Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A review of the reported foliar residue data has revealed a number of deficiencies in the reentry intervals currently regulated, in particular, by the EPA and some by California. Deficiencies were also identified in the available information necessary to recommend better reentry intervals. Information regarding the frequency of exposure for individual or groups of harvesters is the most fundamental deficiency. It is needed to define a more realistic chronic criterion of allowable daily cholinesterase inhibition without cumulative symptoms. The second criterion of preventing acute overexposure is more readily defined. For the purposes of this study, the criteria of 4% mean daily inhibition and 50% acute inhibition were chosen as acceptable. Based on these criteria, the available data, and by using the unified field model assessment as the basis for comparison (Table 9), EPA reentry intervals for nine insecticides in Table 4 appear inadequate (i.e., not within the range of the model recommendations); 10 are adequate; and only one appears excessive as summarized in Table 10. A similar comparison of California's reentry intervals indicates only two may be inadequate or marginal; 13 are adequate; and five may be excessive. Although these conclusions are based on a considerable amount of residue data, the data are not equally distributed among all pesticides nor has the model been confirmed in all the cropping and harvest conditions examined. However, the model has been developed under realistic field tests, most of its premises have been confirmed in a limited number of tests, and its simulated predictions appear to parallel experience in California where pesticide use and decay conditions may have been most severe but recently well scrutinized. The model's recommendations largely substantiate the regulations developed in California. However, its conclusions definitely suggest that improved levels of protection are needed in other regions. Future reentry intervals will require more comprehensive residue data. The toxicities of detectable metabolites for a few insecticides will need to be determined. More crop residue dosing coefficients are also needed for manually harvested crops. These data must be interpreted in terms of the potential both for acute poisoning from variable residues and for chronic poisoning from repeated exposure to more consistent residues. Surveys of the temporal exposure patterns of harvesters or crews of harvesters are vital to assess the cumulative effects and set the most appropriate chronic cholinesterase response limits. While we await further data, there is sufficient information now to justify longer reentry intervals to protect harvesters nationally.
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PMID:Reentry field data and conclusions. 141 Jun 90

The carcinogen potential of methidathion, a dimethoxyorganic phosphorus pesticide and cholinesterase inhibitor, was evaluated by the Health Effects Division of the Office of Pesticide Programs using a consensus peer review process and the EPA's guidelines for risk assessment. Methidathion was categorized as a Group C (possible human) carcinogen based upon evidence of an increased incidence of benign and malignant hepatocellular tumors, alone and in combination, in a single study involving male Chr-CD-1 mice. The compound was not carcinogenic in female Chr-CD-1 mice in the same study or in Sprague-Dawley rats of either sex in a second study. Methidathion was not genotoxic in a variety of in vitro or in vivo tests designed to detect DNA damage, chromosome aberrations, gene mutations, and sister chromatid exchange. Although methidathion was identified as being structurally similar to two other organophosphate insecticides, prothidathion and lythidathion, no toxicological data were available on either of these agents for comparative purposes. The biological information on methidathion was reviewed by the agency's FIFRA Scientific Advisory Panel who agreed with the category C designation for methidathion. The data were not found to be sufficient to quantify human risk to methidathion.
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PMID:Evaluation of the carcinogenic potential of pesticides. 2. Methidathion. 225 53

After 30 years of experience with human exposure to dichlorvos (DDVP) in the home, workplace, and sickroom, the U.S. EPA has published its intent to revoke the food additive registration of this cholinesterase-inhibiting insecticide. The basis for the Agency action is the result of the National Toxicology Program (NTP) toxicology and carcinogenesis study of DDVP in rats and mice (NTP Technical Report No. 342, September 1989). In those experiments the NTP considered the result in the female mouse portion of the study to afford unequivocal evidence of carcinogenicity. The NTP considered the interpretations of the male and female rat and the male mouse studies to be less than clear. Despite the NTP interpretation, the EPA considers the male rat data (increased incidence of mononuclear cell leukemia) to be sufficient to warrant the regulatory change. The purpose of this report is to summarize a review of the interpretation of the NTP data and to assess the predictive validity of the results relative to potential human health impact. Critical review of experimental data indicates that the evidence for a carcinogenic effect of DDVP in animals is equivocal. Further, DDVP possess no in vivo mutagenic activity in mammalian assay systems and it bears no significant structural similarity to known carcinogens. Therefore, a weight-of-the-evidence analysis leads to the conclusion that DDVP poses neither mutagenic nor carcinogenic risks to humans exposed under normal conditions of use of foreseeable conditions of misuse.
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PMID:Dichlorvos carcinogenicity: an assessment of the weight of experimental evidence. 772 38

