  physiological   and  pathophysiological  effects  of  CPF  in  the  body.        These  papers  were:     Stability  of  chlorpyrifos  for  termiticidal  control  in  six  Australian  soils.  Murray  RT,   von  Stein  C,  Kennedy  IR,  Sanchez-­Bayo  F.  J  Agric  Food  Chem.  2001  Jun;;49(6):2844-­7.   PMID:  11409976  [PubMed  -­  indexed  for  MEDLINE]   Determining  kinetic  and  nonequilibrium  sorption  behavior  for  chlopyrifos  using  a   hybrid  batch/column  experiment.  Cryer  SA.  J  Agric  Food  Chem.  2005  May   18;;53(10):4103-­9.  PMID:  15884846  [PubMed  -­  indexed  for  MEDLINE]   The  effect  of  cooking  on  chlorpyrifos  and  3,5,6-­trichloro-­2-­pyridinol  levels  in   chlorpyrifos-­fortified  produce  for  use  in  refining  dietary  exposure.  Byrne  SL,  Pinkerton  SL.   J  Agric  Food  Chem.  2004  Dec  15;;52(25):7567-­73.  PMID:  15675805  [PubMed  -­  indexed   for  MEDLINE]   U.S.  market  basket  study  to  determine  residues  of  the  i  nsecticide  chlorpyrifos.   Bolles  HG,  Dixon-­White  HE,  Peterson  RK,  Tomerlin  JR,  Day  EW  Jr,  Oliver  GR.  J  Agric   Food  Chem.  1999  May;;47(5):1817-­22.  PMID:  10552457  [PubMed  -­  indexed  for   MEDLINE]       Of  the  remaining  papers,  nine  were  identified  as  the  “core”  literature.  They  had   the  following  characteristics:    a)  study  subjects  were  mammals  (rats,  mice,  rabbits);;  b)  the   studies  were  experimental  in  nature  (i.e.,  where  subjects  were  exposed  experimentally  to   CPF,  and  endpoints  were  then  measured;;  c)  endpoints  were  physiological  or  behavioral.   d)  the  structures  of  the  experiments  were  such  that  the  paper  gave  insight  as  to  the  safety   of  CPF.     The  nine  papers  were:     #1.  Deacon  MM,  Murray  JS,  Pilny  MK,  Rao  KS,  Dittenber  DA,  Hanley  TR  Jr,  John   JA.    Embryotoxicity  and  fetotoxicity  of  orally  administered  chlorpyrifos  in  mice.     Toxicol  Appl  Pharmacol.  1980  Jun  15;;54(1):31-­40.  No  abstract  available.    PMID:  6156524   [PubMed  -­  indexed  for  MEDLINE]     #2.  Maurissen  JP,  Hoberman  AM,  Garman  RH,  Hanley  TR  Jr.  Lack  of  selective   developmental  neurotoxicity  in  rat  pups  from  dams  treated  by  gavage  with   chlorpyrifos.  Toxicol  Sci.  2000  Oct;;57(2):250-­63.  PMID:  11006355  [PubMed  -­  indexed   for  MEDLINE]     #3.  Maurissen  JP,  Shankar  MR,  Mattsson  JL.  Chlorpyrifos:  lack  of  cognitive   effects  in  adult  Long-­Evans  rats.  Neurotoxicol  Teratol.  2000  Mar-­Apr;;22(2):237-­46.   PMID:  10758353  [PubMed  -­  indexed  for  MEDLINE] 8 #4.  Yano  BL,  Young  JT,  Mattsson  JL.  Lack  of  carcinogenicity  of  chlorpyrifos   insecticide  in  a  high-­dose,  2-­year  dietary  toxicity  study  in  Fischer  344  rats.  Toxicol  Sci.   2000  Jan;;53(1):135-­44.  PMID:  10653531  [PubMed  -­  indexed  for  MEDLINE]     #5.  Hanley  TR  Jr,  Carney  EW,  Johnson  EM.  Developmental  toxicity  studies  in  rats   and  rabbits  with  3,5,6-­trichloro-­2-­pyridinol,  the  major  metabolite  of  chlorpyrifos.  Toxicol   Sci.  2000  Jan;;53(1):100-­8.  PMID:  10653527  [PubMed  -­  indexed  for  MEDLINE]     #6.  