The Experts below are selected from a list of 4737954 Experts worldwide ranked by ideXlab platform
Theodore J. Baird - One of the best experts on this subject based on the ideXlab platform.
-
Is there a role for the no observed adverse effect Level in safety pharmacology
Journal of pharmacological and toxicological methods, 2020Co-Authors: Tomas Mow, Simon Authier, Jean-pierre Valentin, Alan S. Bass, Carrie Markgraf, Ninette K. Andersen, Nils Dragsted, Anders B. Lassen, Morten Laursen, Theodore J. BairdAbstract:In nonclinical toxicology the highest dose or exposure without test article-related adverse effects, known as the No Observed Adverse Effect Level (NOAEL), is a variable that may be determined. In safety pharmacology the vast majority of the endpoints measured are quantitative numeric functional endpoints such as changes in heart rate, blood pressure or respiratory frequency, endpoints that are usually not assessed using a defined framework of adversity. Therefore, we asked the question: is there a role for the NOAEL in safety pharmacology? To populate our consideration, we conducted a survey via the Safety Pharmacology Society. We found that within safety pharmacology there is no formal definition of adversity and no guidance on defining NOAEL. We also found, perhaps unsurprisingly, there is no agreed rubric for using a NOAEL in safety pharmacology and we learned that the NOAEL is not a requirement in order to progress a new investigational drug through the regulatory process. Thus, a summary label such as NOAEL lacks nuance and disregards context in relation to the nature and the severity of the safety pharmacology findings. Consequently, defining ‘adversity’ and determining a NOAEL in safety pharmacology studies are not recommended since the range of functional endpoints investigated do not conform to a binary ‘toxic/non-toxic’ rubric. Focusing on describing test article-related effects on safety pharmacology endpoints, using reasoned arguments as part of an integrated risk assessment, will ensure that the clinical pharmacologists and regulatory bodies see a clear description of relevant findings at each dose or exposure Level. This will inform a narrative about the potential risks of the test article and support a recommendation for optimal dose setting and optimal monitoring of vital signs in clinical trials
-
Is there a role for the no observed adverse effect Level in safety pharmacology
Journal of Pharmacological and Toxicological Methods, 2020Co-Authors: Tomas Mow, Simon Authier, Jean-pierre Valentin, Alan S. Bass, Carrie Markgraf, Ninette K. Andersen, Nils Dragsted, Anders B. Lassen, Morten Laursen, Theodore J. BairdAbstract:Abstract In nonclinical toxicology the highest dose or exposure without test article-related adverse effects, known as the No Observed Adverse Effect Level (NOAEL), is a variable that may be determined. In safety pharmacology the vast majority of the endpoints measured are quantitative numeric functional endpoints such as changes in heart rate, blood pressure or respiratory frequency, endpoints that are usually not assessed using a defined framework of adversity. Therefore, we asked the question: is there a role for the NOAEL in safety pharmacology? To help answer this question, we conducted a survey via the Safety Pharmacology Society. We found that within safety pharmacology there is no formal definition of adversity and no guidance on defining NOAEL. We also found, perhaps unsurprisingly, there is no agreed rubric for using a NOAEL in safety pharmacology and we learned that the NOAEL is not a requirement in order to progress a new investigational drug through the regulatory process. Thus, a summary label such as NOAEL lacks nuance and disregards context in relation to the nature and the severity of the safety pharmacology findings. Consequently, defining ‘adversity’ and determining a NOAEL in safety pharmacology studies are not recommended since the range of functional endpoints investigated do not conform to a binary ‘toxic/non-toxic’ rubric. Focusing on describing test article-related effects on safety pharmacology endpoints, using reasoned arguments as part of an integrated risk assessment, will ensure that the clinical pharmacologists and regulatory bodies see a clear description of relevant findings at each dose or exposure Level.
Ian R. Falconer - One of the best experts on this subject based on the ideXlab platform.
