Paul Duckett Brixham Environmental Laboratory Site Manager

A world class environmental testing Laboratory Brixham Environmental Laboratory (BEL), located in Devon, England has for over 60 years provided a specialised service to the chemical industry. The objective of BEL is to deliver fit-for-purpose, cost effective environmental support to industry world-wide, providing assessments of the environmental fate and effects of new and existing products. Key activities at Brixham Environmental Laboratory include the testing and risk assessments required to increase understanding of the environmental impact of AstraZeneca’s Active Pharmaceutical Ingredients (APIs), manufacturing intermediates, processes and effluents, to ensure they meet the required regulatory approval. Brixham Environmental Laboratory provides specialised scientific services to a number of different industry sectors, helping them understand the lifecycle of chemicals in our environment and the impact this has on the ecosystem.

“A wide range of disciplines” Ecotoxicology/Ecology Animal Physiology Biochemistry Microbiology Genomics Mathematical Modelling/Statistics Information Scientists Chemical Engineering 79Full Time Equivalent staff 4 Industrial Trainees 9 Contractors 52% Women 48% Men 80% Approximately are Graduates 40% Approximately have a Post Graduate Qualification World Class Specialists with an innovative approach to Environmental Science

Zebrafish - alternative model for predicting human drug safety Why are we doing this work? Some new drugs have side effects. Many side effects are not detected until late in a drug’s development ~ this is expensive if the drug has to be discontinued. The zebrafish may allow us to detect many of these side effects earlier. This saves time, money, animals and allows earlier prioritization. Valuable attributes: Physiology/development parallels mammals in many areas Whole organism Rapid life cycle and development Transparent embryo/organogenesis Small size ~ multiwell plate in vivo (low compound/space requirements), potential for automation Overall ~ high throughput = more compounds = earlier use in pipeline

Application of Zebrafish in drug development Developmental toxicity Early stage assessment of the potential for chemicals to induce teratogenicity within developing Zebrafish embryo-larvae. Involves multiple endpoint assessment such as major organ morphology, cranial facial defects, abnormal body shape etc. providing a LOEC value in relation to the LC 25. This assay is part of an ongoing, cross-pharmaceutical company ring test (Gustafson et al., 2012, Reproductive Toxicology 33, ). Ototoxicity The lateral line (neuromast) hair cells of the Zebrafish embryo-larvae are used as a surrogate model for mammalian inner-ear hair cells as they respond to ototoxic (hair cell damaging) chemicals in a comparative way. This response can be used as an early screen for assessing this undesirable side effect (Buck et al., 2012, Hearing Research, 284, 67-81). Bioanalysis Assessment of compound uptake into Zebrafish embryo-larvae forms an integral part of many of our assays, and can be critical for interpretation of animals responses to chemical challenge.

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