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Chronic effects of low level exposure to anticholinesterases
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Workshop 7. Do Animal Toxicology Studies Really Predict Human Toxicity or Do We Need to "Re-engineer" ?
nence. Syndrome variants identified 63 patients (63/249, 25%) with 91 syndromes. With pyridostigmine bromide as the drug in these drug-chemical exposures, syndrome chemicals were: #1 pesticide containing fiea & tick collars (p < 0.(01), #2 alarms from chemical weapons attacks (p < 0.(01), being in a sector later found to have nerve agent exposure (p < 0.04) and #3 insect repellent (DEET) (p < 0.001) . From CB24, 23 cases, 10 deployed and 10 non-deployed controls were studied. Auditory evoked potentials showed dysfunction (p < 0.02), nystagmic velocity on rotation testing, asymmetry on saccadic velocity (p < 0.04), somatosensory evoked potentials both sides (right p < 0.03, left p < 0.005) and synstagmic velocity after caloric stimulation bilaterally (p range 0.02-0.04). Brain dysfunction was shown on the Halstead Impairment Index (p < 0.01), General Neuropsychological Deficit Scale (p < 0.03) and Trail Making part B (p < 0.03). Butylcholinesterase phenotypes did not trend for inherent abnormalities . Parallel hen studies at Duke University established similar drug-chemical delayed neurotoxicity. These investigations lend credibility that sublethal exposures to drug-chemical combinations caused delayed-onset neurotoxic variants.
IW6/L41
CHRONIC EFFECTS OF LOWLEVELEXPOSURE TO ANTlCHOLINESTERASES
D.E. Ray. Medical Research Council Toxicology Unit, Leicester, UK Low level exposure to anticholinesterases may be defined as that producing no overt cholinergic signs at any time during exposure. Higher level exposures can cause both acute intoxication and also long lasting effects due to excitotoxicity, secondary hypoxic damage, and (probably) the stress of intoxication . Some organophosphorus esters can also cause a specific delayed onset polyneuropathy (OPlON) which can be poorly reversible. A very small number of agents can cause OPlON after low level exposure. Other low level effects are less well defined: The most reliable data comes from controlled low level clinical trials with specific agents. Repeated doses of metrifonate (for treatment of schistosomiasis) or mevinphos , or a single dose of sarin have produced only transient adverse effects at doses causing substantial acetylcholinesterase inhibition . Other data comes from epidemiological surveys. These have often used more sensitive indices than the clinical studies, but are less reliable due to the almost universal use of cross-sectional study designs , difficulty of matching control and exposed populations, and difficulty in defining the nature and extent of exposure . Small, subtle cognitive differences between low level exposed and non-exposed populations are sometimes seen, the largest study showing this difference to be proportionate to estimated lifetime exposure , Mechanistically it is known that medium-term down-regulation of cholinergic systems can occur in response to low level exposure. This effect is reversible. A range of non-cholinergic effects (such as the potential to produce OPlON) are very structure specific, and hazard cannot be generalised across classes . Other molecular targets sensitive to low level exposure to some organophosphates exist in the brain, but their functional significance is not yet fully characterised.
W7. Do Animal Toxicology StudiesReallyPredict Human Toxicity or Do WeNeed to "Re-engineer"?
