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Evaluating MoE and its uncertainty and variability for food contaminants
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Abstracts / Toxicology Letters 229S (2014) S22–S39
PS3.4-O5 Evaluating MoE and its uncertainty and variability for food contaminants R. Woodrow Setzer US Environmental Protection Agency, Research Triangle Park, NC, USA Margin of Exposure (MoE), is a metric for quantifying the relationship between exposure and hazard. Ideally, it is the ratio of the dose associated with hazard and an estimate of exposure. For example, hazard may be characterized by a benchmark dose (BMD), and, for food contaminants, exposure by a measure of ingested chemical in the same units (say, mg/kg/day). Generally, both measures are uncertain, and may vary based on lifestyle and differ between children and adults. Use of BMD rather than NOAELs or T25 to characterize hazard is more appropriate when computing the MoE because the BMD is well-defined, can be efficiently calculated from typical bioassay data, and statistical methods for characterizing its uncertainty are relatively mature. However, for most chemicals there is substantially greater uncertainty in the denominator of the MoE. Available modeling approaches show promise, but often require substantial effort to parameterize. One challenge to the MoE approach is the limited availability of empirical hazard data for most chemicals. Promising new technologies are being developed to solve this data gap. This includes the US EPA’s ExpoCast program which enables prediction of exposure estimates for thousands of chemicals based on use and production. In addition, reverse toxicokinetics (rTK) and in vitro to in vivo predictive models are connecting in vitro hazard concentrations to daily exposure estimates. New models and methods like these show great promise in reducing uncertainties in risk estimates for data poor chemicals. This abstract does not necessarily reflect U.S. EPA policy. http://dx.doi.org/10.1016/j.toxlet.2014.06.132 Workshop 5: Skin sensitisation safety assessment: current perspective on mechanistic steps of induction by hair dyes and its quantification PS4.3-O1 Mechanistic steps in the immune response to skin sensitising chemicals Ian Kimber University of Manchester, Manchester, UK Skin sensitisation resulting in allergic contact dermatitis is an important occupational and environmental health issue, and many hundreds of chemicals have been implicated as contact allergens. For the effective acquisition of skin sensitisation a number of biological and immunological hurdles have to be negotiated successfully. Included among the important events or processes on the pathway to the development of skin sensitisation are the following. (1) An initial requirement is that a chemical must gain access, via the stratum cornuem, to the viable epidermis where initial interaction with elements of the immune system takes place. (2) Chemicals are not directly immunogenic, and to elicit an immune response they are required to form stable associations with proteins. There is a need, therefore, that skin sensitising chemicals are naturally electrophilic, or that they are converted to electrophilic species within the skin. (3) A critical requirement is that chemical allergens are recognised, internalised and processed by cutaneous dendritic cells (epidermal Langerhans cells and dermal dendritic cells) and
transported from the skin to regional lymph nodes. (4) The activation of dendritic cells, and the initiation of adaptive immune responses requires what are known as ‘danger signals’ reflecting some local trauma associated with exposure. It is important that chemical allergens cause some local tissue irritation/disruption to ensure optimal priming of the skin immune system. (5) The chemical allergen, presented in the context of activated dendritic cells, must trigger the activation and clocal expansion of responsive T lymphocytes. These processes resulting in the acquisition of skin sensitisation will be reviewed. http://dx.doi.org/10.1016/j.toxlet.2014.06.134 PS4.3-O2 Activation and deactivation of aromatic amine hair dyes in the skin Brunhilde Blömeke Trier University, Trier, Germany Skin represents the largest organ of the human body and provides an important barrier role in protecting the body from external factors, such as pathogens and chemicals. Although known for its barrier function to the environment, skin is also an extra hepatic metabolizing organ, with low levels of phase I xenobiotic enzymes (XME) but considerable levels of phase II enzymes. Consequently, skin metabolism impacts the bioavailability of penetrated chemicals and their ability to trigger skin effects such as allergic contact dermatitis (ACD). Results of studies using well known sensitizers such as 2,4-dinitrochlorobenzene, cinnamic alcohol, and aromatic amine hair dye precursors such as para-phenylenediamine (PPD) or para-toluenediamine (PTD) showed their biotransformation by skin cells through glutathione S-transferase, alcohol/aldehyde dehydrogenase and N-acetyltransferase activities, respectively. For these molecules and pathways results indicate that skin reveals a more detoxifying than a bioactivating behavior. However, the effects (ACD) can be induced if the actual amounts of the compound in skin exceed the capacity of the relevant enzyme(s) to deactivate it. This may occur via oxidation of these compounds, especially when the expression of the key enzymes is decreased or deficient in the skin or when a relevant cofactor is depleted. Results for the aromatic amines PPD and PTD and how modification of the molecular structure of PPD impacts these parameters are discussed. In conclusion, in case of ACD, studies of the kinetic parameters between deactivation and oxidation in addition to protein reactivity of these activated chemicals will increase our mechanistical understanding and should be viewed in order to assess hazard. http://dx.doi.org/10.1016/j.toxlet.2014.06.135
PS4.3-O3 In vitro sensitization and primary T cell responses to contact allergens: Towards the development of human T cell priming assays Marc Vocanson CIRI, International Center for Infectiology Research, Université de Lyon, Inserm, U1111, Lyon, France To develop an in vitro assay that recapitulates the key events of Allergic Contact Dermatitis (ACD), that is the priming of hapten-specific effector T cells (Teff), represents a major challenge. Significant progresses have been made through recent research projects done by the EU ‘Sensit-iv’ consortium and by the
