AUTHORS: Byrne SL; Shurdut BA; Saunders DG

AUTHOR AFFILIATION: Environmental Chemistry Laboratories-Indianapolis Laboratory, Dow AgroSciences, Indianapolis, IN 46268-1054 USA.

SOURCE: Environ Health Perspect 1998 Nov;106(11):725-31

CITATION IDS: PMID: 9799188 UI: 99016022

ABSTRACT: Multipathway exposures were evaluated for residents of houses over a 10- day period following a crack and crevice application of a chlorpyrifos- based formulation. Three multiroom houses with two adults each were treated. Air concentration, total deposition, and dislodgeable residues on horizontal surfaces were measured to assess potential respiratory, oral, and dermal exposures, respectively, in treated and untreated high activity rooms. In addition, urine samples collected from the adults were analyzed for the primary metabolite of chlorpyrifos, 3,5,6- trichloropyridinol, to determine absorbed dose. The maximum chlorpyrifos air concentration observed was 2.3 microgram/m3, with air concentrations generally decreasing to levels ranging from 0.1 to 0.3 microgram/m3 within 10 days. Carpet dislodgeable residues, used to evaluate the amount of residues potentially transferred upon contact, were less than the analytical method limit of quantitation (1.6 microgram/m2). Hard plastic balls placed in the homes on the day before application contained no detectable dislodgeable residues (<6.5 microgram/m2). Ten-day cumulative nontarget residues deposited on surfaces, as determined by deposition pads, were less than 2.3 microgram/100 cm2. Deposition samples from all living area floors collected 2 hr after application contained less than 9.9 microgram/100 cm2. Therefore, contact with household surfaces and subsequent hand-to- mouth activity are not expected to significantly contribute to overall exposure. Estimated exposures to children, based on the passive dosimetry measurements, ranged from 0.26 to 2.1% of the no observed effect level for plasma cholinesterase depression. In addition, potential exposures to the adult residents, as indicated by the urinary 3,5,6-TCP biomonitoring, did not increase as a result of the application.

AUTHORS: Furlong CE; Li WF; Costa LG; Richter RJ; Shih DM; Lusis AJ

AUTHOR AFFILIATION: Department of Medicine, University of Washington, Seattle 98195-7360, USA.

SOURCE: Neurotoxicology 1998 Aug-Oct;19(4-5):645-50

CITATION IDS: PMID: 9745924 UI: 98417006

ABSTRACT: Several organophosphorus insecticides and nerve agents are detoxified through the cytochrome P450/paraoxonase (PON1) pathway. PON1 is an HDL- associated enzyme encoded as a 355 amino acid protein in humans. The PON1 Arg192 isoform hydrolyzes paraoxon rapidly while the Gln192 isoform hydrolyzes this compound slowly. Both isoforms hydrolyze phenylacetate and chlorpyrifos oxon at approximately the same rate. We recently found that the effect of this polymorphism is dramatically reversed for sarin hydrolysis. The PON1 Arg192 isoform has virtually no sarinase activity while the Gln192 isoform has substantial activity. The Gln192 isoform also hydrolyzes diazoxon and soman faster than the Arg192 isoform. In addition to the large differences in rates of hydrolysis observed for some OP substrates by the two PON1 isoforms, there is also a large variability in serum PON1 concentrations that is stable over time between individuals. Thus, two factors govern the PON1 status of a given individual, the PON1 genotype as well as the amount of protein expressed from each allele. A two-dimensional enzyme analysis provides an excellent assessment of an individual's PON1 status, ie. the position 192 genotype as well as phenotype, or level of serum PON1 (Nature Genet 14:334-336). Do these interindividual differences in rates of substrate hydrolysis by PON1 reflect an individual's sensitivity or resistance to OP compounds processed through the P450/PON1 pathway? Injection of purified PON1 into mice clearly demonstrates the protective effect of having high serum levels of PON1 against toxicity by chlorpyrifos oxon or chlorpyrifos. Preliminary experiments with PON1 knockout mice, on the other hand, clearly demonstrate that low PON1 levels result in dramatically increased sensitivity to chlorpyrifos oxon. Attempts to express human PON1 in mice from constructs containing either of the human PON1 cDNA sequences were unsuccessful, despite the generation of the respective transgenic mice.

AUTHORS: Amitai G; Moorad D; Adani R; Doctor BP

AUTHOR AFFILIATION: Division of Biochemistry, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA. amitai@iibr.gov.il

SOURCE: Biochem Pharmacol 1998 Aug 1;56(3):293-9

CITATION IDS: PMID: 9744565 UI: 98415814

ABSTRACT: Phosphorothionate insecticides such as parathion (O,O-diethyl O-p- nitrophenyl phosphorothioate) and chlorpyrifos (CPS; O,O-diethyl O- 3,5,6-trichloro-2-pyridyl phosphorothioate; Dursban) are metabolically converted by oxidative desulfuration into paraoxon and chlorpyrifos- oxon (CPO). The insecticidal action of chlorpyrifos stems from inhibition of acetylcholinesterase (AChE) by CPO, resulting in severe cholinergic toxicity. Sensory peripheral neuropathy was observed in people exposed environmentally to chlorpyrifos sprayed in confined areas. We have examined the kinetics of inhibition of AChE and butyrylcholinesterase (BChE) by paraoxon and CPO. The bimolecular rate constants (ki) for inhibition by paraoxon of recombinant human (rH) AChE, recombinant mouse (rM) AChE, and fetal bovine serum (FBS) AChE were 7.0, 4.0, and 3.2 x 10(5) M(-1) min(-1). The ki values for the inhibition by CPO of rH AChE, fetal bovine serum AChE, human RBC AChE, Torpedo AChE, and recombinant mouse (rM) AChE were 9.3, 2.2, 3.8, 8.0, and 5.1 x 10(6) M(-1) min(-1), respectively. Inhibition of human serum BChE, rH BChE, and rM BChE by CPO yielded ki values of 1.65, 1.67, and 0.78 x 10(9) M(-1) min(-1), respectively. The ki values obtained for BChE from various species were 160- to 750-fold larger than those of AChE from parallel sources. Inhibition of the single-site mutant A328Y of rH BChE by CPO displayed a 21-fold lower rate than that of wild-type rH BChE (ki, 7.9 x 10(7) vs 1.67 x 10(9) M(-1) min(-1)). The double mutant of acyl pocket residues of rH AChE, F295L/F297V, was inhibited by CPO with a 150-fold larger ki than wild type (1.5 x 10(9) vs 1.0 x 10(7) M(-1) min(-1)). The increased rate obtained with the double mutant displaying characteristics of the BChE active center provides a rationale for higher efficacy of CPO scavenging by BChE, compared with AChE.

AUTHORS: Harvey PW; Marks GC; Heywood PF

AUTHOR AFFILIATION: Nutrition Program, Australian Centre for International & Tropical Health & Nutrition, University of Queensland, Brisbane. pharvey2@bellsouth.net

SOURCE: Aust N Z J Public Health 1998 Apr;22(2):266-8

CITATION IDS: PMID: 9744190 UI: 98416853

ABSTRACT: The purpose of this work was to integrate existing chemical residue and food consumption data for individuals to improve estimates of the dietary intake of chemical residues in the population of Brisbane. Previous estimates of intakes from the Australian Market Basket Survey (AMBS) have been based on energy-adjusted 'hypothetical national diets' and so allow no assessment of variation in intakes between individuals or groups. Data on concentration of fenitrothion, chlorpyrifos-methyl, pirimiphos-methyl, heptachlor and dieldrin in selected foods were taken from reports of the AMBS. Food consumption data were based upon the National Dietary Survey of Adults (NDSA) 1983; the same data from which the hypothetical diets are derived. The distribution of estimated 24- hour intakes was adjusted to represent usual intakes. Mean intakes of all residues were about one third those reported previously. None of the observed diets contained levels of residues that were greater than the Acceptable Daily Intakes. These findings support reassurances to the public that residues of agricultural chemicals monitored in the AMBS do not pose a health risk.