-
oral toxicity of the cyanobacterial toxin cylindrospermopsin in male swiss albino mice determination of no observed adverse effect Level for deriving a drinking water guideline value
Environmental Toxicology, 2003Co-Authors: Andrew R. Humpage, Ian R. FalconerAbstract:The cyanobacterial toxin cylindrospermopsin (CYN) is a frequent contaminant of freshwaters throughout the world, including those that are sources of drinking water. The first cases of human poisoning attributed to this toxin occurred from a treated drinking water supply in Queensland, Australia, in 1979. The toxin causes extensive damage to the liver, kidneys, spleen, heart, and other organs. It is known to be a potent protein synthesis inhibitor, but there is mounting evidence for genotoxicity and that it metabolizes to even more toxic forms. As part of a risk assessment process leading to a guideline for a safe drinking water Level for this toxin, we performed a series of experiments to determine a No-Observed-Adverse-Effect Level (NOAEL) for this toxin. In the first trial male mice were exposed to CYN-containing cyanobacterial extract in their drinking water (0–657 μg CYN kg−1 day−1) for 10 weeks. In the second trial mice received purified CYN by daily gavage (0–240 μg CYN kg−1 day−1) for 11 weeks. Body and organ weights were recorded; urine, serum, and hematology analyses were performed; and histopathological examination of tissues was carried out. Body weights were significantly increased at low doses (30 and 60 μg kg−1 day−1) and decreased at high doses (432 and 657 μg kg−1 day−1). Liver and kidney weights were significantly increased at doses of 240 μg kg−1 day−1 and 60 μg kg−1 day−1, respectively. Serum bilirubin Levels were significantly increased and bile acids significantly decreased at doses of 216 μg kg day−1 and greater. Urine total protein was significantly decreased at doses above 60 μg kg−1 day−1. The kidney appeared to be the more sensitive organ to this toxin. If it is assumed that increased organ weights and changes in functional capacity are responses to an underlying toxic effect, then the NOAEL based on this data is 30 μg kg−1 day−1, which, with standard calculations and uncertainty factors, provides a proposed guideline safety value of 1 μg/L in drinking water. © 2003 Wiley Periodicals, Inc. Environ Toxicol 18: 94–103, 2003.
-
oral toxicity of the cyanobacterial toxin cylindrospermopsin in male swiss albino mice determination of no observed adverse effect Level for deriving a drinking water guideline value
Environmental Toxicology, 2003Co-Authors: Andrew R. Humpage, Ian R. FalconerAbstract:: The cyanobacterial toxin cylindrospermopsin (CYN) is a frequent contaminant of freshwaters throughout the world, including those that are sources of drinking water. The first cases of human poisoning attributed to this toxin occurred from a treated drinking water supply in Queensland, Australia, in 1979. The toxin causes extensive damage to the liver, kidneys, spleen, heart, and other organs. It is known to be a potent protein synthesis inhibitor, but there is mounting evidence for genotoxicity and that it metabolizes to even more toxic forms. As part of a risk assessment process leading to a guideline for a safe drinking water Level for this toxin, we performed a series of experiments to determine a No-Observed-Adverse-Effect Level (NOAEL) for this toxin. In the first trial male mice were exposed to CYN-containing cyanobacterial extract in their drinking water (0-657 microg CYN kg(-1) day(-1)) for 10 weeks. In the second trial mice received purified CYN by daily gavage (0-240 microg CYN kg(-1) day(-1)) for 11 weeks. Body and organ weights were recorded; urine, serum, and hematology analyses were performed; and histopathological examination of tissues was carried out. Body weights were significantly increased at low doses (30 and 60 microg kg(-1) day(-1)) and decreased at high doses (432 and 657 microg kg(-1) day(-1)). Liver and kidney weights were significantly increased at doses of 240 microg kg(-1) day(-1) and 60 microg kg(-1) day(-1), respectively. Serum bilirubin Levels were significantly increased and bile acids significantly decreased at doses of 216 microg kg day(-1) and greater. Urine total protein was significantly decreased at doses above 60 microg kg(-1) day(-1). The kidney appeared to be the more sensitive organ to this toxin. If it is assumed that increased organ weights and changes in functional capacity are responses to an underlying toxic effect, then the NOAEL based on this data is 30 microg kg(-1) day(-1), which, with standard calculations and uncertainty factors, provides a proposed guideline safety value of 1 microg/L in drinking water.
