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Klaus Schneider - One of the best experts on this subject based on the ideXlab platform.
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allometric principles for interspecies extrapolation in Toxicological Risk Assessment empirical investigations
Regulatory Toxicology and Pharmacology, 2004Co-Authors: Klaus Schneider, J Oltmanns, M HassauerAbstract:Abstract Four types of data (toxicokinetic data of pharmaceuticals from six species including humans, LD50 values from eight animal species, long-term NOAEL values of pesticides from mice, rats, and dogs, and toxicity data on anti-neoplastic agents from six species including humans) were used for interspecies comparisons. Species differences with regard to kinetic parameters and toxicity were evaluated and the concordance with predictions by allometric scaling according to caloric demand (allometric exponent 0.75) or to body weight (allometric exponent 1) was checked. For LD50 values, agreement was poor for both allometric concepts. Recently reported concordance of LD50 species differences with body weight scaling could be traced back to biased data selection. The other three datasets are clearly in agreement with the allometric scaling according to caloric demand. Caloric demand scaling is thus proposed as a generic interspecies extrapolation method in the absence of substance-specific data. Moreover, the evaluated data make it possible to describe uncertainty associated with the process of interspecies extrapolation by allometric rules.
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Allometric principles for interspecies extrapolation in Toxicological Risk Assessment—empirical investigations
Regulatory toxicology and pharmacology : RTP, 2004Co-Authors: Klaus Schneider, J Oltmanns, M HassauerAbstract:Abstract Four types of data (toxicokinetic data of pharmaceuticals from six species including humans, LD50 values from eight animal species, long-term NOAEL values of pesticides from mice, rats, and dogs, and toxicity data on anti-neoplastic agents from six species including humans) were used for interspecies comparisons. Species differences with regard to kinetic parameters and toxicity were evaluated and the concordance with predictions by allometric scaling according to caloric demand (allometric exponent 0.75) or to body weight (allometric exponent 1) was checked. For LD50 values, agreement was poor for both allometric concepts. Recently reported concordance of LD50 species differences with body weight scaling could be traced back to biased data selection. The other three datasets are clearly in agreement with the allometric scaling according to caloric demand. Caloric demand scaling is thus proposed as a generic interspecies extrapolation method in the absence of substance-specific data. Moreover, the evaluated data make it possible to describe uncertainty associated with the process of interspecies extrapolation by allometric rules.
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Uncertainty in Toxicological Risk Assessment for non-carcinogenic health effects.
Regulatory toxicology and pharmacology : RTP, 2003Co-Authors: Fritz Kalberlah, Klaus Schneider, Ulrike Schuhmacher-wolzAbstract:Uncertainty in Risk Assessment results from the lack of knowledge on toxicity to the target population for a substance. Currently used deterministic Risk Assessment methods yield human limit values or margins of safety (MOS) without quantitative measurements of uncertainty. Qualitative and quantitative uncertainty analysis would enable Risk managers to better judge the consequences of different management options. This article discusses sources of uncertainty and possibilities for quantification of uncertainty associated with different steps in the Risk Assessment of non-carcinogenic health effects. Knowledge gaps causing uncertainty in Risk Assessment are overcome by extrapolation. Distribution functions for extrapolation factors are based on empirical data and provide information about the extent of uncertainty introduced by these factors. Whereas deterministic methods can account only qualitatively for uncertainty of the resulting human limit value, probabilistic Risk Assessment methods are able to quantify several aspects of uncertainty. However, there is only limited experience with these methods in practice. Their acceptance and future application will depend on the establishment of evidence based distribution functions, flexibility and practicability of the methods, and the unambiguity of the results.
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Toxicological Risk Assessment of Soil Contaminants
International Journal of Toxicology, 1997Co-Authors: Fritz Kalberlah, Martin Hassauer, Nicole Frijus-plessen, Klaus SchneiderAbstract:International bodies such as the World Health Organization (WHO) and national governmental agencies like the U.S. Environmental Protection Agency (EPA) use the same basic concept to derive acceptable daily intake (ADI) and reference dose (RfD). This customary concept is used in Toxicological Risk Assessment of soil contaminants in Germany. It is used in the following ways: with extension to new substances not yet assessed by, for example, WHO or EPA; with reevaluations for substances with new Toxicologically relevant input data; with explicitly stated absorption rates used to calculate internal exposure; its results are presented differently and are better suited to multipathway situations of exposure such as in contaminated sites; and with extensions in Assessment by assigning quality criteria to unit Risk quantifications to carcinogenic substances. The respective derived doses are called TRD (tolerable resorbiente dosis—tolerable absorbed dose) values, that is, reference values equivalent to a no observ...
Bas J. Blaauboer - One of the best experts on this subject based on the ideXlab platform.