AUTHORS: Gibson JE; Peterson RK; Shurdut BA

AUTHOR AFFILIATION: Dow AgroSciences LLC, Indianapolis, IN 46268, USA.

SOURCE: Environ Health Perspect 1998 Jun;106(6):303-6

CITATION IDS: PMID: 9618344 UI: 98283861

ABSTRACT: 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.

AUTHORS: Davis DL; Ahmed AK

AUTHOR AFFILIATION: World Resources Institute, Washington, DC 20006, USA.

SOURCE: Environ Health Perspect 1998 Jun;106(6):299-301

CITATION IDS: PMID: 9618343 UI: 98283860

ABSTRACT: Recent findings of indoor exposure studies of chlorpyrifos indicate that young children are at higher risks to the semivolatile pesticide than had been previously estimated [Gurunathan et al., Environ Health Perspect 106:9-16 (1998)]. The study showed that after a single broadcast use of the pesticide by certified applicators in apartment rooms, chlorpyrifos continued to accumulate on children's toys and hard surfaces 2 weeks after spraying. Based on the findings of this and other research studies, the estimated chlorpyrifos exposure levels from indoor spraying for children are approximately 21-119 times above the current recommended reference dose of 3 microg/kg/day from all sources. A joint agreement reached between the U.S. Environmental Protection Agency and the registrants of chlorpyrifos-based products will phase out a number of indoor uses of the pesticide, including broadcast spraying and direct uses on pets. While crack and crevice treatment of insects (such as cockroaches and termites) by chlorpyrifos will still continue, it appears prudent to explore other insect control options, including the use of baits, traps, and insect sterilants and growth regulators. To ensure global protection, adequate dissemination of appropriate safety and regulatory information to developing regions of the world is critical, where importation and local production of chlorpyrifos-based products for indoor uses may be significant.

AUTHORS: Brzak KA; Harms DW; Bartels MJ; Nolan RJ

AUTHOR AFFILIATION: Health and Environmental Research Laboratories, Dow Chemical Company, Midland, Michigan 48674, USA.

SOURCE: J Anal Toxicol 1998 May-Jun;22(3):203-10

CITATION IDS: PMID: 9602936 UI: 98265646

ABSTRACT: Analytical methods to quantitate chlorpyrifos and two potential metabolites, chlorpyrifos oxon (oxon) and 3,5,6-trichloro-2-pyridinol (TCP), in human and rat blood are described. Chlorpyrifos and the oxon were extracted simultaneously with a methanol/hexane mixture from 0.5 mL blood that was deactivated with an acidic salt solution. The extract was then concentrated and analyzed by negative-ion chemical ionization gas chromatography-mass spectrometry (NCI-GC-MS). TCP was extracted from a separate 0.1-mL aliquot of blood, also deactivated by the addition of acid. The t-butyldimethylsilyl derivative of TCP was formed using MTBSTFA, and the analysis was performed by NCI-GC-MS. Stable isotope analogues of chlorpyrifos (-13C2-15N), oxon (-13C2-15N), and TCP (-13C2) were used as internal standards. Oxon was observed to partially degrade to TCP during the sample analysis. Accurate oxon and TCP measurements were obtained with the use of oxon-13C2-15N, TCP-13C2, and TCP-13C2-15N internal standards, which compensated for both the degradation of oxon and the formation of artifactual TCP during analysis. The limits of quantitation were 1 ng/mL blood for both chlorpyrifos and oxon and 10 ng/mL for TCP. Calibration curves were linear over the concentration range of 2.5-2500 ng/mL solvent for chlorpyrifos and oxon and between 5 and 1060 ng/mL solvent for TCP. Taking concentration factors and extraction efficiencies into account, these linear ranges represent blood concentrations of approximately 0.3- 300 ng/mL blood for chlorpyrifos and the oxon and 6-1300 ng/mL blood for TCP. The lowest spike level for chlorpyrifos and the oxon was 1 ng/mL blood, and the lowest spike level for TCP was 10 ng/mL blood. Recoveries from rat blood were as follows: 106-119% for chlorpyrifos, 94-104% for oxon, and 85-102% for TCP. In addition, chlorpyrifos and oxon were incubated with rat and human blood for various time intervals before deactivation to determine precautions that needed to be taken when collecting and handling specimens. No change in chlorpyrifos concentration was observed in rat blood up to 180 min at 37 degrees C. In contrast, the oxon was rapidly hydrolyzed to TCP in both rat (t 1/2 approximately 10 s) and human (t 1/2 approximately 55 s) blood held at 37 degrees C. The hydrolysis rate for the oxon was independent of whether a rat had been administered chlorpyrifos previously, the initial oxon concentration, the presence of chlorpyrifos, and the age or gender of the human volunteers. These results suggest rapid sample preparation is critical for accurate determinations of the oxon metabolite of chlorpyrifos. These methods provide excellent tools for use in chlorpyrifos pharmacokinetic modeling studies.

AUTHORS: Gurunathan S; Robson M; Freeman N; Buckley B; Roy A; Meyer R; Bukowski J; Lioy PJ

AUTHOR AFFILIATION: Environmental and Occupational Health Sciences Institute, Rutgers University and the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08855 USA; Joint Ph.D. Program in Exposure Assessmen.

SOURCE: Environ Health Perspect 1998 Apr;106 Suppl 2:9-16

[MEDLINE record in process]

CITATION IDS: PMID: 9417768 UI: 98079181

ABSTRACT: Quantitative examination of major pathways and routes of exposure to pesticides is essential for determining human risk. The current study was conducted in two apartments and examines the accumulation of the pesticide chlorpyrifos in childrens' toys after the time suggested for reentry after application. It has been established for the first time that a semivolatile pesticide will accumulate on and in toys and other sorbant surfaces in a home via a two-phase physical process that continues for at least 2 weeks postapplication. A summation of the above for a 3-6-year-old child yielded an estimated nondietary total dose of 208 microg/kg/day. Potential exposure from the inhalation pathway was negligible, while dermal and nondietary oral doses from playing with toys contributed to 39 and 61% of the total dose, respectively. If children with high frequency mouthing behavior are considered as candidates for acute exposure to chlorpyrifos residues, the estimated acute dose could be as high as 356 microg/kg/day. Routine reapplication of pesticides could lead to continued accumulation in toys and other sorbant surfaces, e.g., pillows, with large sorbant reservoirs, which can become a long-term source of exposure to a child. Estimates of a child's nondietary exposure to chlorpyrifos associated with toys and other sorbant surfaces for a period of 1 week following application appear to be of public health concern, and studies of actual childhood exposure from this pathway are warranted in the home environment. The above information should be used to determine if current procedures for postapplication reentry are sufficient and to evaluate the need for procedures to store frequently used household toys, pillows, and other sorbant objects during insecticidal application.

AUTHORS: Moretto A; Lotti M

AUTHOR AFFILIATION: Universita degli Studi di Padova, Istituto di Medicina del Lavoro, Italy.

