Background and Stage-Setting
      •  I spent 18 yrs at NIEHS doing male reproductive tox, developing 
         methods in primary cell culture, running a lab and overseeing contract 
         studies. 
      •  Been at Pfizer for 9 yrs now, in a lab which develops in vitro predictive 
         assays and troubleshoots DART issues. 
      •  I am a very strong advocate of and believer in a future for toxicology 
         based increasingly on measuring biochemical and genomic responses in 
         cells in culture, and in computational modeling of complex systems. 
      •  My comments will come mostly from the pharma perspective, we’ll 
         spend less time on environmental chemicals. 
      What are the motivations to get safety right?
      •  Chasing positives:
          – The more specific and beneficial our meds can be, the more people will be helped 
             by them.
          – Safer meds have an easier time finding a new indication.
          – Safer and more specific pesticides (“plant protection agents”) will provide more 
             food for a hungry world with less environmental damage
      •  Avoiding negatives
          – Every adverse effect is undesired
          – No one wants them; toll of human suffering, etc
      Safety Assessment
      •  Current state: We give animals more and more of a compound and 
         watch what goes wrong. We then examine the low end of the dose-
         response curve and extrapolate that to humans based on experience and 
         some “safety factors”. It’s certainly not perfect, but it’s worked pretty 
         well (we think).
      •  “Alternative models” are cell culture or tissue culture methods (or any 
         other method) which reduce the numbers of animals treated with 
         toxicants. 
      Alternatives going mainstream:
      •  Future state: as laid out in the NAS book “Toxicity Testing in the 21st 
         Century”.  Focused on cell culture (with human cells) and progressively 
         more computational predictions. 
      •  We’ll use the term “predictive model”. This  can be
          – a well-characterized cell culture system whose data are massaged a certain way to 
             give a prediction of toxicity
          – A combination of different kinds of data from cell cultures which, when combined 
             using a certain statistical method, yields an estimate of the in vivo activity of 
             this compound
          – A combination of different computer programs (each of which predicts different things) 
             which together predict the in vivo toxicity of an exposure
  Historically
  Safety assessors have relied on animals because
    – Assumptions of relevance based on conserved evolutionary features
    – Have integrated ADME (absorption, distribution, metabolism, and 
     excretion)
    – Have integrated physiology that allows for recovery and adaptation
    – All target tissues are there in the relevant milieus
    – The target tissues have all the appropriate cells there in the right 
     configuration