Many publications, primarily of work performed in Japan, report findings in human populations of an increased incidence of myopia and of a more advanced visual disease syndrome (Saku disease), which reportedly correlated with increasing use of organophosphate pesticides in agriculture. Follow-up studies in animals performed in Japan using such agents as ethylthiometon, fenthion and fenitrothion demonstrate adverse effects of organophosphates on the visual system. The several ocular effects in question are dose dependent, ranging in severity from lenticular and electro-retinographic changes to the seemingly more serious histophysiological changes in such tissues as the ciliary body and retina. An important question arising from this work is that of the role of cholinesterase inhibition in the etiology of the effects. Studies currently in progress on particular organophosphates being conducted at EPA's research facility and by certain registrants of pesticides, which are in various stages of completion, appear to be substantiating much that has been reported in Japan. While animal studies clearly show that some organophosphates elicit ocular toxicity, there are many knowledge gaps with regard to effects in humans and the ocular toxicity in general, e.g. time and dose dependency, cholinesterase inhibition vs ocular effects and effects of routes of exposure. Consequently, the office is unable at this time to incorporate hazard assessment data with exposure assessment data or to perform risk assessments on organophosphates based on the ocular toxicity potential of this class of chemicals.
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PMID:Ocular effects of organophosphates: a historical perspective of Saku disease. 802 7

Sulprofos, disulfoton, azinphos-methyl, methamidophos, trichlorfon, and tebupirimphos were screened for neurotoxic potential, in accordance with U.S. EPA (FIFRA) requirements. Each organophosphate was administered through the diet for 13 weeks to separate groups of Fischer 344 rats at four dose levels, including a vehicle control. For each study, 12 rats/sex/dietary level were tested using a functional observational battery (FOB), automated measures of activity (figure-8 maze), and detailed clinical observations, with half of the animals perfused at term for microscopic examination of neural and muscle tissues. Separate groups of satellite animals (6/sex/dietary level) were used to measure the effect of each treatment on plasma, erythrocyte (RBC), and brain cholinesterase (ChE) activity. The results show that measures of ChE activity were consistently the most sensitive indices of exposure and assisted in the interpretation of findings. All treatment-related neurobehavioral findings were ascribed to cholinergic toxicity, occurring only at dietary levels that produced more than 20% inhibition of plasma, RBC, and brain ChE activity. Neurobehavioral tests provided no evidence of additional cumulative toxicity after 8 weeks of treatment. The FOB and motor activity findings did not alter the conclusions and generally did not reduce the neurobehavioral no-observed-effect level (NOEL) for any of the six compounds, relative to the results from detailed clinical observations as conducted in these studies. The one exception occurred with tebupirimphos, where the NOEL for motor activity was one dose level lower than the NOEL for the FOB and clinical observations. These results support the value of detailed clinical observations to screen for the neurotoxic potential of organophosphates and a general standard of more than 20% inhibition of brain ChE activity for cholinergic neurotoxicity.
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PMID:Subchronic neurotoxicity screening studies with six organophosphate insecticides: an assessment of behavior and morphology relative to cholinesterase inhibition. 902 78