SOURCE: J Neurol Neurosurg Psychiatry 1998 Apr;64(4):463-8

CITATION IDS: PMID: 9576536 UI: 98236073

ABSTRACT: OBJECTIVES: Poisoning by organophosphate insecticides causes cholinergic toxicity. Organophosphate induced delayed polyneuropathy (OPIDP) is a sensory-motor distal axonopathy which usually occurs after ingestion of large doses of certain organophosphate insecticides and has so far only been reported in patients with preceding cholinergic toxicity. Surprisingly, it was recently reported by other authors that an exclusively sensory neuropathy developed in eight patients after repeated unquantified exposures to chlorpyrifos, which did not cause clear-cut cholinergic toxicity. The objective was to assess whether an exclusively sensory neuropathy develops in patients severely poisoned by various OPs. METHODS: Toxicological studies and electrophysiological measurements were performed in peripheral motor and sensory nerves in 11 patients after acute organophosphate poisoning among which two subjects were poisoned with chlorpyrifos. RESULTS: Three patients developed OPIDP, including one poisoned by chlorpyrifos. Exclusively sensory neuropathy was never seen after either single or repeated acute organophosphate poisoning. A mild sensory component was associated with a severe motor component in two of the three cases of OPIDP, the other was an exclusively motor polyneuropathy. CONCLUSION: A sensory-motor polyneuropathy caused by organophosphate insecticides might occur after a severe poisoning and the sensory component, if present, is milder than the motor one. Bearing in mind the toxicological characteristics of these organophosphate insecticides, other causes should be sought for sensory peripheral neuropathies in patients who did not display severe cholinergic toxicity a few weeks before the onset of symptoms and signs.

AUTHORS: Sherman JD

SOURCE: Arch Environ Health 1997 Sep-Oct;52(5):332-3

CITATION IDS: PMID: 9546754 UI: 98206831

MAIN MESH HEADINGS: Abnormalities, Drug-Induced/*etiology, *Centers for Disease Control and Prevention (U.S.), Chlorpyrifos/*poisoning, Insecticides, Organothiophosphate/*poisoning, *Maternal Exposure, *United States Environmental Protection Agency

ADDITIONAL MESH HEADINGS: Abnormalities, Drug-Induced/epidemiology, Female, Human, Infant, Newborn, Population Surveillance, Pregnancy, Pregnancy Outcome/epidemiology, United States/epidemiology

AUTHORS: Burns CJ; Cartmill JB; Powers BS; Lee MK

AUTHOR AFFILIATION: Dow Chemical Company, Midland, MI 48674, USA.

SOURCE: Occup Environ Med 1998 Jan;55(1):65-70

CITATION IDS: PMID: 9536166 UI: 98197228

ABSTRACT: OBJECTIVES: Chlorpyrifos, an organophosphate ingredient of several important insecticides, has been manufactured at The Dow Chemical Company for 25 years. A previous morbidity study among employees of The Dow Chemical Company found no increased prevalence of illness or symptoms among employees potentially exposed to chlorpyrifos from 1977 to 1985 compared with matched controls. The purpose of the current study was to update the original study to 1994, thereby increasing the statistical power. METHODS: In the present study, 496 potentially exposed subjects were identified and matched for age, race, sex, pay, and year of hire to 911 control subjects. Morbidity data were abstracted from company medical records. RESULTS: The prevalence of peripheral neuropathy was not significantly increased among this group of employees potentially exposed to chlorpyrifos. Significantly increased prevalence odds ratios were identified for five diagnostic categories: diseases of the ear and mastoid process; acute respiratory infections; other diseases of the respiratory system; general symptoms, signs, and ill defined conditions; and symptoms, signs, and ill defined conditions involving the digestive system. There was a strong association of diagnosis with duration of observation period, indicating that the exposed workers were more likely than unexposed workers to have a diagnosis abstracted from the company medical records due to their longer mean period of follow up. Analyses by exposure classification and mean plasma cholinesterase activity did not show a dose response. CONCLUSIONS: These data do not support a cause and effect relation of the diagnoses mentioned and exposure to chlorpyrifos.

SOURCE: Health News 1998 Mar 10;4(3):7

CITATION IDS: PMID: 9516345 UI: 98171388

MAIN MESH HEADINGS: Chlorpyrifos/*adverse effects, Insecticides, Organothiophosphate/*adverse effects

ADDITIONAL MESH HEADINGS: Human, Infant, Play and Playthings

AUTHORS: Saleh MA; Kamel A; el-Demerdash A; Jones J

AUTHOR AFFILIATION: Department of Chemistry, Texas Southern University, Houston 77004, USA.

SOURCE: Chemosphere 1998 Mar;36(7):1543-52

CITATION IDS: PMID: 9503577 UI: 98164318

ABSTRACT: Six different types of fabrics were compared for their ability to protect against human exposure to three different commercial household aerosol insecticides. Fabrics used in this investigation were, 100% cotton, cotton-polyester thermal underwear, cotton-polyester blend (twill), 100% acrylic, 100% wool and artificial silk (rayon). The household insecticides were, Black Flag (Ant and Roach Killer), Raid (Ant and Roach Killer) and Hot Shot (Wasp and Hornet Killer) containing propoxur, permethrin/pyrethrins and chlorpyrifos/allethrins as their active ingredients respectively. A fluorescent tracer, 4-methyl-7- diethyl amino coumarin was mixed with the aerosol (or equivalent aliquot) and sprayed onto cloth squares fitted on Whatman paper patches. The percentage of penetration through the cloth was quantified by the intensity of the fluorescence spectrum of each patch extract and the amount of the tracer recovered was calculated. The extract was concentrated to 1/10th of the volume to measure the content of each of the insecticides by supercritical fluid chromatography (SFC) using electron capture (ECD) and diode array detectors. Scanning electron microscope (SEM) images of the fabrics showed the geometry of the yarn. The results obtained from the fluorescence spectra, SFC and SEM showed that cotton-polyester (twill), cotton, wool and cotton thermal underwear were the least penetrable materials for the aerosols. On the other hand, acrylic and artificial silk (rayon) were the most penetrable cloth types.

AUTHORS: Gordon CJ; Rowsey PJ

AUTHOR AFFILIATION: Neurotoxicology Division, National Health Effects and Environmental Research Laboratory, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. GORDON@HERL45.HERL.EPA.GOV

SOURCE: Clin Exp Pharmacol Physiol 1998 Feb;25(2):145-9

CITATION IDS: PMID: 9493505 UI: 98152499

ABSTRACT: 1. Dysfunction of the thermoregulatory system is one of many pathologies documented in experimental animals and humans exposed to toxic chemicals. The mechanism of action responsible for many types of poison-induced fevers is not understood. Some elevations in body temperature are attributed to the peripheral actions of some poisons that stimulate metabolic rate and cause a forced hyperthermia. Exposure to organophosphate (OP) pesticides and certain metal fumes appears to cause a prolonged, regulated elevation in body temperature (Tb). 2. Activation of cyclo-oxygenase (COX) and the production of prostaglandin (PG)E2 in central nervous system (CNS) thermoregulatory centres is required to elicit a fever. Activating the COX-PGE2 pathway by a poison may occur by one of three mechanisms: (i) induction of cell-mediated immune responses and the subsequent release of cytokines; (ii) induction of lipid peroxidation in the CNS; and (iii) direct neurochemical activation. 3. Radiotelemetric monitoring of core temperature in unstressed rodents has led to an experimental animal model of poison-induced fever. Rats administered the OP agents chlorpyrifos and diisopropyl fluorophosphate display an initial hypothermic response lasting approximately 24 h, followed by an elevation in diurnal core temperature for 24-72 h after exposure. The hyperthermia is apparently a result of the activation of the COX-PGE2 pathway because it is blocked by the anti-pyretic sodium salicylate. Overall, the delayed hyperthermia resulting from OP exposure involves activation of thermoregulatory pathways that may be similar to infection-mediated fever.