Mattsson  JL,  Wilmer  JW,  Shankar  MR,  Berdasco  NM,  Crissman  JW,   Maurissen  JP,  Bond  DM.  Single-­dose  and  13-­week  repeated-­dose  neurotoxicity   screening  studies  of  chlorpyrifos  insecticide.  Food  Chem  Toxicol.  1996  Apr;;34(4):393-­ 405.  PMID:  8641666  [PubMed  -­  indexed  for  MEDLINE]     #7.  Breslin  WJ,  Liberacki  AB,  Dittenber  DA,  Quast  JF.  Evaluation  of  the   developmental  and  reproductive  toxicity  of  chlorpyrifos  in  the  rat.  Fundam  Appl  Toxicol.   1996  Jan;;29(1):119-­30.  PMID:  8838647  [PubMed  -­  indexed  for  MEDLINE]     #8.  Gollapudi  BB,  Mendrala  AL,  Linscombe  VA.  Evaluation  of  the  genetic  toxicity  of   the  organophosphate  insecticide  chlorpyrifos.  Mutat  Res.  1995  Mar;;342(1-­2):25-­36.   PMID:  7533892  [PubMed  -­  indexed  for  MEDLINE]     #9.  Corley  RA,  Calhoun  LL,  Dittenber  DA,  Lomax  LG,  Landry  TD.  Chlorpyrifos:  a   13-­week  nose-­only  vapor  inhalation  study  in  Fischer  344  rats.  Fundam  Appl  Toxicol.  1989   Oct;;13(3):616-­8.  PMID:  2482212  [PubMed  -­  indexed  for  MEDLINE]     Henceforth,  throughout  this  report,  these  will  be  referred  to  as  the  “core”   Dow  CPF  papers.     The  remaining  10  papers  were  identified  as  the  “secondary”  set  of  papers.    All  of   were  capable  of  producing  results  pertinent  to  the  safety  of  CPF.      They  were  either:       A.    Epidemiological  (i.e.,  the  relationship  between  spontaneous  patterns  of  disease   and  of  CPF  exposure  in  populations  of  humans).    These  were  not  included  in  the  core  set   of  papers  because  of  the  non-­experimental  nature  of  the  studies  (i.e.,  in  contrast  to  the   studies  with  animals  in  which  there  was  intentional  exposure  to  CPF).        The  nature  of  the   errors  detected  in  the  initial  set  of  Dow  papers  was  mostly  intrinsic  to  experimental   studies.         B.    Concerned  with  pharmacodynamics  of  CPF  (i.e.,  the  dynamics  of  how  it   distributes  in  various  compartments  in  the  body).      These  were  not  included  in  the  core   set  of  papers  because  they  did  not  concern  whether  CPF  had  an  adverse  effect  on  the   body.      Instead,  they  concerned  the  time  course  of  CPF  presence  in  the  body.           C.    Concerned  with  the  effects  of  CPF  on  cholinesterases.    This  differs  from  the   “core”  set  of  papers.      In  that  group,  it  is  not  known  if  CPF  causes  toxicity,  and  the  studies   are  meant  to  determine  that.      In  this  category,  inhibition  of  cholinesterases  is  the  defining   action  of  CPF  and  is  not  in  question;;  these  papers  look  at  the  effects  of  CPF  on  different 9 cholinesterases  in  the  body,  determining,  for  example,  whether  they  are  all  inhibited  by   CPF  to  the  same  extent.     a.  Papers  (total  of    5)  that  were  epidemiological  in  nature:     Albers  JW,  Garabrant  DH,  Mattsson  JL,  Burns  CJ,  Cohen  SS,  Sima  C,  Garrison   RP,  Richardson  RJ,  Berent  S.    Dose-­effect  analyses  of  occupational  chlorpyrifos   exposure  and  peripheral  nerve  electrophysiology.    