Repeated-dose 90-day Oral Toxicity Studies on Whole ... - Europabio

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1. Defining toxicologically relevant differences (continued) • Identifying a toxicologically-relevant difference for individual endpoints in isolation is very difficult, especially when there is no evidence of adverse changes in related parameters. • However, to perform power calculations, relevant effect sizes must be defined. • EFSA guidance acknowledges that this is no easy task, and does not provide specific guidance in this respect. • To determine endpoints and effect sizes with the greatest potential to identify toxicity, EuropaBio toxicologists examined numerous guidance documents. • Guidance documents on determining a Maximum Tolerated Dose (MTD) provided definitive endpoints and effect sizes. 12
1. Endpoints and effect sizes Endpoint Change relative to control Body weight Decrease 10% Liver weight Increase 25% Kidney weight Increase 25% Leukocyte count Decrease/increase 30% Lymphocyte count Decrease/increase 30% Cholesterol Increase 200% Blood urea nitrogen Increase 50% Creatinine Increase 50% Alkaline phosphatase Increase 200% (Foster, 2002; EPA, 2002; EPA, 2003; Rhomberg et al., 2007). 13
Page 1 and 2: Repeated-d
Page 3 and 4: Existing safety data and the weight
Page 5 and 6: Hazard Identification and multiple
Page 7 and 8: Section summary • EuropaBio Membe
Page 9 and 10: Part 1: Study design and conduct 9
Page 11: 1. Defining toxicologically relevan
Page 15 and 16: 1. Toxicological endpoints for powe
Page 17 and 18: 2. Experimental design • EFSA gui
Page 19 and 20: 2. Experimental design (continued)
Page 21 and 22: 2. Section summary/discussion • E
Page 23 and 24: 3. Group or single housing (continu
Page 27 and 28: 4. Endpoints and effect sizes Endpo
Page 29 and 30: 4. Average coefficients of variatio
Page 31 and 32: 4. Analysis details • For the 3-t
Page 33 and 34: 4. Results 1 animal/cage, 3 treatme
Page 35 and 36: 4. Results 2 animals/cage, 3 treatm
Page 37 and 38: 4. Provisos for power analyses •
Page 39 and 40: 4. Should males and females be anal
Page 41 and 42: Part 2: Study analysis and interpre
Page 43 and 44: 1. Toxicological interpretation •
Page 45 and 46: 2. Presentation of results on the s
Page 49 and 50: 3. Summary statistics and raw analy
Page 51 and 52: 3. Section summary/discussion • P
Page 53 and 54: References • EFSA. 2011c. Guidanc
Page 55 and 56: References • WHO. 2003. GEMS/FOOD

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