Categorical regression is a mathematical tool that can be adapted to estimate potential health risk from chemical exposures. By regressing ordered categories of toxic severity or pathological staging on exposure dose, this method can estimate the likelihood of observing any of the categories of severity at any dose level. Depending on the nature of the available data, these estimates can take the form of incidence rates for any of the categories in an exposed population or the probability of a new study conducted at a specified dose level being classified as one of the categories. Categorical regression is illustrated using toxicity data on aldicarb. For aldicarb, the data fall into three different groups: human clinical studies, dietary exposures in experimental animals, and accidental human exposure by contaminated crops. The U.S. EPA has assessed this literature and developed a reference dose (RfD) of 0.001 mg/kg-day. The results of applying categorical regression to data from human clinical studies suggests a maximum likelihood risk estimate of adverse effects of 0.008% at a 10-fold higher dose than the RfD when blood cholinesterase inhibition is not considered as an adverse effect. When blood cholinesterase inhibition of 20% or more is considered as an adverse effect, a maximum likelihood risk estimate of adverse effects is 0.1% at a dose 10-fold higher than the RfD.
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PMID:Categorical regression of toxicity data: a case study using aldicarb. 918 88

The toxicity, exposure, and risk from chlorpyrifos are briefly discussed in juxtaposition with two recent articles in Environmental Health Perspectives concerning potential exposures to children. In studies conducted according to EPA guidelines, chlorpyrifos has been shown not to be mutagenic, carcinogenic, or teratogenic, nor does it adversely affect reproduction. Chlorpyrifos toxicity does not occur in the absence of significant cholinesterase inhibition. If exposures are less than those that cause significant cholinesterase depression, then no signs or symptoms related to chlorpyrifos exposure occur. The weight of empirical evidence indicates that the risk of adults or children experiencing an adverse health effect from exposure to chlorpyrifos through both nondietary and dietary sources is negligible. Both the research supporting the registration of these products and their long history of widespread use suggest that unless these products are seriously misused, their margins of safety are wide enough to protect everyone with the potential to be exposed. A weight-of-evidence review of the entire scientific knowledge base relating to chlorpyrifos products supports these conclusions.
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PMID:Human exposure and risk from indoor use of chlorpyrifos. 1039 32

Chlorpyrifos (CPF) was administered daily in the feed to evaluate toxicity and oncogenicity potential in male and female Fischer 344 rats, according to U.S. EPA guidelines. Doses for the 2-year study were based on findings in a 13-week feeding study in which lower body weights, urinary perineal staining, adrenal cortical vacuolization, and inhibition (slightly more than 60%) of brain cholinesterase (ChE) occurred at 15 mg/kg/day. The high dose in the subsequent 2-year study was 10 mg/kg/day, with lower doses of 0, 0.05, 0.1, or 1.0 mg/kg/day chosen to define dose-response patterns. Rats given 10 mg/kg/day for 2 years were healthy and there was no evidence of premature deaths. Mild toxicity occurred only in rats given 10 mg/kg/day and consisted of perineal urine soiling in females and a 6-8% body-weight decrease in males. Males given 10 mg/kg/day also had increased adrenal weights and vacuolation of the adrenal zona fasciculata. ChE was considered a measure of exposure. Plasma, RBC, and brain ChE activities were inhibited in rats given 10 mg/kg/day, and the plasma and RBC ChE activities were inhibited in rats given 1.0 mg/kg/day. Chronic exposure to 0.1 mg/kg/day was considered a threshold exposure level for inhibition of plasma ChE. Rats given 10 mg/kg/day, considered a maximum-tolerated dose, had approximately 60% chronic inhibition of brain ChE. This group had similar numbers and types of neoplasms as control rats. Consequently, CPF was not carcinogenic at dose levels up to 10 mg/kg/day.
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PMID:Lack of carcinogenicity of chlorpyrifos insecticide in a high-dose, 2-year dietary toxicity study in Fischer 344 rats. 1065 31