Toxicol  Sci.  2007  May;;97(1):196-­204.   Epub  2007  Feb  PMID:  17324952  [PubMed  -­  indexed  for  MEDLINE]     Brenner  FE,  Bond  GG,  McLaren  EA,  Green  S,  Cook  RR.  Morbidity  among   employees  engaged  in  the  manufacture  or  formulation  of  chlorpyrifos.  Br  J  Ind  Med.  1989   Feb;;46(2):133-­7.  PMID:  2466478  [PubMed  -­  indexed  for  MEDLINE]     Byrne  SL,  Shurdut  BA,  Saunders  DG.  Potential  chlorpyrifos  exposure  to  residents   following  standard  crack  and  crevice  treatment.  Environ  Health  Perspect.  1998   Nov;;106(11):725-­31.  PMID:  9799188  [PubMed  -­  indexed  for  MEDLINE]     Burns  CJ,  Cartmill  JB,  Powers  BS,  Lee  MK.  Update  of  the  morbidity  experience  of   employees  potentially  exposed  to  chlorpyrifos.  Occup  Environ  Med.  1998  Jan;;55(1):65-­ 70.  PMID:  9536166  [PubMed  -­  indexed  for  MEDLINE]     Gibson  JE,  Peterson  RK,  Shurdut  BA.  Human  exposure  and  risk  from  indoor  use   of  chlorpyrifos.  Environ  Health  Perspect.  1998  Jun;;106(6):303-­6.  Review.  PMID:  9618344   [PubMed  -­  indexed  for  MEDLINE]     b.  Pharmacodynamics  papers  (total  of  2):     Brzak  KA,  Harms  DW,  Bartels  MJ,  Nolan  RJ.  Determination  of  chlorpyrifos,   chlorpyrifos  oxon,  and  3,5,6-­trichloro-­2-­pyridinol  in  rat  and  human  blood.    J  Anal  Toxicol.   1998  May-­Jun;;22(3):203-­10.      PMID:  9602936  [PubMed  –     Nolan  RJ,  Rick  DL,  Freshour  NL,  Saunders  JH.    Chlorpyrifos:  pharmacokinetics  in   human  volunteers.    Toxicol  Appl  Pharmacol.  1984  Mar  30;;73(1):8-­15.    PMID:  6200956   [PubMed  -­  indexed  for  MEDLINE]     c.  Papers  (total  of  3)  concerned  with  cholinesterase  as  an  endpoint:     Marable  BR,  Maurissen  JP,  Mattsson  JL,  Billington  R.    Differential  sensitivity  of   blood,  peripheral,  and  central  cholinesterases  in  beagle  dogs  following  dietary  exposure   to  chlorpyrifos.    Regul  Toxicol  Pharmacol.  2007  Apr;;47(3):240-­8.  Epub  2006  Dec  PMID:   17141929  [PubMed  -­  indexed  for  MEDLINE]     Mattsson  JL,  Maurissen  JP,  Nolan  RJ,  Brzak  KA.    Lack  of  differential  sensitivity  to   cholinesterase  inhibition  in  fetuses  and  neonates  compared  to  dams  treated  perinatally   with  chlorpyrifos.    Toxicol  Sci.  2000  Feb;;53(2):438-­46.    PMID:  10696792 10 Mattsson  JL,  Holden  L,  Eisenbrandt  DL,  Gibson  JE.    Reanalysis  with  optimized   power  of  red  blood  cell  acetylcholinesterase  activity  from  a  1-­year  dietary  treatment  of   dogs  to  chlorpyrifos.    Toxicology.  2001  Mar  7;;160(1-­3):155-­64.    PMID:  11246135     The  initial  wave  of  analyses  was  done  on  a)  the  “core”  9  papers,  and  b)  the   core  plus  the  10  “secondary”  papers.

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Stability of chlorpyrifos for termiticidal control in six Australian soils. Murray RT, effects in adult Long-Evans rats power of red blood cell acetylcholinesterase activity from a 1-year dietary treatment of dogs to .. in levels of acetylcholine-esterase (“ChE,” a key enzyme in the brain) in
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