Postapplication Fipronil Exposure Following Use on Pets.

Fipronil is a pyrazole acaricide and insecticide that may be used for insect, tick, lice, and mite control on pets. Residents' short-term and long-term postapplication exposures to fipronil, including secondary environmental exposures, were estimated using data from chemical-specific studies. Estimations of acute (24-h) absorbed doses for residents were based on U.S. Environmental Protection Agency (U.S. EPA) 2012 standard operating procedures (SOPs) for postapplication exposure. Chronic exposures were not estimated for residential use, as continuous, long-term application activities were unlikely to occur. Estimated acute postapplication absorbed doses were as high as 0.56 µg/kg-d for toddlers (1-2 yr) in households with treated pets based on current U.S. EPA SOPs. Acute toddler exposures estimated here were fivefold larger in comparison to adults. Secondary exposure from the household environment in which a treated pet lives that is not from contacting the pet, but from contacting the house interior to which pet residues were transferred, was estimated based on monitoring socks worn by pet owners. These secondary exposures were more than an order of magnitude lower than those estimated from contacting the pet and thus may be considered negligible.

Absorption and excretion of organophosphorous insecticide biomarkers of malathion in the rat: implications for overestimation bias and exposure misclassification from environmental biomonitoring.

Malathion is an organophosphorous (OP) insecticide widely used for crop protection. Its degradates, malathiondiacid (MDA), malathion monoacid (MMA), dimethylphosphate (DMP), dimethylthiophosphate (DMTP) and dimethyldithiophosphate (DMDTP) are formed in strawberries and other produce. These same chemical biomarkers are measured in urine in human studies as quantitative measures of exposure. The excretion of malathion and its common biomarkers including MDA, MMA, DMP, DMTP and DMDTP at equal molar doses (73 µmol/kg b.w.) was studied following oral dosing of female Holtzmann rats (240-300 g). Following MDA administration, 36.3±5.4% was recovered as MDA, 0.05±0.02% as DMP, 5.5±0.3% as DMTP, 3.8±2.9% as DMDTP (mole percent), and totally 45.6±7.0% of administered dose in urine after 120 h (over 94% in the first 24h). Following DMTP administration, 8.3±7.7% was recovered as DMP, 46.6±16.5% as DMTP, and totally 55.0±10.3% of administered dose in urine after 120 h (over 92% in the first 24h). Similar results were obtained with other malathion biomarkers. Preformed biomarkers of malathion and other OP insecticides when ingested in produce are readily absorbed and excreted. Low level human dietary and non-occupational urine biomonitoring studies will be confounded by preformed pesticide biomarkers used to infer potential human pesticide exposure. This has profound implications for epidemiology studies where subject's biomarker excretion is used as a surrogate for OP exposures that cannot be related to a particular insecticide residue.

Implications of estimates of residential organophosphate exposure from dialkylphosphates (DAPs) and their relevance to risk.

Recent epidemiological studies have claimed to associate a variety of toxicological effects of organophosphorus insecticides (OPs) and residential OP exposure based on the dialkyl phosphates (DAPs; metabolic and environmental breakdown products of OPs) levels in the urine of pregnant females. A key premise in those epidemiology studies was that the level of urinary DAPs was directly related to the level of parent OP exposure. Specific chemical biomarkers and DAPs representing absorbed dose of OPs are invaluable to reconstruct human exposures in prospective occupational studies and even in non-occupational studies when exposure to a specific OP can be described. However, measurement of those detoxification products in urine without specific knowledge of insecticide exposure is insufficient to establish OP insecticide exposure. DAPs have high oral bioavailability and are ubiquitously present in produce at concentrations several-fold greater than parent OPs. Studies relying on DAPs as an indicator of OP exposure that lack credible information on proximate OP exposure are simply measuring DAP exposure and misattributing OP exposure.

Detoxication enzymes in the guts of caterpillars: an evolutionary answer to plant defenses?

Higher activity of midgut microsomal oxidase enzymes in polyphagous than in monophagous species indicates that the natural function of these enzymes is to detoxify natural insecticides present in the larval food plants. Differing strategies of adaptation to plant defenses may partly account for the great diversity of insect herbivores.

Accumulation and perchlorate exposure potential of lettuce produced in the Lower Colorado River region.