IW7/L1 I THE PHARMACEUTICAL INDUSTRY'S EXPERIENCE CONCERNING ANIMAL TOXICITY STUDIES PREDICTING ADVERSE EFFECTS IN CLINICAL TRIALS- THE ILSIIHESI REPORT
H.M. Olson. Bayer Corporation, West Haven, CT, USA This presentation describes the procedure for compiling data and presents the results to-date from a multinational pharmaceutical company survey titled, "HESI Project on the Predictivity of the Toxicity of Pharmaceuticals in Humans from Animal Data:. The main aim of this project is to better understand the usefulnes s of animal studies to identify toxicity biomarkers for pharmaceutical-associated human toxicity, and to identify opportunities to improve detection of human toxicity. The strategy for developing the database was originated by Dr. Alastair Monro (Pfizer) a collaborator in this effort. This database for the survey resides in two sets of participant company records: (1) human toxicity for therapeutics identified in Phase I-IV studies which is "significant" in nature, and (2) based on this data, the determination of whether animal toxicity studies performed did or did not identify biomarkers for the relevant human toxicity. A standardized tabular format has been developed for consistency in collection of information including : identification of therapeutic category, the type (organ system) of human toxicity that was identified, and the duration of animal studies in which the corresponding toxicity was either first identified or was not observed . It is important to have objective data compilation to accurately determine the areas (therapeutic categories, human target organs) in which current toxicology procedures predict human toxicity outcomes, and areas where additional resources could improve the detection of clinically relevant toxicities. To-date the survey includes imput from 10 pharmaceutical companies with data compiled from approximately 160 compounds with more than 200 human toxicity events reported. The results of this data analysis will be summarized and recommendations for additional company participation explored.
IW7/L21 WHAT THE CLINICAL PHARMACOLOGIST WANTS TO KNOW FROMANIMAL TOXICOLOGY STUDIES
D. K. Jorkasky. SmithKline Beecham Pharmac euticals, Philadelphia. PA. USA The most vexing problem facing the clinician taking a drug into humans for the first time is the potential for adverse events. The toxicological profile in animals is often well characterized, but may not have relevance to humans in these early trials. Safety pharmacology, if performed adequately, has more relevance to early clinical studies than does long-term pathology. The reverse, however, is true as the drug advances into later stages of development. The purpose of this talk is to focus on what toxicology clinicians find relevant in early stage development, and for later stages of development , to delineate a challenge to toxicologists I) to achieve greater predictability of the relevance of animal toxicology to humans and 2) to identify ways to predict the idiosyncratic reactions in human s, not observed in traditional animal models. The advantages and disadvantages of potential models of genetically altered animals will be discussed in this context.
Workshop 7. Do Animal Toxicology Studies Really Predict Human Toxicity or Do We Need to "Re-engineer" ?
nence. Syndrome variants identified 63 patients (63/249, 25%) with 91 syndromes. With pyridostigmine bromide as the drug in these drug-chemical exposures, syndrome chemicals were: #1 pesticide containing fiea & tick collars (p < 0.(01), #2 alarms from chemical weapons attacks (p < 0.(01), being in a sector later found to have nerve agent exposure (p < 0.04) and #3 insect repellent (DEET) (p < 0.001) . From CB24, 23 cases, 10 deployed and 10 non-deployed controls were studied. Auditory evoked potentials showed dysfunction (p < 0.02), nystagmic velocity on rotation testing, asymmetry on saccadic velocity (p < 0.04), somatosensory evoked potentials both sides (right p < 0.03, left p < 0.005) and synstagmic velocity after caloric stimulation bilaterally (p range 0.02-0.04). Brain dysfunction was shown on the Halstead Impairment Index (p < 0.01), General Neuropsychological Deficit Scale (p < 0.03) and Trail Making part B (p < 0.03). Butylcholinesterase phenotypes did not trend for inherent abnormalities . Parallel hen studies at Duke University established similar drug-chemical delayed neurotoxicity. These investigations lend credibility that sublethal exposures to drug-chemical combinations caused delayed-onset neurotoxic variants.
