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The Ramazzini Institute Integrated Experimental Design

The Ramazzini Institute Integrated Experimental Design. Fabiana Manservisi. Cesare Maltoni Cancer Research Center. Annual Ramazzini Days. Carpi, October 28th, 2016. Current guidelines. 2. Background: chronic toxicity/carcinogenicity.

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The Ramazzini Institute Integrated Experimental Design

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  1. The Ramazzini Institute Integrated Experimental Design Fabiana Manservisi Cesare Maltoni CancerResearch Center Annual Ramazzini Days Carpi, October 28th, 2016

  2. Current guidelines 2

  3. Background: chronic toxicity/carcinogenicity • OECD TG 453 “Chronic toxicity/carcinogenicity” (OECD, 2009) : the objective is to characterize both the toxicological response and the carcinogenic potential of a substance. • In utero exposure is not involved • Study is terminated after 2 years (104 weeks) of exposure • NTP 2-year bioassay (NTP, 2011) : the aim is to determine the toxicologic and/or carcinogenic effects of long-term exposure on rats and mice. For some test articles, rats are exposed during the perinatal phase (starting from GD 6). • Study is terminated after 2 years (104 weeks) of exposure

  4. Background: reproductive/developmental toxicity • OECD TG 416 “two generation toxicity study”(OECD, 2001):rats belonging to F0, F1 and F2 generations are all monitored for reproductive parameters. • High number of animals used (∼2600 rats) • Developmental neurotoxicity and immunotoxicity endpoints are not evaluated • OECD TG 443 “Extended One-generation Reproductive Toxicity Study” (OECD, 2012) : toxicity is tested across life-stages investigating simultaneously parameters for developmental reproductive toxicity, neurotoxicity and immunotoxicity. • F2 generation can be waived • NTP's Modified One-Generation (MOG) Reproduction Study (NTP, 2011): information on the effects of agents on prenatal and postnatal development, and reproduction. • Not included in the regulatory information requirements of REACH

  5. The RI integrated experimental design 5

  6. Integrated approach • Carcinogenicity, toxicity and reproductive/developmental toxicity endpoints are investigated in a single protocol, with animals of the same generation, exploring windows of susceptibility that are currently not addressed in the other guidelines design.

  7. Toxicity/Carcinogenicity study • The RI protocol includes: prolonged period of exposure/observation of experimental animals, starting exposures from the gestation and continuing through lactation and weaning until at least 130 weeks or longer

  8. Reproductive/Developmental toxicity • The Reproductive/Developmental Toxicity arm mimics human exposure during critical windows of susceptibility (WOS) for the development

  9. Number of animals • Our integrated experimental protocol requires 1720 animals for each tested compound, • Multiple toxicological endpoints together are investigated, sparing animal lives in accordance with the 3Rs rule • Reduction up to 53% in animal use as compared to using separate test protocols, • * Considering 15pups/litter in F2 generation (OECD TG 443 generates F2 only if triggered, while NTP MOG and RI include F2 generation by default)

  10. Advantages of the RI proposal • Carcinogenicity, toxicity and reproductive/developmental toxicity endpoints are investigated in a single protocol • Windows of susceptibility • Rats from the same generation (opportunity to compare the results among each arm) • Sparing of animal lives in accordance with the 3Rs rule • The costs are lower than the required to conduct several separte studies

  11. Challenges of the RI proposal • It is a flexible protocol that could lead to uncertainties in terms of how to conduct the test and how to deal with the additional data obtained • A validation is required: we are planning our first integrated project on Glyphosate/Roundup • Labour intensive testing procedure

  12. Conclusion • For nearly five decades long-term studies in rodents have been the accepted benchmark for assessing chronic long-term toxic effects, particularly carcinogenicity, of chemicals. • Current set of internationally utilized test methods only capture some of the potential adverse effects. • There is a need to stimulate new adaptive approaches that break down institutional and traditional scientific barriers. • Interdisciplinary and multidisciplinary team science should be stimulated • An overall reduction in the use of resources (animals, costs, time…)

  13. Conclusion

  14. “The reward of great men is that, long after they have died, one is not quite sure that they are dead” Jules Renard , 1864 -1910

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