The Colorado River is contaminated with perchlorate concentrations of 1.5-8 microg/L, an anion linked to thyroid dysfunction. Over 90% of the lettuce (Lactuca sativa L.) consumed during the winter months in the United States is produced in the Lower Colorado River region. Studies were conducted in this region to survey the potential for lettuce perchlorate accumulation and estimate potential human exposure to perchlorate from lettuce. Total uptake of perchlorate in the above-ground plant of iceberg lettuce was approximately 5 g/ha. Exposure estimates ranged from 0.45 to 1.8 microg/day depending on lettuce types and trimming. For all lettuce types, hypothetical exposures were less than 4% of the reference dose recommended by the National Academy of Sciences. Results show the relative iodide uptake inhibition potential because of lettuce nitrate was 2 orders of magnitude greater than that associated with the corresponding trace levels of perchlorate. These data support the conclusion that potential perchlorate exposures from lettuce irrigated with Colorado River water are negligible relative to acute or long-term harmful amounts.

The failure of a school-based child sexual abuse prevention program.

Structured interviews were administered to 22 children, ranging in age from 6 to 10 years old, who did not disclose long-term sexual abuse by an auxiliary school employee, despite having been exposed to a school-based child sexual abuse prevention program. The results are presented in the context of a review of existing literature on school-based child sexual abuse prevention programs. Results point to the ineffectiveness of brief, single presentation, prevention efforts not geared to specific developmental levels of the audience, the need to explore the impact of the variable of group versus individual victimization on disclosure, and the need for further study of sexually victimized children who received prevention programming with the addition of a control group sample.

Multiple ionic mechanisms are activated by the potent agonist quisqualate in cultured cerebellar Purkinje neurons.

Current clamp recordings were used to analyze responses of cultured cerebellar Purkinje neurons to quisqualate and several other selective non-N-methyl- D-aspertate (NMDA) agonists. Quisqualate, a potent agonist in the cerebellar Purkinje neuron, evoked both short- and long-term changes in excitability, that activated within seconds and lasted for several minutes. Two components of the response were activated differentially by subtype selective agonists, and differed in their mechanism of expression and time course. The initial component of the response was activated by ionotropic agonists ((RS)-d-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) domoate), and by quisqualate and glutamate which are effective at both the ionotropic and metabotropic quisqualate receptor subtypes, but not by the metabotropic agonist trans (+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD). This component was dependent on extracellular Na+, and characterized by a rapid depolarization with a short latency (less than 1-2 s) and a decrease in membrane resistance as expected for an ionotropic reponse. The rapid depolarization extended into an agonist-dependent plateau phase, which could not be evoked by depolarization alone. The second ('late') phase of the response was a slowly-activating, long-lasting change in membrane excitability, accompanied by little or no change in the membrane potential. The late phase, marked by an increase in voltage-dependent bursting spike activity, was induced by the metabotropic agonist, ACPD, and by quisqualate and glutamate, but not by ionotropic selective agonists such as AMPA. Little or no bursting was evoked by AMPA, domoate, kainate or homocysteate. This late phase was also accompanied by increases in the magnitude and duration of the complex spikes and in the afterhyperpolarization following brief current-driven depolarizations. The slower time course of the late component is consistent with a pathway involving second messenger systems. Our results support the hypothesis that coregulation of both ionotropic and metabotropic mechanisms produces the complex and prolonged excitatory response characteristic of the Purkinje neuron.

Contamination of small-volume medication nebulizers and its association with oropharyngeal colonization.

The effect of the use of small-volume medication nebulizers on oropharyngeal colonization with potentially pathogenic Gram-negative bacilli was investigated in 95 patients with respiratory disease, of whom 54 used nebulizers and 41 were controls. Inhalation therapy had a significant effect on colonization, with a relative risk of more than four. Age over 60 years also showed a significant association with colonization. One-third of the nebulizers sampled were contaminated, 71% with Gram-negative bacilli. A direct route of contamination could be demonstrated in 28% of the patients. Medication nebulizers should be thoroughly cleaned after use and stored dry between patients.

Radioimmunoassay of serum conjugated cholic acid.

A radioimmunoassay for serum conjugated cholic acid is described using antiserum obtained five weeks after immunization of rabbits with cholic acid bovine serum albumin conjugate. Prior to the radioimmunoassay, extraction of bile acids was performed with Amberlite XAD-2. The displacement curve of glyco[3H]cholic acid was linear on a logit-log plot from 5 to 80 pmol of unlabelled glycocholic acid. Values for 8 normal fasting subjects ranged from 0.18 to 1.25 mumol/1. In 31 fasting subjects with or without liver disease serum values of conjugated cholic acid are related to serum bilirubin. Endoscopic retrograde cholangiopancreatography may influence serum levels of conjugated cholic acid.

Effect of route of exposure and repeated doses on the acute toxicity in mice of the cyanobacterial nicotinic alkaloid anatoxin-a.

Anatoxin-a (ANTX-a) is a potent nicotinic cholinergic alkaloid produced by some toxigenic strains of cyanobacteria. We have examined i.p. and oral LD50 values of two ANTX-a producing Anabaena sp. and synthetic (+)-ANTX-a in outbred Swiss Webster mice. All three appeared equivalent by i.p. injection, but Anabaena flos-aquae NRC-44-1 was approximately twice as potent orally as the other two. Additionally, we were unable to demonstrate development of any biologically significant tolerance to acute ANTX-a exposure using two different repeated dose regimens.