AUTHORS: Worek F; Backer M; Thiermann H; Szinicz L; Mast U; Klimmek R; Eyer P

AUTHOR AFFILIATION: Institut fur Pharmakologie und Toxikologie, Akademie des Sanitats- und Gesundheitswesens der Bundeswehr, Garching, Germany.

SOURCE: Hum Exp Toxicol 1997 Aug;16(8):466-72

CITATION IDS: PMID: 9292287 UI: 97437754

ABSTRACT: 1 In vitro studies with human erythrocyte acetylcholinesterase (AChE) and the mouse diaphragm model were performed to unravel the various microscopic reaction parameters that contribute to the dynamic equilibrium of AChE inhibition, ageing and reactivation. These data may help to define more precisely the indications and limitations of oxime therapy in organophosphate (OP) poisoning. 2 Diethylphosphoryl-AChE resulting from intoxications with parathion, chlorpyrifos, chlorfenvinphos, diazinon and other OPs is characterized by slow spontaneous reactivation and low propensity for ageing. This kind of phosphorylated enzyme is particularly susceptible to reactivation by oximes. 3 None of the oximes tested (pralidoxime, obidoxime, HI 6 and HLo 7) can be regarded as a universally suitable reactivator. Obidoxime turned out to be the most potent and most efficacious oxime in reactivating AChE inhibited by various classes of OP insecticides and tabun. Obidoxime, however, was inferior to HI 6 against soman, sarin, cyclosarin and VX. Pralidoxime was generally less potent. 4 The kinetic data of reactivation established for diethylphosphoryl-AChE of human red cells indicate that the usually recommended dosage to attain a plasma concentration of 4 micrograms/ml does not permit exploitation of the full therapeutic potential of the oximes, in particular of pralidoxime. However, in suicidal mega-dose poisoning, oximes, even at optimal plasma concentrations, may be unable to cope with the fast re- inhibition of reactivated AChE in the first days following intoxication. 5 It is suggested that oximes be administered by continuous infusion following an initial bolus dose as long as reactivation can be expected and until permanent clinical improvement is achieved.

AUTHORS: Ehrich M; Correll L; Veronesi B

AUTHOR AFFILIATION: Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg, Virginia, 24061, USA.

SOURCE: Fundam Appl Toxicol 1997 Jul;38(1):55-63

CITATION IDS: PMID: 9268605 UI: 97415729

ABSTRACT: The differential inhibition of the target esterases acetylcholinesterase (AChE) and neuropathy target esterase (NTE, neurotoxic esterase) by organophosphorus compounds (OPs) is followed by distinct neurological consequences in exposed subjects. The present study demonstrates that neuroblastoma cell lines (human SH-SY5Y and murine NB41A3) can be used to differentiate between neuropathic OPs (i.e., those inhibiting NTE and causing organophosphorus-induced delayed neuropathy) and acutely neurotoxic OPs (i.e., those highly capable of inhibiting AChE). In these experiments, concentration- response data indicated that the capability to inhibit AChE was over 100x greater than the capability to inhibit NTE for acutely toxic, nonneuropathic OPs (e.g., paraoxon and malaoxon) in both cell lines. Inhibition of AChE was greater than inhibition of NTE, without overlap of the concentration-response curves, for OPs which are more likely to cause acute, rather than delayed, neurotoxic effects in vivo (e.g., chlorpyrifos-oxon, dichlorvos, and trichlorfon). In contrast, concentrations inhibiting AChE and NTE overlapped for neuropathy- causing OPs. For example, apparent IC50 values for NTE inhibition were less than 9.6-fold the apparent IC50 values for AChE inhibition when cells were exposed to the neuropathy-inducing OPs diisopropyl phosphorofluoridate, cyclic tolyl saligenin phosphate, phenyl saligenin phosphate, mipafox, dibutyl dichlorovinyl phosphate, and di-octyl- dichlorovinyl phosphate. In all cases, esterase inhibition occurred at lower concentrations than those needed for cytoxicity. These results suggest that either mouse or human neuroblastoma cell lines can be considered useful in vitro models to distinguish esterase-inhibiting OP neurotoxicants.

AUTHORS: Kaiser J

SOURCE: Science 1997 Apr 11;276(5310):201

CITATION IDS: PMID: 9132941 UI: 97268586

MAIN MESH HEADINGS: Chlorpyrifos/*toxicity, Cholinesterase Inhibitors/*toxicity, *Dinoflagellida, Insecticides, Organophosphate/*toxicity, Marine Toxins/*toxicity, Myopia/*chemically induced

ADDITIONAL MESH HEADINGS: Animal, Cell Death, Chickens, Gastrointestinal System/cytology, Gastrointestinal System/drug effects, Human, Learning/drug effects, Neurons/cytology, Neurons/drug effects

AUTHORS: Lemus R; Abdelghani AA; Akers TG; Horner WE

AUTHOR AFFILIATION: Department of Environmental Health Sciences, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA. assafa@mailhost.tcs.tulane.edu

SOURCE: Rev Environ Health 1997 Apr-Jun;12(2):91-7

CITATION IDS: PMID: 9273925 UI: 97419359

ABSTRACT: A four-season, indoor air quality survey was conducted in Southern Louisiana to determine the indoor air levels of the pesticide chlorpyrifos. Gas chromatographic analysis of 213 air samples collected from 53 houses revealed levels of chlorpyrifos ranging from non- detected to 2.13 micrograms/m3. Using the Florida-Pinella exposure guideline (24-hr exposure to chlorpyrifos at 0.48 microgram/m3), it was noted that 14% of the samples exceeded this guideline. The exposure of occupants to the indoor air concentrations of the pesticide, however, were below either the irritation or the odor thresholds, and effects on acute and chronic health responses remains uncertain.

AUTHORS: Bradman MA; Harnly ME; Draper W; Seidel S; Teran S; Wakeham D; Neutra R

AUTHOR AFFILIATION: Division of Environmental and Occupational Disease Control, California Department of Health Services, Emeryville, USA. abradman@hwl.cahwnet.gov

SOURCE: J Expo Anal Environ Epidemiol 1997 Apr-Jun;7(2):217-34

CITATION IDS: PMID: 9185013 UI: 97328475

ABSTRACT: In response to concerns about pesticide use and evidence that contaminants may accumulate in house dust, the California Department of Health Services (DHS) conducted a pilot study of pesticide contamination in rural children's home environments. House dust samples for pesticide analysis were collected from eleven homes, five of which had at least one farmworker (FW) resident. Handwipe samples were collected from one child at each residence (ages 1-3 years). Ten of 33 pesticides tested in house dust were detected. Excluding non-detects, concentrations for diazinon ranged from 0.7-169 ppm in four FW homes and 0.2-2.5 ppm in three non-farmworker (NFW) homes (overall median = 1 ppm), suggesting a difference between FW and NFW homes. Chlorpyrifos ranged from 0.2-33 ppm in three FW homes and < 1 ppm in two NFW homes (overall median < 0.5 ppm). All other pesticides were detected at < 2 ppm at four or fewer homes. The sources of these compounds could not be determined. Co-located samples were considerably different in concentration and loading, indicating intra-household variation. Of nine compounds tested, diazinon and chlorpyrifos were found on the hands of two or three FW children (20-220 ng/hand). Dust ingestion scenarios show child exposures could exceed the United States Environmental Protection Agency Office of Pesticide Program diazinon chronic reference dose (9 x 10(5) mg/kg/day). The results suggested that pesticide residues are present in the home environment of some California children and are likely to contribute to exposures. Additional research is feasible and needed to assess the magnitude and distribution of these risks.

