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Analysis of developmental neurotoxicity
Abstracts / Toxicology Letters 221S (2013) S4–S30
S19
S11-3 Analysis of developmental neurotoxicity
influencing genesis, maturation and functionality of the reproductive organs.
Sandra L. Allen
http://dx.doi.org/10.1016/j.toxlet.2013.06.067
Regulatory Science Associates, Dunoon, Argyll, UK The assessment of developmental neurotoxicity requires the use of a variety of methods from a number of different scientific fields. Regulatory guideline studies require offspring from control and treated litters to be evaluated for gross neurological and behavioural abnormalities during postnatal development and adulthood. These include assessments of physical development, behavioural ontogeny, motor activity, motor and sensory function, learning and memory, and post-mortem evaluation of brain weights and neuropathology. The studies are complicated in terms of design, conduct and interpretation and great care is needed in the practical aspects of study design in order to ensure robust interpretable data and avoid potential confounders. The presentation will discuss selection of appropriate methods and their strengths and weaknesses. It will also cover replicated designs, technical challenges of directly dosing pups and other aspects of study management. Interpretational issues include: (i) the challenges to the maternal animal in terms of degree of toxicity expected; (ii) impact of maternal toxicity on pup behaviour; (iii) impact of pup body weight on test results; (iv) differentiating acute effects from developmental effects; (v) relative sensitivity and what constitutes increased sensitivity. Data will be presented giving some examples of the above. http://dx.doi.org/10.1016/j.toxlet.2013.06.066
S11-5 Epigenetics: how genes and environment interact Randy L. Jirtle McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, USA Human epidemiological and animal experimental data indicate that the risk of developing adult onset diseases and neurological disorders is influenced by persistent adaptations to prenatal and early postnatal environmental exposures. One group of epigenetically regulated genes that potentially links environmental exposures early in development to adult diseases are those with metastable epialleles. These genes have highly variable expression because of stochastic allelic changes in the epigenome rather than mutations in the genome. The viable yellow agouti (Avy) mouse harbors a metastable Agouti gene because of an upstream insertion of a transposable element. We have used the Avy mouse to investigate the importance of epigenetic alterations in determining adult disease risk in response to early developmental exposure to both chemical agents and ionizing radiation. The importance of these studies with regard to human health and disease risk will be discussed. http://dx.doi.org/10.1016/j.toxlet.2013.06.068
S11-4 Developmental toxicity in reproductive organs
Symposium 12: Integration of human and environmental risk assessment – is it the future?
Geertje Lewin Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany Within the design of the EOGRTS the cohort 1A+B encompasses the largest number of offspring, serving the assessment of reproductive and general toxicity effects. Parameter assessment on development and maturation of the reproductive organ systems contains several new parameters compared to other guidelines. The examinations start with postnatal external examinations (abnormalities of genital organs, retentions of male nipples and areolae), measurement of the ano-genital distance, organ weight and macroscopic examinations from F1 weanlings, achievement of sexual maturity, testing of sperm parameters, oestrus cyclicity and thyroid hormones as indicators of hormonal balance and terminate in a detailed histopathology of the reproductive system in adult offspring. In the case, when no mating of F1 to produce a second generation is triggered, this list is sufficient to detect weather adverse effects on reproductive organ development have occurred. The challenge in interpreting an EOGRT study will be to understand the interplay of maternal effects, hormonal influences and pre- and postnatal maturational processes. While the indifferent bipotential embryonic gonad differentiates based on genetic determination and hormonal influences, the development of other structures such as the reproductive tract with its accessory sex organs majorly depends on the delicate interplay of hormonal interactions. Therefore, multiple targets for interference are present. An emphasis will be laid upon several practical examples on how the assessed parameters are affected by different modes of action
S12-1 HEROIC – an integrated European approach to the coordination of human and environmental risk assessment M.F. Wilks 1,∗ , D. Barcelò 2 , E. Capri 3 , P. Ciffroy 4 , M. Faust 5 , C.R. Glass 6 , K. Machera 7 , A.R. Péry 8 , G. Schüürmann 9 1
SCAHT, University of Basel, Switzerland, 2 Consejo Superior de Investigaciones Cientificas, Spain, 3 Università Cattolica del Sacro Cuore, Italy, 4 EDF Research & Development, France, 5 Faust und Backhaus Environmental Consulting GbR, Germany, 6 Food and Environment Research Agency, UK, 7 Benaki Phytopathological Institute, Greece, 8 Institut National de l’EnvironmentIndustriel et des Risques, France, 9 UFZ Helmholtz Centre for Environmental Research, Leipzig and Technical University Bergakademie Freiberg, Germany While the integration of human and environmental risk assessment (RA) has been discussed and promoted for more than a decade, existing European regulations of chemical substances such as REACH, the Plant Protection Products and Biocide Regulations continue to ask for sector-specific RAs, each of which have their specific information requirements and use different methodologies for the ultimate risk quantification. In response to this gap between the vision for integration and current scientific and regulatory practice, the EU FP7 project HEROIC aims to contribute to the development of harmonised approaches which meet the challenges of RA. A comprehensive landscaping exercise has identified common methodological and data needs and opportunities in current human and environmental RA practices (Péry et al., 2013). Existing in vivo,
S19
S11-3 Analysis of developmental neurotoxicity
influencing genesis, maturation and functionality of the reproductive organs.