Approximately 230,000 kg of organophosphate (OP) pesticides are applied annually in California's Salinas Valley. These activities have raised concerns about exposures to area residents. We collected three spot urine samples from pregnant women (between 1999 and 2001) enrolled in CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas), a longitudinal birth cohort study, and analyzed them for six dialkyl phosphate metabolites. We used urine from 446 pregnant women to estimate OP pesticide doses with two deterministic steady-state modeling methods: method 1, which assumed the metabolites were attributable entirely to a single diethyl or dimethyl OP pesticide; and method 2, which adapted U.S. Environmental Protection Agency (U.S. EPA) draft guidelines for cumulative risk assessment to estimate dose from a mixture of OP pesticides that share a common mechanism of toxicity. We used pesticide use reporting data for the Salinas Valley to approximate the mixture to which the women were exposed. Based on average OP pesticide dose estimates that assumed exposure to a single OP pesticide (method 1), between 0% and 36.1% of study participants' doses failed to attain a margin of exposure (MOE) of 100 relative to the U.S. EPA oral benchmark dose(10) (BMD(10)), depending on the assumption made about the parent compound. These BMD(10) values are doses expected to produce a 10% reduction in brain cholinesterase activity compared with background response in rats. Given the participants' average cumulative OP pesticide dose estimates (method 2) and regardless of the index chemical selected, we found that 14.8% of the doses failed to attain an MOE of 100 relative to the BMD(10) of the selected index. An uncertainty analysis of the pesticide mixture parameter, which is extrapolated from pesticide application data for the study area and not directly quantified for each individual, suggests that this point estimate could range from 1 to 34%. In future analyses, we will use pesticide-specific urinary metabolites, when available, to evaluate cumulative OP pesticide exposures.
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PMID:Cumulative organophosphate pesticide exposure and risk assessment among pregnant women living in an agricultural community: a case study from the CHAMACOS cohort. 1452 44

Environmental exposures generally involve chemical mixtures instead of single chemicals. Statistical models such as the fixed-ratio ray design, wherein the mixing ratio (proportions) of the chemicals is fixed across increasing mixture doses, allows for the detection and characterization of interactions among the chemicals. In this study, we tested for interaction(s) in a mixture of five organophosphorus (OP) pesticides (chlorpyrifos, diazinon, dimethoate, acephate, and malathion). The ratio of the five pesticides (full ray) reflected the relative dietary exposure estimates of the general population as projected by the US EPA Dietary Exposure Evaluation Model (DEEM). A second mixture was tested using the same dose levels of all pesticides, but excluding malathion (reduced ray). The experimental approach first required characterization of dose-response curves for the individual OPs to build a dose-additivity model. A series of behavioral measures were evaluated in adult male Long-Evans rats at the time of peak effect following a single oral dose, and then tissues were collected for measurement of cholinesterase (ChE) activity. Neurochemical (blood and brain cholinesterase [ChE] activity) and behavioral (motor activity, gait score, tail-pinch response score) endpoints were evaluated statistically for evidence of additivity. The additivity model constructed from the single chemical data was used to predict the effects of the pesticide mixture along the full ray (10-450 mg/kg) and the reduced ray (1.75-78.8 mg/kg). The experimental mixture data were also modeled and statistically compared to the additivity models. Analysis of the 5-OP mixture (the full ray) revealed significant deviation from additivity for all endpoints except tail-pinch response. Greater-than-additive responses (synergism) were observed at the lower doses of the 5-OP mixture, which contained non-effective dose levels of each of the components. The predicted effective doses (ED20, ED50) were about half that predicted by additivity, and for brain ChE and motor activity, there was a threshold shift in the dose-response curves. For the brain ChE and motor activity, there was no difference between the full (5-OP mixture) and reduced (4-OP mixture) rays, indicating that malathion did not influence the non-additivity. While the reduced ray for blood ChE showed greater deviation from additivity without malathion in the mixture, the non-additivity observed for the gait score was reversed when malathion was removed. Thus, greater-than-additive interactions were detected for both the full and reduced ray mixtures, and the role of malathion in the interactions varied depending on the endpoint. In all cases, the deviations from additivity occurred at the lower end of the dose-response curves.
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PMID:Neurotoxicological and statistical analyses of a mixture of five organophosphorus pesticides using a ray design. 1580 32


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