AUTHORS: Ziem G; McTamney J

AUTHOR AFFILIATION: Occupational and Environmental Medicine, Baltimore, Maryland, USA.

SOURCE: Environ Health Perspect 1997 Mar;105 Suppl 2:417-36

CITATION IDS: PMID: 9167975 UI: 97311258

ABSTRACT: Patients reporting sensitivity to multiple chemicals at levels usually tolerated by the healthy population were administered standardized questionnaires to evaluate their symptoms and the exposures that aggravated these symptoms. Many patients were referred for medical tests. It is thought that patients with chemical sensitivity have organ abnormalities involving the liver, nervous system (brain, including limbic, peripheral, autonomic), immune system, and porphyrin metabolism, probably reflecting chemical injury to these systems. Laboratory results are not consistent with a psychologic origin of chemical sensitivity. Substantial overlap between chemical sensitivity, fibromyalgia, and chronic fatigue syndrome exists: the latter two conditions often involve chemical sensitivity and may even be the same disorder. Other disorders commonly seen in chemical sensitivity patients include headache (often migraine), chronic fatigue, musculoskeletal aching, chronic respiratory inflammation (rhinitis, sinusitis, laryngitis, asthma), attention deficit, and hyperactivity (affected younger children). Less common disorders include tremor, seizures, and mitral valve prolapse. Patients with these overlapping disorders should be evaluated for chemical sensitivity and excluded from control groups in future research. Agents whose exposures are associated with symptoms and suspected of causing onset of chemical sensitivity with chronic illness include gasoline, kerosene, natural gas, pesticides (especially chlordane and chlorpyrifos), solvents, new carpet and other renovation materials, adhesives/glues, fiberglass, carbonless copy paper, fabric softener, formaldehyde and glutaraldehyde, carpet shampoos (lauryl sulfate) and other cleaning agents, isocyanates, combustion products (poorly vented gas heaters, overheated batteries), and medications (dinitrochlorobenzene for warts, intranasally packed neosynephrine, prolonged antibiotics, and general anesthesia with petrochemicals). Multiple mechanisms of chemical injury that magnify response to exposures in chemically sensitive patients can include neurogenic inflammation (respiratory, gastrointestinal, genitourinary), kindling and time-dependent sensitization (neurologic), impaired porphyrin metabolism (multiple organs), and immune activation.

AUTHORS: Wadman M

SOURCE: Nature 1997 Jan 16;385(6613):187

CITATION IDS: PMID: 9000059 UI: 97152476

MAIN MESH HEADINGS: Persian Gulf Syndrome/*etiology

ADDITIONAL MESH HEADINGS: Chemical Warfare, Chlorpyrifos, Deet, Environmental Exposure, Government, Human, Persian Gulf Syndrome/epidemiology, Politics, Pyridostigmine Bromide, Research, Risk Factors, United States/epidemiology, Veterans

AUTHORS: Fischer AB; Eikmann T

AUTHOR AFFILIATION: Institute of Hygiene and Environmental Medicine, Justus-Liebig- University, Giessen, Germany.

SOURCE: Toxicol Lett 1996 Nov;88(1-3):359-64

CITATION IDS: PMID: 8920761 UI: 97079029

ABSTRACT: In a German kindergarten cockroaches were destroyed by a commercial firm. A preparation containing pyrethrum and its synergist piperonyl butoxide and the organic phosphorus pesticide chlorpyriphos was sprayed. While cleaning the rooms, the staff complained of health effects. Thereupon the kindergarten was closed until further notice, samples were taken by the health authorities for chemical analysis, and an environmental medical evaluation was initiated. The analytical results are presented. The toxicological significance of the employed insecticides, their environmental persistence, and the problems associated with pest control in such institutions are discussed and recommendations given.

AUTHORS: MacIntosh DL; Spengler JD; Ozkaynak H; Tsai L; Ryan PB

AUTHOR AFFILIATION: Environmental Science and Engineering Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.

SOURCE: Environ Health Perspect 1996 Feb;104(2):202-9

CITATION IDS: PMID: 8820589 UI: 96417798

ABSTRACT: Average daily dietary exposures to 11 contaminants were estimated for approximately 120,000 U.S. adults by combining data on annual diet, as measured by a food frequency questionnaire, with contaminant residue data for table-ready foods that were collected as part of the annual U.S. Food and Drug Administration Total Diet Study. The contaminants included in the analysis were four heavy metals (arsenic, cadmium, lead, mercury), three organophosphate pesticides (chlorpyrifos, diazinon, malathion), and four organochlorine pesticides (dieldrin, p,p'-DDE, lindane, heptachlor epoxide). Dietary exposures to these contaminants were highly variable among individuals, spanning two to three orders of magnitude. Intraindividual exposures to the metals, organophosphates, and organochlorines were estimated to be strongly correlated; Pearson's correlation coefficients ranged from 0.28 for lindane:dieldrin to 0.84 for lead:mercury. For some of the compounds (e.g., arsenic and dieldrin), a substantial fraction of the population was estimated to have dietary intakes in excess of health-based standards established by the EPA. Before use for risk assessment or epidemiologic purposes, however, the validity of the exposure estimates must be evaluated by comparison with biological indicators of chronic exposure. Because of their low detection rate in table-ready foods, the estimated distributions of exposures for dieldrin, p,p'-DDE, heptachlor epoxide, lindane, diazinon, and chlorpyrifos were found to be sensitive to assumed values for nondetect samples. Reliable estimates of the population distribution of dietary exposures to most other contaminants cannot be made currently, due to their low rate of detection in table- ready foods. Monitoring programs that use more sensitive study designs and population-based assessments for other subpopulations should be a priority for future research.

AUTHORS: Sherman JD

AUTHOR AFFILIATION: Department of Sociology, Western Michigan University, Kalamazoo, Michigan, USA.

SOURCE: Arch Environ Health 1996 Jan-Feb;51(1):5-8

CITATION IDS: PMID: 8629864 UI: 96226384

ABSTRACT: Extensive and unusual patterns of birth defects noted in four children included defects of the brain, eyes, ears, palate, teeth, heart, feet, nipples, and genitalia. Brain defects were present in the ventricles, corpus callosum, choroid plexus, and septum pellucidum, and genital defects included the testes (undescended), microphallus, and labia (fused). All children had growth retardation, and three had hypotonia and profound mental retardation. The children were exposed in utero to chlorpyrifos (Dursban). Published literature and unpublished documents by the U.S. Environmental Protection Agency contain reports that identify similarities in defects found in test animals and in children exposed to Dursban. A pattern of defects found in the four children in this study may represent a heretofore unrecognized syndrome that should be considered when Dursban-exposed women have children with birth defects.

AUTHORS: Simcox NJ; Fenske RA; Wolz SA; Lee IC; Kalman DA

AUTHOR AFFILIATION: Department of Environmental Health, University of Washington, Seattle 98195, USA.