Tomas Mow - One of the best experts on this subject based on the ideXlab platform.
-
Is there a role for the no observed adverse effect Level in safety pharmacology
Journal of pharmacological and toxicological methods, 2020Co-Authors: Tomas Mow, Simon Authier, Jean-pierre Valentin, Alan S. Bass, Carrie Markgraf, Ninette K. Andersen, Nils Dragsted, Anders B. Lassen, Morten Laursen, Theodore J. BairdAbstract:In nonclinical toxicology the highest dose or exposure without test article-related adverse effects, known as the No Observed Adverse Effect Level (NOAEL), is a variable that may be determined. In safety pharmacology the vast majority of the endpoints measured are quantitative numeric functional endpoints such as changes in heart rate, blood pressure or respiratory frequency, endpoints that are usually not assessed using a defined framework of adversity. Therefore, we asked the question: is there a role for the NOAEL in safety pharmacology? To populate our consideration, we conducted a survey via the Safety Pharmacology Society. We found that within safety pharmacology there is no formal definition of adversity and no guidance on defining NOAEL. We also found, perhaps unsurprisingly, there is no agreed rubric for using a NOAEL in safety pharmacology and we learned that the NOAEL is not a requirement in order to progress a new investigational drug through the regulatory process. Thus, a summary label such as NOAEL lacks nuance and disregards context in relation to the nature and the severity of the safety pharmacology findings. Consequently, defining ‘adversity’ and determining a NOAEL in safety pharmacology studies are not recommended since the range of functional endpoints investigated do not conform to a binary ‘toxic/non-toxic’ rubric. Focusing on describing test article-related effects on safety pharmacology endpoints, using reasoned arguments as part of an integrated risk assessment, will ensure that the clinical pharmacologists and regulatory bodies see a clear description of relevant findings at each dose or exposure Level. This will inform a narrative about the potential risks of the test article and support a recommendation for optimal dose setting and optimal monitoring of vital signs in clinical trials
-
Is there a role for the no observed adverse effect Level in safety pharmacology
Journal of Pharmacological and Toxicological Methods, 2020Co-Authors: Tomas Mow, Simon Authier, Jean-pierre Valentin, Alan S. Bass, Carrie Markgraf, Ninette K. Andersen, Nils Dragsted, Anders B. Lassen, Morten Laursen, Theodore J. BairdAbstract:Abstract In nonclinical toxicology the highest dose or exposure without test article-related adverse effects, known as the No Observed Adverse Effect Level (NOAEL), is a variable that may be determined. In safety pharmacology the vast majority of the endpoints measured are quantitative numeric functional endpoints such as changes in heart rate, blood pressure or respiratory frequency, endpoints that are usually not assessed using a defined framework of adversity. Therefore, we asked the question: is there a role for the NOAEL in safety pharmacology? To help answer this question, we conducted a survey via the Safety Pharmacology Society. We found that within safety pharmacology there is no formal definition of adversity and no guidance on defining NOAEL. We also found, perhaps unsurprisingly, there is no agreed rubric for using a NOAEL in safety pharmacology and we learned that the NOAEL is not a requirement in order to progress a new investigational drug through the regulatory process. Thus, a summary label such as NOAEL lacks nuance and disregards context in relation to the nature and the severity of the safety pharmacology findings. Consequently, defining ‘adversity’ and determining a NOAEL in safety pharmacology studies are not recommended since the range of functional endpoints investigated do not conform to a binary ‘toxic/non-toxic’ rubric. Focusing on describing test article-related effects on safety pharmacology endpoints, using reasoned arguments as part of an integrated risk assessment, will ensure that the clinical pharmacologists and regulatory bodies see a clear description of relevant findings at each dose or exposure Level.
Andrew R. Humpage - One of the best experts on this subject based on the ideXlab platform.