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the long and winding road of progress in the use of in vitro data for Risk Assessment purposes from carnation test to integrated testing strategies
Toxicology, 2015Co-Authors: Bas J. BlaauboerAbstract:This paper introduces the special issue on quantitative in vitro-in vivo extrapolations (QIVIVE). It highlights important issues in the development of in vitro toxicology towards its implementation in Toxicological Risk Assessment.
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The long and winding road of progress in the use of in vitro data for Risk Assessment purposes : From "carnation test" to integrated testing strategies
Toxicology, 2014Co-Authors: Bas J. BlaauboerAbstract:This paper introduces the special issue on quantitative in vitro-in vivo extrapolations (QIVIVE). It highlights important issues in the development of in vitro toxicology towards its implementation in Toxicological Risk Assessment. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
M Hassauer - One of the best experts on this subject based on the ideXlab platform.
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allometric principles for interspecies extrapolation in Toxicological Risk Assessment empirical investigations
Regulatory Toxicology and Pharmacology, 2004Co-Authors: Klaus Schneider, J Oltmanns, M HassauerAbstract:Abstract Four types of data (toxicokinetic data of pharmaceuticals from six species including humans, LD50 values from eight animal species, long-term NOAEL values of pesticides from mice, rats, and dogs, and toxicity data on anti-neoplastic agents from six species including humans) were used for interspecies comparisons. Species differences with regard to kinetic parameters and toxicity were evaluated and the concordance with predictions by allometric scaling according to caloric demand (allometric exponent 0.75) or to body weight (allometric exponent 1) was checked. For LD50 values, agreement was poor for both allometric concepts. Recently reported concordance of LD50 species differences with body weight scaling could be traced back to biased data selection. The other three datasets are clearly in agreement with the allometric scaling according to caloric demand. Caloric demand scaling is thus proposed as a generic interspecies extrapolation method in the absence of substance-specific data. Moreover, the evaluated data make it possible to describe uncertainty associated with the process of interspecies extrapolation by allometric rules.
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Allometric principles for interspecies extrapolation in Toxicological Risk Assessment—empirical investigations
Regulatory toxicology and pharmacology : RTP, 2004Co-Authors: Klaus Schneider, J Oltmanns, M HassauerAbstract:Abstract Four types of data (toxicokinetic data of pharmaceuticals from six species including humans, LD50 values from eight animal species, long-term NOAEL values of pesticides from mice, rats, and dogs, and toxicity data on anti-neoplastic agents from six species including humans) were used for interspecies comparisons. Species differences with regard to kinetic parameters and toxicity were evaluated and the concordance with predictions by allometric scaling according to caloric demand (allometric exponent 0.75) or to body weight (allometric exponent 1) was checked. For LD50 values, agreement was poor for both allometric concepts. Recently reported concordance of LD50 species differences with body weight scaling could be traced back to biased data selection. The other three datasets are clearly in agreement with the allometric scaling according to caloric demand. Caloric demand scaling is thus proposed as a generic interspecies extrapolation method in the absence of substance-specific data. Moreover, the evaluated data make it possible to describe uncertainty associated with the process of interspecies extrapolation by allometric rules.
V. Narayan - One of the best experts on this subject based on the ideXlab platform.
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BIOLOGICAL AND Toxicological Risk Assessment OF AN ANTIOXIDANT-STABILISED POLYETHYLENE
2018Co-Authors: V. NarayanAbstract:The ATTUNE™ Knee System (DePuy Synthes) comprises of a tibial insert that is made from AOX™, an antioxidant-stabilized polyethylene. The antioxidant used in AOX is pentaerythritol tetrakis [3-(3, 5-di-tertiary butyl-4-hydroxyphenyl)] propionate (PBHP). A biological Risk Assessment of the degradation products arising from PBHP has been performed. This Assessment focuses on the requirements of ISO 10993–1:2009, ISO 14971:2007, and the Medical Device Directive 93/42/EEC.Because the orthopedic implant is a permanent implant, consideration has been given to all relevant endpoints defined by ISO 10993–1 Biological evaluation of medical devices – Part 1: Evaluation and testing within a Risk management process. Comprehensive biocompatibility testing including long-term (26 weeks) subcutaneous implantation has been conducted which confirms the biosafety of the polyethylene compound[1]. In addition to the biological safety testing completed, the overall safety and the associated Toxicological Risk of exposure to de...