SOURCE: Environ Health Perspect 1995 Dec;103(12):1126-34

CITATION IDS: PMID: 8747019 UI: 96359988

ABSTRACT: Child of agriculture families are likely to be exposed to agricultural chemicals, even if they are not involved in farm activities. This study was designed to determine whether such children are exposed to higher levels of pesticides than children whose parents are not involved in agriculture and whose homes are not close to farms. Household dust and soil samples were collected in children's play areas from 59 residences in eastern Washington State (26 farming, 22 farmworker, and 11 nonfarming families). The majority of the farm families lived within 200 feet of an operating apple or pear orchard, whereas all reference homes were located at least a quarter of a mile from an orchard. Four organophosphorous (OP) insecticides commonly used on tree fruit were targeted for analysis: azinphosmethyl, chlorpyrifos, parathion, and phosmet. Samples were extracted and analyzed by gas chromatography/mass selective detection. Pesticide concentrations in household dust were significantly higher than in soil for all groups. OP levels for farmer/farm-worker families ranged from nondetectable to 930 ng/g in soil (0.93 ppm) and from nondetectable to 17,000 ng/g in dust (17 ppm); all four OP compounds were found in 62% of household dust samples, and two-thirds of the farm homes contained at least one OP above 1000 ng/g. Residues were found less frequently in reference homes and all levels were below 1000 ng/g. Household dust concentrations for all four target compounds were significantly lower in reference homes when compared to farmer/farmworker homes (Mann Whitney, U test; p < 0.05). These results demonstrate that children of agricultural families have a higher potential for exposure to OP pesticides than children of nonfarm families in this region. Measurable residues of a toxicity, I compound registered exclusively for agricultural use, azcnphosmettyl were found in household dust samples from all study homes, suggesting that low level exposure to such chemicals occurs throughout the region. Children's total and cumulative exposure to this pesticide class from household dust, soil, and other sources warrants further investigation.

AUTHORS: Beard J; Westley-Wise V; Sullivan G

AUTHOR AFFILIATION: North Coast Public Health Unit, NSW Health Department, Lismore.

SOURCE: Aust J Public Health 1995 Aug;19(4):357-62

CITATION IDS: PMID: 7578535 UI: 96019400

ABSTRACT: Ambient air was monitored for pesticides at four sites in Coffs Harbour, a coastal town (population about 50,000) surrounded by banana plantations. Air was sampled continuously for five consecutive months during the peak agricultural spraying period using vacuum pumps set to sample one litre per minute through ORBO-42 absorption tubes. Six pesticides were detected: three organochlorines and three organophosphates. The most commonly detected pesticide (14 per cent of all samples) was chlorpyrifos (maximum detected level 208.0 ng/m3, mean 3.6 ng/m3). Heptachlor was detected in 7.1 per cent of all samples (maximum detected level 133 ng/m3, mean 2.7 ng/m3). Other pesticides were only rarely detected. The only pesticide applied by air in the district (propiconazole) was not detected. If international health guidelines are used as a yardstick, these levels of exposure appear unlikely to present an appreciable health risk. Chlorpyrifos detection was associated with low wind speed (P = 0.012) and high temperature (P = 0.015), and detection at one site was associated with detection at another (P < 0.001). Chlorpyrifos detection was also associated with domestic applications within the town area as reported by pesticide applicators (P = 0.045). Peak agricultural use of chlorpyrifos did not coincide with peak detection periods. None of the detected organochlorines is registered for agricultural use, although at the time, heptachlor was permitted for use as a domestic termiticide. Even in a semirural town with nearby widespread use of agricultural chemicals, community exposures to pesticides in ambient air may largely relate to their nonagricultural use.

AUTHORS: Cochran RC; Kishiyama J; Aldous C; Carr WC Jr; Pfeifer KF

AUTHOR AFFILIATION: Department of Pesticide Regulation (DPR), California Environmental Protection Agency, Sacramento 95814-5604.

SOURCE: Food Chem Toxicol 1995 Feb;33(2):165-72

CITATION IDS: PMID: 7532610 UI: 95172459

ABSTRACT: Analyses of potential dietary exposure to chlorpyrifos residues were conducted by the Department of Pesticide Regulation (DPR). Potential acute dietary ingestion of chlorpyrifos for all labelled uses was based on the 95th percentile of user-day exposures. Margins of safety (MOSs) for potential acute dietary exposure to chlorpyrifos residues were based on a no-observed-effect level (NOEL) for cholinergic signs in a human study, and ranged from 52 to 205 for all population subgroups. MOSs for potential chronic dietary exposure to chlorpyrifos residues were based on a NOEL for inhibition of brain cholinesterase activity in rats and dogs, and ranged from 2198 to 8065 for all population subgroups. The limitations on toxicity, consumption and residue data are discussed, with the assumptions necessitated by those limitations.

AUTHORS: Richardson RJ

AUTHOR AFFILIATION: Department of Environmental and Industrial Health, University of Michigan, Ann Arbor 48109-2029.

SOURCE: J Toxicol Environ Health 1995 Feb;44(2):135-65

CITATION IDS: PMID: 7531775 UI: 95156508

ABSTRACT: Chlorpyrifos (diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate) is a broad-spectrum organophosphorus (OP) insecticide. Anticipated increases in the already extensive use of this compound have prompted this reassessment of its neurotoxicity. Because chlorpyrifos and other OP insecticides are designed to produce acute cholinergic effects through inhibition of acetylcholinesterase (AChE) and some OP compounds can cause OP compound-induced delayed neurotoxicity (OPIDN) via chemical modification of neurotoxic esterase (neuropathy target esterase, NTE), this review focuses on the capacity of chlorpyrifos to precipitate these and other adverse neurological consequences. Chlorpyrifos exhibits only moderate acute toxicity in many mammalian species, due largely to detoxification of the active metabolite, chlorpyrifos oxon, by A-esterases. Rats given large doses of chlorpyrifos (sc in oil) have prolonged inhibition of brain AChE, possibly due to slow release of the parent compound from a depot. Associated cognitive and motor deficits return to normal well before recovery of AChE activity and muscarinic receptor down-regulation, as expected from classic tolerance. Controlled studies of OP compound exposures in humans also indicate that cognitive dysfunction requires substantial AChE inhibition. Information is relatively sparse on neurological dysfunction that is secondary to theoretical reproductive, developmental, or immunological effects, but the best available data indicate that such effects are unlikely to result from exposures to chlorpyrifos. In accord with the much greater inhibitory potency of chlorpyrifos oxon for AChE than for NTE, clinical reports and experimental studies indicate that OPIDN from acute exposures to chlorpyrifos requires doses well in excess of the LD50, even when followed by repeated doses of the OPIDN potentiator phenylmethanesulfonyl fluoride (PMSF). Likewise, studies in hens show that subchronic exposures at the maximum tolerated daily dose do not result in OPIDN. Although exposure to chlorpyrifos as a result of normal use is unlikely to produce classical OPIDN, a recent report stated that mild reversible sensory neuropathy had occurred in eight patients who had been exposed subchronically to unknown amounts of chlorpyrifos. It is not clear whether these cases represent an incorrect linkage of cause and effect, a newly disclosed reversible sensory component of OPIDN, or an entirely new phenomenon. The question of the potential for chlorpyrifos to cause this mild sensory neuropathy could be resolved by the use of quantitative tests of sensory function in animal experiments and/or prospective studies of humans with known exposures to chlorpyrifos.

