Challenges of 21 st Century Toxicology

Transcription

1 Challenges of 21 st Century Toxicology Toxicology and Mathematical Modelling 2 nd March 2012 Cameron MacKay Unilever Safety and Environmental Assurance Centre

2 What is Unilever? Consumer goods company Unilever s portfolio of categories 2bn consumers worldwide use a Unilever product on any day Products sold in more than 180 countries Personal Care Homecare Ice Cream & Beverages Savoury, Dressings & Spreads Brands

3 What is? We provide the scientific evidence and expertise so that Unilever can identify and manage: Risks for consumers, workers and environment Safety of products and supply chain technology Risk is the chance of an adverse outcome Environmental impacts Sustainability an adverse of Unilever s health or environmental brands, products effect & supply chain

4 Terminology: Risk, Hazard & Exposure Hazard: the list of adverse effects a chemical is known to induce (e.g. irritant, corrosive) Hazard characterisation: a dose response relationship of the chemical to the adverse effect (LOEL, NOAEL, BmD) Exposure: The amount of chemical the consumer is exposed to (mg/kg/day, ug/cm 2, mm, mg/m3) Safety decisions are based on Risk: usually the ratio of the Effect level to the Exposure level P(Adverse Event Occurring Exposure level, Effect level)

5 All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy. Paracelsus ( )

6 Toxicology: Risk Assessment Strategy Tox Endpoint Skin Sensitisation NOAEL Carcinogenicity Systemic Tox NOAEL

7 Where s the maths? Tox Endpoint Skin Sensitisation Carcinogenicity Systemic Tox Data-driven models of hazard (Q)uantitative (S)tructural (A)ctivity (R)elationships Similar chemicals => similar activity Structures quantified properties Regression models Predictors: chemical properties Response: biological activity Biological activity: concentration required to give a certain response EC50: conc. that gives 50% effect

8 Where s the maths? Dose-Response Modelling Determine the adverse effect level (+ uncertainty) Regression modelling Effects: continuous, categorical, present/absent

9 Where s the maths? Physiologically Based Pharmacokinetic Models (PBPK) / Toxicokinetics Prediction of concentration at target: Blood / Organ / Intracellular Ordinary differential equation models State variables are ingredient/drug concentrations Determine bioavailability and species extrapolation

10 Toxicology: where s the challenge?

11 Current Challenges 1. What are the sequence of events leading to an adverse effect? Modification of skin proteins allergic contact dermatitis DNA damage perturbation of p53 pathway cancer???? mitochondrial toxicity myopathy & pancreatitis

12 Current Challenges 2. When we understand the sequence of events can we use in vitro models (receptor occupancy, cellular responses) mathematical modelling (systems biology, organ models) to link dose responses across scales of biological organisation

13 Current Challenges For known toxins and adverse outcome pathways we can pick a few case studies and make a start on linking levels together e.g. modelling of p53 and the skin allergy response The majority of the time we will not know the sequence of events

14 Current Challenges What can be done if we don t know the sequence of events? Need to appeal to knowledge of the exposure and chemistry A = some measure of activity for an ingredient across space of receptors Obtained from chemical structure or in vitro assays C = concentration at the target site Obtained from PBPK models E = the presence or absence of a pharmacological effect Ideally in humans from clinical studies, possibly adverse events data Use the above to calculate P(E A, C) Vary chemical/dose to ensure the probability remains acceptably small

15 Summary Toxicology risk assessment has focused on apical endpoints measured in experimental animals at high doses extrapolation of effect levels in these tests to humans comparison of extrapolated effect level to human exposure indirect estimates of risk (ratio of effect level to exposure) deterministic output with systematic bias NOAEL

16 Summary Future Challenges 1. Understanding the mechanisms of toxicity from molecular initiating event to adverse effect 2. When the sequence is known, using in vitro and math models to link dose responses across biological scales 3. When the sequence is unknown, being able to say something about P(adverse effect exposure, activity) based on human data