Sandra L. Allen
http://dx.doi.org/10.1016/j.toxlet.2013.06.067
Regulatory Science Associates, Dunoon, Argyll, UK The assessment of developmental neurotoxicity requires the use of a variety of methods from a number of different scientific fields. Regulatory guideline studies require offspring from control and treated litters to be evaluated for gross neurological and behavioural abnormalities during postnatal development and adulthood. These include assessments of physical development, behavioural ontogeny, motor activity, motor and sensory function, learning and memory, and post-mortem evaluation of brain weights and neuropathology. The studies are complicated in terms of design, conduct and interpretation and great care is needed in the practical aspects of study design in order to ensure robust interpretable data and avoid potential confounders. The presentation will discuss selection of appropriate methods and their strengths and weaknesses. It will also cover replicated designs, technical challenges of directly dosing pups and other aspects of study management. Interpretational issues include: (i) the challenges to the maternal animal in terms of degree of toxicity expected; (ii) impact of maternal toxicity on pup behaviour; (iii) impact of pup body weight on test results; (iv) differentiating acute effects from developmental effects; (v) relative sensitivity and what constitutes increased sensitivity. Data will be presented giving some examples of the above. http://dx.doi.org/10.1016/j.toxlet.2013.06.066
S11-5 Epigenetics: how genes and environment interact Randy L. Jirtle McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, USA Human epidemiological and animal experimental data indicate that the risk of developing adult onset diseases and neurological disorders is influenced by persistent adaptations to prenatal and early postnatal environmental exposures. One group of epigenetically regulated genes that potentially links environmental exposures early in development to adult diseases are those with metastable epialleles. These genes have highly variable expression because of stochastic allelic changes in the epigenome rather than mutations in the genome. The viable yellow agouti (Avy) mouse harbors a metastable Agouti gene because of an upstream insertion of a transposable element. We have used the Avy mouse to investigate the importance of epigenetic alterations in determining adult disease risk in response to early developmental exposure to both chemical agents and ionizing radiation. The importance of these studies with regard to human health and disease risk will be discussed. http://dx.doi.org/10.1016/j.toxlet.2013.06.068
S11-4 Developmental toxicity in reproductive organs
Symposium 12: Integration of human and environmental risk assessment – is it the future?
Geertje Lewin Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany Within the design of the EOGRTS the cohort 1A+B encompasses the largest number of offspring, serving the assessment of reproductive and general toxicity effects. Parameter assessment on development and maturation of the reproductive organ systems contains several new parameters compared to other guidelines. The examinations start with postnatal external examinations (abnormalities of genital organs, retentions of male nipples and areolae), measurement of the ano-genital distance, organ weight and macroscopic examinations from F1 weanlings, achievement of sexual maturity, testing of sperm parameters, oestrus cyclicity and thyroid hormones as indicators of hormonal balance and terminate in a detailed histopathology of the reproductive system in adult offspring. In the case, when no mating of F1 to produce a second generation is triggered, this list is sufficient to detect weather adverse effects on reproductive organ development have occurred. The challenge in interpreting an EOGRT study will be to understand the interplay of maternal effects, hormonal influences and pre- and postnatal maturational processes. While the indifferent bipotential embryonic gonad differentiates based on genetic determination and hormonal influences, the development of other structures such as the reproductive tract with its accessory sex organs majorly depends on the delicate interplay of hormonal interactions. Therefore, multiple targets for interference are present. An emphasis will be laid upon several practical examples on how the assessed parameters are affected by different modes of action
S12-1 HEROIC – an integrated European approach to the coordination of human and environmental risk assessment M.F. Wilks 1,∗ , D. Barcelò 2 , E. Capri 3 , P. Ciffroy 4 , M. Faust 5 , C.R. Glass 6 , K. Machera 7 , A.R. Péry 8 , G. Schüürmann 9 1
SCAHT, University of Basel, Switzerland, 2 Consejo Superior de Investigaciones Cientificas, Spain, 3 Università Cattolica del Sacro Cuore, Italy, 4 EDF Research & Development, France, 5 Faust und Backhaus Environmental Consulting GbR, Germany, 6 Food and Environment Research Agency, UK, 7 Benaki Phytopathological Institute, Greece, 8 Institut National de l’EnvironmentIndustriel et des Risques, France, 9 UFZ Helmholtz Centre for Environmental Research, Leipzig and Technical University Bergakademie Freiberg, Germany While the integration of human and environmental risk assessment (RA) has been discussed and promoted for more than a decade, existing European regulations of chemical substances such as REACH, the Plant Protection Products and Biocide Regulations continue to ask for sector-specific RAs, each of which have their specific information requirements and use different methodologies for the ultimate risk quantification. In response to this gap between the vision for integration and current scientific and regulatory practice, the EU FP7 project HEROIC aims to contribute to the development of harmonised approaches which meet the challenges of RA. A comprehensive landscaping exercise has identified common methodological and data needs and opportunities in current human and environmental RA practices (Péry et al., 2013). Existing in vivo,