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BIOLOGICAL AND Toxicological Risk Assessment OF AN ANTIOXIDANT-STABILISED POLYETHYLENE
Journal of Bone and Joint Surgery-british Volume, 2016Co-Authors: V. NarayanAbstract:The ATTUNE™ Knee System (DePuy Synthes) comprises of a tibial insert that is made from AOX™, an antioxidant-stabilized polyethylene. The antioxidant used in AOX is pentaerythritol tetrakis [3-(3, 5-di-tertiary butyl-4-hydroxyphenyl)] propionate (PBHP). A biological Risk Assessment of the degradation products arising from PBHP has been performed. This Assessment focuses on the requirements of ISO 10993–1:2009, ISO 14971:2007, and the Medical Device Directive 93/42/EEC. Because the orthopedic implant is a permanent implant, consideration has been given to all relevant endpoints defined by ISO 10993–1 Biological evaluation of medical devices – Part 1: Evaluation and testing within a Risk management process . Comprehensive biocompatibility testing including long-term (26 weeks) subcutaneous implantation has been conducted which confirms the biosafety of the polyethylene compound[1]. In addition to the biological safety testing completed, the overall safety and the associated Toxicological Risk of exposure to degradation products of PBHP has been given due consideration. The guidelines for the Threshold for Toxicological Concern (TTC) provided by The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group were used in the Assessment[2]. This working group is a collaboration of chemists and toxicologists from the U.S. Food and Drug Administration (FDA), industry, and academia. The TTC principle allows safety Assessment in the absence of substance-specific hazard data, based on very low levels of exposure to that substance. A Margin of Safety (MOS) is calculated as the ratio of the threshold safety value to the actual exposure quantities determined and used in the Assessment. A MOS value greater than 1 is typically judged by Risk assessors and regulatory bodies to be unlikely to cause harm and the Risk may be considered low. The identity of the degradation products as well as the corresponding 30-day leachable quantities from a water:acetone extraction media has been previously reported [3] and provided here (Table 1). The amount of leachables determined from Table 1 for all products were well below the TTC of 150 ng/device and hence no Toxicological Risks were identified for these compounds. In order to further examine the Toxicological Risk Assessment, aggressive extraction using Dynamic Head Space (DHS) extraction was done and analytical testing was performed on the degradation products of PBHP using gas chromatography/mass spectrometry (GC /MS). These estimated quantities along with literature information from biological safety studies of the chemicals that were identified from the quantitative GC/MS analysis of degradation products of PBHP were used in the review and Toxicological Assessment per the methodology described in ISO 14971 and ISO 10993–18. The extraction and analysis confirmed the same sixteen compounds previously identified. The quantities and the calculated margins of safety are summarized (Table 2). In conclusion, upon review of actual test results of PBHP degradation products (Table 1), there is little probability that these organic degradation products would cause a systemic reaction and not be safe. Thus, the potential biological hazards identified in ISO 10993–1:2009 due to the quantified leachables have been verified to be minimal with a high Margin of Safety relative to the Threshold of Toxicological Concern.
J Oltmanns - One of the best experts on this subject based on the ideXlab platform.
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allometric principles for interspecies extrapolation in Toxicological Risk Assessment empirical investigations
Regulatory Toxicology and Pharmacology, 2004Co-Authors: Klaus Schneider, J Oltmanns, M HassauerAbstract:Abstract Four types of data (toxicokinetic data of pharmaceuticals from six species including humans, LD50 values from eight animal species, long-term NOAEL values of pesticides from mice, rats, and dogs, and toxicity data on anti-neoplastic agents from six species including humans) were used for interspecies comparisons. Species differences with regard to kinetic parameters and toxicity were evaluated and the concordance with predictions by allometric scaling according to caloric demand (allometric exponent 0.75) or to body weight (allometric exponent 1) was checked. For LD50 values, agreement was poor for both allometric concepts. Recently reported concordance of LD50 species differences with body weight scaling could be traced back to biased data selection. The other three datasets are clearly in agreement with the allometric scaling according to caloric demand. Caloric demand scaling is thus proposed as a generic interspecies extrapolation method in the absence of substance-specific data. Moreover, the evaluated data make it possible to describe uncertainty associated with the process of interspecies extrapolation by allometric rules.
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Allometric principles for interspecies extrapolation in Toxicological Risk Assessment—empirical investigations
Regulatory toxicology and pharmacology : RTP, 2004Co-Authors: Klaus Schneider, J Oltmanns, M HassauerAbstract:Abstract Four types of data (toxicokinetic data of pharmaceuticals from six species including humans, LD50 values from eight animal species, long-term NOAEL values of pesticides from mice, rats, and dogs, and toxicity data on anti-neoplastic agents from six species including humans) were used for interspecies comparisons. Species differences with regard to kinetic parameters and toxicity were evaluated and the concordance with predictions by allometric scaling according to caloric demand (allometric exponent 0.75) or to body weight (allometric exponent 1) was checked. For LD50 values, agreement was poor for both allometric concepts. Recently reported concordance of LD50 species differences with body weight scaling could be traced back to biased data selection. The other three datasets are clearly in agreement with the allometric scaling according to caloric demand. Caloric demand scaling is thus proposed as a generic interspecies extrapolation method in the absence of substance-specific data. Moreover, the evaluated data make it possible to describe uncertainty associated with the process of interspecies extrapolation by allometric rules.