-
oral toxicity of the cyanobacterial toxin cylindrospermopsin in male swiss albino mice determination of no observed adverse effect Level for deriving a drinking water guideline value
Environmental Toxicology, 2003Co-Authors: Andrew R. Humpage, Ian R. FalconerAbstract:The cyanobacterial toxin cylindrospermopsin (CYN) is a frequent contaminant of freshwaters throughout the world, including those that are sources of drinking water. The first cases of human poisoning attributed to this toxin occurred from a treated drinking water supply in Queensland, Australia, in 1979. The toxin causes extensive damage to the liver, kidneys, spleen, heart, and other organs. It is known to be a potent protein synthesis inhibitor, but there is mounting evidence for genotoxicity and that it metabolizes to even more toxic forms. As part of a risk assessment process leading to a guideline for a safe drinking water Level for this toxin, we performed a series of experiments to determine a No-Observed-Adverse-Effect Level (NOAEL) for this toxin. In the first trial male mice were exposed to CYN-containing cyanobacterial extract in their drinking water (0–657 μg CYN kg−1 day−1) for 10 weeks. In the second trial mice received purified CYN by daily gavage (0–240 μg CYN kg−1 day−1) for 11 weeks. Body and organ weights were recorded; urine, serum, and hematology analyses were performed; and histopathological examination of tissues was carried out. Body weights were significantly increased at low doses (30 and 60 μg kg−1 day−1) and decreased at high doses (432 and 657 μg kg−1 day−1). Liver and kidney weights were significantly increased at doses of 240 μg kg−1 day−1 and 60 μg kg−1 day−1, respectively. Serum bilirubin Levels were significantly increased and bile acids significantly decreased at doses of 216 μg kg day−1 and greater. Urine total protein was significantly decreased at doses above 60 μg kg−1 day−1. The kidney appeared to be the more sensitive organ to this toxin. If it is assumed that increased organ weights and changes in functional capacity are responses to an underlying toxic effect, then the NOAEL based on this data is 30 μg kg−1 day−1, which, with standard calculations and uncertainty factors, provides a proposed guideline safety value of 1 μg/L in drinking water. © 2003 Wiley Periodicals, Inc. Environ Toxicol 18: 94–103, 2003.
-
oral toxicity of the cyanobacterial toxin cylindrospermopsin in male swiss albino mice determination of no observed adverse effect Level for deriving a drinking water guideline value
Environmental Toxicology, 2003Co-Authors: Andrew R. Humpage, Ian R. FalconerAbstract:: The cyanobacterial toxin cylindrospermopsin (CYN) is a frequent contaminant of freshwaters throughout the world, including those that are sources of drinking water. The first cases of human poisoning attributed to this toxin occurred from a treated drinking water supply in Queensland, Australia, in 1979. The toxin causes extensive damage to the liver, kidneys, spleen, heart, and other organs. It is known to be a potent protein synthesis inhibitor, but there is mounting evidence for genotoxicity and that it metabolizes to even more toxic forms. As part of a risk assessment process leading to a guideline for a safe drinking water Level for this toxin, we performed a series of experiments to determine a No-Observed-Adverse-Effect Level (NOAEL) for this toxin. In the first trial male mice were exposed to CYN-containing cyanobacterial extract in their drinking water (0-657 microg CYN kg(-1) day(-1)) for 10 weeks. In the second trial mice received purified CYN by daily gavage (0-240 microg CYN kg(-1) day(-1)) for 11 weeks. Body and organ weights were recorded; urine, serum, and hematology analyses were performed; and histopathological examination of tissues was carried out. Body weights were significantly increased at low doses (30 and 60 microg kg(-1) day(-1)) and decreased at high doses (432 and 657 microg kg(-1) day(-1)). Liver and kidney weights were significantly increased at doses of 240 microg kg(-1) day(-1) and 60 microg kg(-1) day(-1), respectively. Serum bilirubin Levels were significantly increased and bile acids significantly decreased at doses of 216 microg kg day(-1) and greater. Urine total protein was significantly decreased at doses above 60 microg kg(-1) day(-1). The kidney appeared to be the more sensitive organ to this toxin. If it is assumed that increased organ weights and changes in functional capacity are responses to an underlying toxic effect, then the NOAEL based on this data is 30 microg kg(-1) day(-1), which, with standard calculations and uncertainty factors, provides a proposed guideline safety value of 1 microg/L in drinking water.