Abstracts / Toxicology Letters 229S (2014) S22–S39
PS3.4-O5 Evaluating MoE and its uncertainty and variability for food contaminants R. Woodrow Setzer US Environmental Protection Agency, Research Triangle Park, NC, USA Margin of Exposure (MoE), is a metric for quantifying the relationship between exposure and hazard. Ideally, it is the ratio of the dose associated with hazard and an estimate of exposure. For example, hazard may be characterized by a benchmark dose (BMD), and, for food contaminants, exposure by a measure of ingested chemical in the same units (say, mg/kg/day). Generally, both measures are uncertain, and may vary based on lifestyle and differ between children and adults. Use of BMD rather than NOAELs or T25 to characterize hazard is more appropriate when computing the MoE because the BMD is well-defined, can be efficiently calculated from typical bioassay data, and statistical methods for characterizing its uncertainty are relatively mature. However, for most chemicals there is substantially greater uncertainty in the denominator of the MoE. Available modeling approaches show promise, but often require substantial effort to parameterize. One challenge to the MoE approach is the limited availability of empirical hazard data for most chemicals. Promising new technologies are being developed to solve this data gap. This includes the US EPA’s ExpoCast program which enables prediction of exposure estimates for thousands of chemicals based on use and production. In addition, reverse toxicokinetics (rTK) and in vitro to in vivo predictive models are connecting in vitro hazard concentrations to daily exposure estimates. New models and methods like these show great promise in reducing uncertainties in risk estimates for data poor chemicals. This abstract does not necessarily reflect U.S. EPA policy. http://dx.doi.org/10.1016/j.toxlet.2014.06.132 Workshop 5: Skin sensitisation safety assessment: current perspective on mechanistic steps of induction by hair dyes and its quantification PS4.3-O1 Mechanistic steps in the immune response to skin sensitising chemicals Ian Kimber University of Manchester, Manchester, UK Skin sensitisation resulting in allergic contact dermatitis is an important occupational and environmental health issue, and many hundreds of chemicals have been implicated as contact allergens. For the effective acquisition of skin sensitisation a number of biological and immunological hurdles have to be negotiated successfully. Included among the important events or processes on the pathway to the development of skin sensitisation are the following. (1) An initial requirement is that a chemical must gain access, via the stratum cornuem, to the viable epidermis where initial interaction with elements of the immune system takes place. (2) Chemicals are not directly immunogenic, and to elicit an immune response they are required to form stable associations with proteins. There is a need, therefore, that skin sensitising chemicals are naturally electrophilic, or that they are converted to electrophilic species within the skin. (3) A critical requirement is that chemical allergens are recognised, internalised and processed by cutaneous dendritic cells (epidermal Langerhans cells and dermal dendritic cells) and
transported from the skin to regional lymph nodes. (4) The activation of dendritic cells, and the initiation of adaptive immune responses requires what are known as ‘danger signals’ reflecting some local trauma associated with exposure. It is important that chemical allergens cause some local tissue irritation/disruption to ensure optimal priming of the skin immune system. (5) The chemical allergen, presented in the context of activated dendritic cells, must trigger the activation and clocal expansion of responsive T lymphocytes. These processes resulting in the acquisition of skin sensitisation will be reviewed. http://dx.doi.org/10.1016/j.toxlet.2014.06.134 PS4.3-O2 Activation and deactivation of aromatic amine hair dyes in the skin Brunhilde Blömeke Trier University, Trier, Germany Skin represents the largest organ of the human body and provides an important barrier role in protecting the body from external factors, such as pathogens and chemicals. Although known for its barrier function to the environment, skin is also an extra hepatic metabolizing organ, with low levels of phase I xenobiotic enzymes (XME) but considerable levels of phase II enzymes. Consequently, skin metabolism impacts the bioavailability of penetrated chemicals and their ability to trigger skin effects such as allergic contact dermatitis (ACD). Results of studies using well known sensitizers such as 2,4-dinitrochlorobenzene, cinnamic alcohol, and aromatic amine hair dye precursors such as para-phenylenediamine (PPD) or para-toluenediamine (PTD) showed their biotransformation by skin cells through glutathione S-transferase, alcohol/aldehyde dehydrogenase and N-acetyltransferase activities, respectively. For these molecules and pathways results indicate that skin reveals a more detoxifying than a bioactivating behavior. However, the effects (ACD) can be induced if the actual amounts of the compound in skin exceed the capacity of the relevant enzyme(s) to deactivate it. This may occur via oxidation of these compounds, especially when the expression of the key enzymes is decreased or deficient in the skin or when a relevant cofactor is depleted. Results for the aromatic amines PPD and PTD and how modification of the molecular structure of PPD impacts these parameters are discussed. In conclusion, in case of ACD, studies of the kinetic parameters between deactivation and oxidation in addition to protein reactivity of these activated chemicals will increase our mechanistical understanding and should be viewed in order to assess hazard. http://dx.doi.org/10.1016/j.toxlet.2014.06.135
PS4.3-O3 In vitro sensitization and primary T cell responses to contact allergens: Towards the development of human T cell priming assays Marc Vocanson CIRI, International Center for Infectiology Research, Université de Lyon, Inserm, U1111, Lyon, France To develop an in vitro assay that recapitulates the key events of Allergic Contact Dermatitis (ACD), that is the priming of hapten-specific effector T cells (Teff), represents a major challenge. Significant progresses have been made through recent research projects done by the EU ‘Sensit-iv’ consortium and by the