IW6/L41
CHRONIC EFFECTS OF LOWLEVELEXPOSURE TO ANTlCHOLINESTERASES
D.E. Ray. Medical Research Council Toxicology Unit, Leicester, UK Low level exposure to anticholinesterases may be defined as that producing no overt cholinergic signs at any time during exposure. Higher level exposures can cause both acute intoxication and also long lasting effects due to excitotoxicity, secondary hypoxic damage, and (probably) the stress of intoxication . Some organophosphorus esters can also cause a specific delayed onset polyneuropathy (OPlON) which can be poorly reversible. A very small number of agents can cause OPlON after low level exposure. Other low level effects are less well defined: The most reliable data comes from controlled low level clinical trials with specific agents. Repeated doses of metrifonate (for treatment of schistosomiasis) or mevinphos , or a single dose of sarin have produced only transient adverse effects at doses causing substantial acetylcholinesterase inhibition . Other data comes from epidemiological surveys. These have often used more sensitive indices than the clinical studies, but are less reliable due to the almost universal use of cross-sectional study designs , difficulty of matching control and exposed populations, and difficulty in defining the nature and extent of exposure . Small, subtle cognitive differences between low level exposed and non-exposed populations are sometimes seen, the largest study showing this difference to be proportionate to estimated lifetime exposure , Mechanistically it is known that medium-term down-regulation of cholinergic systems can occur in response to low level exposure. This effect is reversible. A range of non-cholinergic effects (such as the potential to produce OPlON) are very structure specific, and hazard cannot be generalised across classes . Other molecular targets sensitive to low level exposure to some organophosphates exist in the brain, but their functional significance is not yet fully characterised.
W7. Do Animal Toxicology StudiesReallyPredict Human Toxicity or Do WeNeed to "Re-engineer"?
IW7/L1 I THE PHARMACEUTICAL INDUSTRY'S EXPERIENCE CONCERNING ANIMAL TOXICITY STUDIES PREDICTING ADVERSE EFFECTS IN CLINICAL TRIALS- THE ILSIIHESI REPORT
H.M. Olson. Bayer Corporation, West Haven, CT, USA This presentation describes the procedure for compiling data and presents the results to-date from a multinational pharmaceutical company survey titled, "HESI Project on the Predictivity of the Toxicity of Pharmaceuticals in Humans from Animal Data:. The main aim of this project is to better understand the usefulnes s of animal studies to identify toxicity biomarkers for pharmaceutical-associated human toxicity, and to identify opportunities to improve detection of human toxicity. The strategy for developing the database was originated by Dr. Alastair Monro (Pfizer) a collaborator in this effort. This database for the survey resides in two sets of participant company records: (1) human toxicity for therapeutics identified in Phase I-IV studies which is "significant" in nature, and (2) based on this data, the determination of whether animal toxicity studies performed did or did not identify biomarkers for the relevant human toxicity. A standardized tabular format has been developed for consistency in collection of information including : identification of therapeutic category, the type (organ system) of human toxicity that was identified, and the duration of animal studies in which the corresponding toxicity was either first identified or was not observed . It is important to have objective data compilation to accurately determine the areas (therapeutic categories, human target organs) in which current toxicology procedures predict human toxicity outcomes, and areas where additional resources could improve the detection of clinically relevant toxicities. To-date the survey includes imput from 10 pharmaceutical companies with data compiled from approximately 160 compounds with more than 200 human toxicity events reported. The results of this data analysis will be summarized and recommendations for additional company participation explored.
IW7/L21 WHAT THE CLINICAL PHARMACOLOGIST WANTS TO KNOW FROMANIMAL TOXICOLOGY STUDIES
D. K. Jorkasky. SmithKline Beecham Pharmac euticals, Philadelphia. PA. USA The most vexing problem facing the clinician taking a drug into humans for the first time is the potential for adverse events. The toxicological profile in animals is often well characterized, but may not have relevance to humans in these early trials. Safety pharmacology, if performed adequately, has more relevance to early clinical studies than does long-term pathology. The reverse, however, is true as the drug advances into later stages of development. The purpose of this talk is to focus on what toxicology clinicians find relevant in early stage development, and for later stages of development , to delineate a challenge to toxicologists I) to achieve greater predictability of the relevance of animal toxicology to humans and 2) to identify ways to predict the idiosyncratic reactions in human s, not observed in traditional animal models. The advantages and disadvantages of potential models of genetically altered animals will be discussed in this context.