144x Filetype PPT File size 0.49 MB Source: www.toxicology.org
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
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