Ninette K. Andersen - One of the best experts on this subject based on the ideXlab platform.
-
Is there a role for the no observed adverse effect Level in safety pharmacology
Journal of pharmacological and toxicological methods, 2020Co-Authors: Tomas Mow, Simon Authier, Jean-pierre Valentin, Alan S. Bass, Carrie Markgraf, Ninette K. Andersen, Nils Dragsted, Anders B. Lassen, Morten Laursen, Theodore J. BairdAbstract:In nonclinical toxicology the highest dose or exposure without test article-related adverse effects, known as the No Observed Adverse Effect Level (NOAEL), is a variable that may be determined. In safety pharmacology the vast majority of the endpoints measured are quantitative numeric functional endpoints such as changes in heart rate, blood pressure or respiratory frequency, endpoints that are usually not assessed using a defined framework of adversity. Therefore, we asked the question: is there a role for the NOAEL in safety pharmacology? To populate our consideration, we conducted a survey via the Safety Pharmacology Society. We found that within safety pharmacology there is no formal definition of adversity and no guidance on defining NOAEL. We also found, perhaps unsurprisingly, there is no agreed rubric for using a NOAEL in safety pharmacology and we learned that the NOAEL is not a requirement in order to progress a new investigational drug through the regulatory process. Thus, a summary label such as NOAEL lacks nuance and disregards context in relation to the nature and the severity of the safety pharmacology findings. Consequently, defining ‘adversity’ and determining a NOAEL in safety pharmacology studies are not recommended since the range of functional endpoints investigated do not conform to a binary ‘toxic/non-toxic’ rubric. Focusing on describing test article-related effects on safety pharmacology endpoints, using reasoned arguments as part of an integrated risk assessment, will ensure that the clinical pharmacologists and regulatory bodies see a clear description of relevant findings at each dose or exposure Level. This will inform a narrative about the potential risks of the test article and support a recommendation for optimal dose setting and optimal monitoring of vital signs in clinical trials
-
Is there a role for the no observed adverse effect Level in safety pharmacology
Journal of Pharmacological and Toxicological Methods, 2020Co-Authors: Tomas Mow, Simon Authier, Jean-pierre Valentin, Alan S. Bass, Carrie Markgraf, Ninette K. Andersen, Nils Dragsted, Anders B. Lassen, Morten Laursen, Theodore J. BairdAbstract:Abstract In nonclinical toxicology the highest dose or exposure without test article-related adverse effects, known as the No Observed Adverse Effect Level (NOAEL), is a variable that may be determined. In safety pharmacology the vast majority of the endpoints measured are quantitative numeric functional endpoints such as changes in heart rate, blood pressure or respiratory frequency, endpoints that are usually not assessed using a defined framework of adversity. Therefore, we asked the question: is there a role for the NOAEL in safety pharmacology? To help answer this question, we conducted a survey via the Safety Pharmacology Society. We found that within safety pharmacology there is no formal definition of adversity and no guidance on defining NOAEL. We also found, perhaps unsurprisingly, there is no agreed rubric for using a NOAEL in safety pharmacology and we learned that the NOAEL is not a requirement in order to progress a new investigational drug through the regulatory process. Thus, a summary label such as NOAEL lacks nuance and disregards context in relation to the nature and the severity of the safety pharmacology findings. Consequently, defining ‘adversity’ and determining a NOAEL in safety pharmacology studies are not recommended since the range of functional endpoints investigated do not conform to a binary ‘toxic/non-toxic’ rubric. Focusing on describing test article-related effects on safety pharmacology endpoints, using reasoned arguments as part of an integrated risk assessment, will ensure that the clinical pharmacologists and regulatory bodies see a clear description of relevant findings at each dose or exposure Level.