AUTHORS: Sherman JD

SOURCE: Toxicol Ind Health 1995 Jan-Feb;11(1):33-9

CITATION IDS: PMID: 7544498 UI: 95381244

COMMENT: Comment in: Toxicol Ind Health 1997 Jan-Feb;13(1):91-3, 95-7

MAIN MESH HEADINGS: Environmental Pollutants/*poisoning, Insecticides, Organophosphate/*poisoning, Nervous System/*drug effects, Organophosphorus Compounds/*poisoning, Respiratory System/*drug effects

ADDITIONAL MESH HEADINGS: Adolescence, Adult, Child, Child, Preschool, Chlorpyrifos/poisoning, Diazinon/poisoning, Female, Human, Insecticides, Organophosphate/chemistry, Male, Occupational Exposure/adverse effects

AUTHORS: Dolara P; Torricelli F; Antonelli N

AUTHOR AFFILIATION: Department of Pharmacology and Toxicology, University of Florence, Italy.

SOURCE: Mutat Res 1994 Sep;325(1):47-51

CITATION IDS: PMID: 7521012 UI: 94352373

ABSTRACT: Lymphocytes obtained from 5 healthy donors were incubated with a mixture of 15 pesticides commonly found in foods of central Italy (dithiocarbamates (20.7%), benomyl (19.6%), thiabendazole (14.9%), diphenylamine (14.4%), chlorthalonil (13.1%), procymidone (8.0%), methidathion (2.3%), chlorpyrifos-ethyl (2%), fenarimol (1.9%), parathion-methyl (1%), chlorpropham, parathion, vinchlozolin, chlorfenvinphos and pirimiphos-ethyl (< 1%)). The percent of each pesticide in the mixture was proportional to its average concentration in foods. Incubated with the lymphocytes at a concentration of 1-20 micrograms/ml the pesticide mixture did not induce significant variations in the number of hypodiploid, hyperdiploid and polyploid cells or in the number of chromosome and chromatid aberrations. On the contrary, we observed a dose-dependent increase in the number of nonsynchronous centromeric separations which reached the level of 37.9% at 20 micrograms/ml of pesticide mixture in the incubation medium. This effect was not observed when benomyl was excluded from the mixture. These data show that the removal of benomyl could decrease the toxicity of pesticide residues present in human food.

AUTHORS: Kaplan JG; Kessler J; Rosenberg N; Pack D; Schaumburg HH

AUTHOR AFFILIATION: Department of Neurology, Albert Einstein College of Medicine, Bronx, NY.

SOURCE: Neurology 1993 Nov;43(11):2193-6

CITATION IDS: PMID: 7694187 UI: 94050601

ABSTRACT: Chlorpyrifos (Dursban) is an organophosphate insecticide with extensive domestic and agricultural applications. It is regarded as safe for these purposes; one report of neurotoxicity is attributed to massive ingestion in a suicide attempt. We report eight people who developed peripheral neuropathy after exposure to exterminator-applied commercial Dursban; five also experienced memory loss and cognitive slowing. Evaluation failed to reveal other causes of neurologic dysfunction; symptoms recurred in one patient following accidental reexposure. We conclude that environmental contact with chlorpyrifos can cause sensory neuropathy and CNS dysfunction and that this agent should be used with caution.

AUTHORS: Gutmann L; Bodensteiner JB

SOURCE: J Pediatr 1993 Nov;123(5):837

CITATION IDS: PMID: 7693903 UI: 94046237

COMMENT: Comment on: J Pediatr 1993 Apr;122(4):658-60

MAIN MESH HEADINGS: Chlorpyrifos/*poisoning, Neuromuscular Diseases/*chemically induced

ADDITIONAL MESH HEADINGS: Child, Electrophysiology, Human, Neuromuscular Diseases/diagnosis

AUTHORS: Furlong CE; Costa LG; Hassett C; Richter RJ; Sundstrom JA; Adler DA; Disteche CM; Omiecinski CJ; Chapline C; Crabb JW; et al

AUTHOR AFFILIATION: Department of Genetics, University of Washington, Seattle 98195.

SOURCE: Chem Biol Interact 1993 Jun;87(1-3):35-48

CITATION IDS: PMID: 8393745 UI: 93345100

ABSTRACT: Human and rabbit paraoxonases/arylesterases were purified to homogeneity by chromatographic and gel electrophoretic/isofocusing procedures coupled with activity stains. N-terminal and peptide sequence analysis suggested retention of the secretion signal sequence and allowed design of oligonucleotide probes. The probes were used to isolate a 1294-bp rabbit paraoxonase cDNA clone, which, in turn, was used to isolate three human cDNA clones. Comparison of rabbit and human protein and cDNA sequences indicated a high degree of sequence conservation (approximately 85% identity) and verified that paraoxonase retains its signal sequence (except for the N-terminal Met). The rabbit cDNA encodes a protein of 359 amino acids and the human a protein of 355 amino acids. In situ hybridization demonstrated, as expected, that the paraoxonase gene maps to the long arm of human chromosome 7. Arginine at position 192 specifies high activity paraoxonase and glutamine low activity human paraoxonase. Variation in protein levels explains the variation of enzyme activity observed within a genetic class. Toxicity studies showed that raising rat plasma paraoxonase levels by i.v. administration of partially purified rabbit paraoxonase protected animals against cholinesterase inhibition by paraoxon and chlorpyrifos oxon. Protection correlated with the relative rates of hydrolysis of these two compounds.

AUTHORS: Drevenkar V; Vasilic Z; Stengl B; Frobe Z; Rumenjak V

AUTHOR AFFILIATION: Institute for Medical Research and Occupational Health, University of Zagreb, Croatia.

SOURCE: Chem Biol Interact 1993 Jun;87(1-3):315-22

CITATION IDS: PMID: 7688273 UI: 93345095

ABSTRACT: Concentrations of parent pesticide and corresponding diethylphosphorus metabolites in blood serum and urine were investigated in persons who had ingested a concentrated solution of organophosphorus pesticide chlorpyrifos. The organophosphate poisoning was indicated by a significant depression of blood cholinesterase (EC 3.1.1.7 and EC 3.1.1.8) activities. Blood and spot urine samples were collected daily after admission of the persons to hospital. Chlorpyrifos was detected only in serum samples in a period up to 15 days after poisoning. In the same samples chlorpyrifos oxygen analogue, chlorpyrifos oxon, was not detected. The presence of diethylphosphorothioate in all serum and urine samples confirmed that part of chlorpyrifos was hydrolysed before its oxidation. The maximum concentrations of chlorpyrifos in serum and of metabolites in serum and urine were measured on the day of admission. The decrease in concentrations followed the first-order kinetics with the initial rate constant faster and the later one slower. In the faster elimination phase chlorpyrifos was eliminated from serum twice as fast (t1/2 = 1.1-3.3 h) as the total diethylphosphorus metabolites (t1/2 = 2.2-5.5 h). The total urinary diethylphosphorus metabolites in six chlorpyrifos poisoned persons were excreted with an average elimination half-time of 6.10 +/- 2.25 h (mean +/- S.D.) in the faster and of 80.35 +/- 25.8 h in the slower elimination phase.

AUTHORS: Richardson RJ; Moore TB; Kayyali US; Fowke JH; Randall JC

AUTHOR AFFILIATION: Department of Environmental and Industrial Health, School of Public Health, University of Michigan, Ann Arbor 48109.

