Do  animal  models  provide  a  sufficient  basis  for  presump5on  of  toxicity  in  safety  tes5ng?  

Applica5on  of  human  cell-­‐based  assays  in  toxicity  tes5ng    

≠  

Severe  blunt  trauma  (n=167:  up  to  28  days)  (4,389  gene  changes  >  2fold)  Burn  injury  (n=244:  up  to  1  year)  (2,251  gene  changes  >  2fold)      Low  dose  bacterial  endotoxin  (n=4:  24  h)  (2,251  gene  changes  >  2fold)  

Correlation of Gene Expression Changes Among Human Burn, Trauma and Endotoxin and the Corresponding Mouse Models

Seok,  J.  et  al.  PNAS  110:  3507,  2013  

28 12

86

322

MOUSE (2527)

HUMAN (554)

2091

RAT (772)

410

418

Total  number  of  mouse,  rat  and  human  orthologs  differen5ally  expressed  at  least  at  one  5me-­‐point  during  a  24  hour  5me-­‐course  in  response  to  TCDD  treatment  of  purified  primary  B  cells.  

Nature  515:346,  2014  

“… essen5ally  all  models  are  wrong  but  some  are  useful.”    George  E.P.  Box  

Path  forward  

•    Employment  of  human  cells  and  5ssues,  when  possible,  as  an  adjunct  to  animal  tes5ng  

•    Development  of  human  synthe5c  in  vitro  models  

•    Con5nue  to  acquire  new  genomic  informa5on  

Animal  models,  especially  rodents,  may  be  poor  surrogates  of  human  biological  responses  to  exogenous  s5muli.