SOURCE: Fundam Appl Toxicol 1993 Apr;20(3):273-9

CITATION IDS: PMID: 7684990 UI: 93279430

ABSTRACT: Chlorpyrifos (CPS; O,O-diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate; Dursban) is a widely used broad-spectrum organophosphorus (OP) insecticide. Because some OP compounds can cause a sensory-motor distal axonopathy called OP compound-induced delayed neurotoxicity (OPIDN), CPS has been evaluated for this paralytic effect. Early studies of the neurotoxicity of CPS in young and adult hens reported reversible leg weakness but failed to detect OPIDN. More recently, a human case of mild OPIDN was reported to result from ingestion of a massive dose (about 300 mg/kg) in a suicide attempt. Subsequent experiments in adult hens (the currently accepted animal model of choice for studies of OPIDN) showed that doses of CPS in excess of the LD50 in atropine-treated animals inhibited brain neurotoxic esterase (NTE) and produced mild to moderate ataxia. Considering the extensive use of CPS and its demonstrated potential for causing OPIDN at supralethal doses, additional data are needed to enable quantitative estimates to be made of the neuropathic risk of this compound. Previous work has shown that the ability of OP insecticides to cause acute cholinergic toxicity versus OPIDN can be predicted from their relative tendency to inhibit the intended target, acetylcholinesterase (AChE), versus the putative neuropathic target, NTE, in brain tissue. The present study was designed to clarify the magnitude of neuropathic risk associated with CPS exposures by measuring hen brain AChE and NTE inhibition following dosing in vivo and determining the bimolecular rate constant of inhibition (ki) for each enzyme by the active metabolite, CPS oxon (CPO), in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

AUTHORS: Aiuto LA; Pavlakis SG; Boxer RA

AUTHOR AFFILIATION: Department of Pediatrics, North Shore University Hospital-Cornell University Medical College, Manhasset, NY 11030.

SOURCE: J Pediatr 1993 Apr;122(4):658-60

CITATION IDS: PMID: 7681876 UI: 93217783

COMMENT: Comment in: J Pediatr 1993 Nov;123(5):837

ABSTRACT: Life-threatening organophosphate-induced delayed polyneuropathy with transient bilateral vocal cord paralysis occurred in a 3-year-old child. Recovery was slow after prolonged ventilatory support. Patients who recover from serious organophosphate intoxications should be closely monitored for the development of organophosphate-induced delayed polyneuropathy.

AUTHORS: Thrasher JD; Madison R; Broughton A

AUTHOR AFFILIATION: Department of Health Science, California State University, Northridge.

SOURCE: Arch Environ Health 1993 Mar-Apr;48(2):89-93

CITATION IDS: PMID: 7682805 UI: 93236433

ABSTRACT: Twelve individuals who were exposed to chlorpyrifos were studied 1-4.5 y following exposure to determine changes in the peripheral immune system. The subjects were found to have a high rate of atopy and antibiotic sensitivities, elevated CD26 cells (p < .01), and a higher rate of autoimmunity, compared with two control groups. Autoantibodies were directed toward smooth muscle, parietal cell, brush border, thyroid gland, myelin, and ANA. Chlorpyrifos exposure was implicated in the immunologic abnormalities reported. The immunologic changes were similar to those reported for other pesticides.

AUTHORS: Leidy RB; Wright CG; Dupree HE Jr

AUTHOR AFFILIATION: Department of Toxicology, North Carolina State University, Raleigh 27695-7613.

SOURCE: Bull Environ Contam Toxicol 1991 Aug;47(2):177-83

CITATION IDS: PMID: 1717083 UI: 92004117

MAIN MESH HEADINGS: Chlorpyrifos/*analysis, Occupational Diseases/*chemically induced

ADDITIONAL MESH HEADINGS: Air/analysis, Human, Photometry, Soil/analysis, Support, Non-U.S. Gov't

AUTHORS: Rosenthal NE; Cameron CL

SOURCE: Am J Psychiatry 1991 Feb;148(2):270

CITATION IDS: PMID: 1702938 UI: 91103358

COMMENT: Comment in: Am J Psychiatry 1991 Oct;148(10):1416-7

MAIN MESH HEADINGS: Depressive Disorder/*chemically induced, Drug Hypersensitivity/*etiology, Insecticides, Organophosphate/*adverse effects

ADDITIONAL MESH HEADINGS: Case Report, Chlorpyrifos/analogs & derivatives, Chlorpyrifos/adverse effects, Fumigation/adverse effects, Human, Insect Control, Insecticides, Organophosphate/poisoning, Male, Middle Age

AUTHORS: Capodicasa E; Scapellato ML; Moretto A; Caroldi S; Lotti M

AUTHOR AFFILIATION: Universita' degli Studi di Padova, Istituto di Medicina del Lavoro, Italy.

SOURCE: Arch Toxicol 1991;65(2):150-5

CITATION IDS: PMID: 1711837 UI: 91282669

ABSTRACT: Chlorpyrifos [0,0-diethyl 0-(3,5,6-trichloro-pyridyl) phosphorothioate] caused delayed polyneuropathy in man. Contrary to previous studies, we report here that it also causes delayed polyneuropathy in the hen, the animal model for this toxicity. The minimal neuropathic dose was 60-90 mg/kg p.o., corresponding to 4-6 times the estimated LD50. Consequently, pralidoxime (2-PAM) in conjunction with atropine was necessary to reverse acetylcholinesterase (AChE) inhibition and cholinergic toxicity in hens given high enough doses of chlorpyrifos to cause neuropathy. Chlorpyrifos was slowly absorbed after single oral doses and the threshold of inhibition (greater than 70%) of neuropathy target esterase (NTE), the putative target for delayed neuropathy, was reached within 5-6 days. High AChE inhibition (greater than 90%), however, was measured within hours after dosing because of the higher potency of chlorpyrifos to inhibit this enzyme. In vitro studies showed that chlorpyrifos-oxon, the active metabolite of chlorpyrifos, was 10- 20 times more active against AChE than against NTE, confirming the clinical observation. No differences were seen between human and hen enzymes in this respect. Hen and human brain homogenates contain A- esterases which hydrolysed chlorpyrifos to about the same extent in both species. In conclusion, chlorpyrifos causes delayed polyneuropathy in the hen, as was reported in man. The reasons for previous negative data in the hen are probably due to the relatively lower doses which were used. Judging from in vitro studies with hen and human enzymes, there are no differences in the two species as far as their relative sensitivity to delayed polyneuropathy. It is likely that delayed polyneuropathy would develop in both species only after severe cholinergic toxicity requiring aggressive antidotal treatment.

AUTHORS: Fenske RA; Black KG; Elkner KP; Lee CL; Methner MM; Soto R

AUTHOR AFFILIATION: Department of Environmental Sciences, Rutgers University, New Brunswick, NJ 08903.

SOURCE: Am J Public Health 1990 Jun;80(6):689-93

CITATION IDS: PMID: 1693041 UI: 90261814

ABSTRACT: Air and surface chlorpyrifos residues were measured for 24 hours following a 0.5 percent Dursban broadcast application for fleas inside a residence. Two of the three treated rooms were ventilated following application. Maximum air concentrations were measured 3-7 hours post- application. Peak concentrations in the infant breathing zone were 94 micrograms/m3 in the nonventilated room and 61 micrograms/m3 in the ventilated room, and were substantially higher than concentrations in the sitting adult breathing zone. Concentrations of approximately 30 micrograms/m3 were detected in the infant breathing zone 24 hours post- application. Surface residues available through wipe sampling were 0.7- 1.6 micrograms/cm2 of carpet on the day of application and 0.3-0.5 micrograms/cm2 24 hours post-application. Estimated total absorbed doses for infants were 0.08-0.16 mg/kg on the day of application and 0.04-0.06 mg/kg the day following application, with dermal absorption representing approximately 68 percent of the totals. These doses are 1.2-5.2 times the human No Observable Effect Level (NOEL). Exposures to cholinesterase inhibiting compounds following properly conducted broadcast applications could result in doses at or above the threshold of toxicological response in infants, and should be minimized through appropriate regulatory policy and public education.