Stability studies on the cyanobacterial nicotinic alkaloid anatoxin-A.

Anatoxin-a (ANTX-a) is a potent nicotinic cholinergic bicyclic secondary amine produced by some toxigenic strains of Anabaena spp. cyanobacteria (LD50 = 0.20-0.25 mg/kg i.p., mouse). Studies were undertaken to examine the effects of sunlight, pH, oxygen, and copper and iron, known catalysts of nitrogen oxidation, on the stability of ANTX-a. Photolysis of this extremely potent toxin was demonstrated under conditions resembling those which occur naturally. First-order decay kinetics of ANTX-a in sunlight was both pH and light intensity dependent. In the solutions examined, which represented expected biological conditions, the half-life of ANTX-a was on the order of 1-2 hr. This compares to half-lives on the order of several days in the absence of sunlight, even in the presence of metal ions. Mouse bioassays indicate that the breakdown products of ANTX-a, by both mechanisms, are inactive. Sunlight photolysis is concluded to be a possible important detoxification route of ANTX-a.

Exposure to pesticide mixer/loaders and applicators in California.

Pesticide exposure occurs both when preparing (mixing/loading) the pesticide for application and when actually applying the pesticide. Equipment cleanup and repair may also contribute to exposure. These separate tasks may be done by different people or a single individual may combine them. Different formulations, handling methods, and application methods may affect levels of exposure. Good workplace hygiene dictates that the first priority in workplace safety is to put in place engineering and administrative controls to make the workplace safer rather than rely on the use of PPE to prevent exposure. Providing a physical barrier, such as closed systems for the mixer/loader and an enclosed cab or cockpit for applicators, is associated with reduced exposures of workers. The Worker Health and Safety Branch in the DPR of Cal/EPA has been monitoring various work task exposures. The results of these studies are summarized in Figures 1-4, where exposure is shown based on both time worked and amount of material handled. The studies were done using dosimeters, skin washes/wipes, and air pumps. Water-soluble packets, which are very popular with users, surpassed closed systems in reducing exposure to mixer/loaders in these studies. Hand spraying proved to present the greatest risk of exposure of the methods of application studied. It was found that the dermal route of exposure is most important, comprising 87-95% of a handler's exposure. Although this survey cannot be considered conclusive, since it leaves many formulations, systems, and methods incompletely studied or unstudied, it is clear that exposure is affected by different handling strategies. Manufacturers, regulators and users should work more closely to refine or develop new systems for safely handling pesticides.

Assessing human exposures to pesticides.

Pesticide use is inevitably associated with chemical exposures that range from inferred nondetectable levels to easily measurable ones using sensitive, readily available analytical tools. Whether these exposures are of any biological significance is determined by duration, dose, and biological reactivity. The overwhelming majority of human exposures occur in a diverse chemical milieu of a nutritive substances and are of no known significance. Technologies that minimize human chemical exposures and maximize pesticide effectiveness are favored. The risk characterization process is ideally suited to assist decision makers concerning the protection of human health and evaluation of agricultural tools. It is the best means available to balance the review of pesticide impacts on health and agriculture. Regulators must be cautious to acknowledge the relative rather than absolute nature of the risk characterization process. Workplace biological monitoring must become more commonplace as a means to evaluate the chemical exposure potential of various work tasks and greater attention must be given to the biological validation of methods. Earlier needs for data to develop workplace hygiene strategies have been replaced in recent years by demands of the risk assessment process, which utilizes direct estimates of exposure and absorbed dose. Animal models, no matter how attractive, are not presently a substitute for human experience. Opportunities to gather more information on human experience associated with pesticide exposures must be more aggressively identified and pursued. Only a very small time lag should exist between identification of pesticide metabolites in rats and evaluation of metabolic similarities in humans. At the present levels of analytical sensitivity, most of our current uncertainty about the extent of worker exposure and patterns of metabolism between species can be at least clarified with the cooperation of persons who are exposed during normal day-to-day activities in the workplace. Only with better human data will the risk assessment process warrant greater reliance in decision making concerning our chemical exposures and human experience.

Acute pesticide morbidity and mortality: California.

The California Pesticide Illness Surveillance Program collects, investigates, abstracts, and records reports received from physicians. A minority of the reports are received through the county health officers who are notified by physicians under a state requirement for reporting pesticide-caused conditions. Most of the cases are identified by review of workers' compensation records. All the cases identified are investigated by the agricultural commissioners of the counties where exposure occurred. The investigation reports are reviewed and abstracted by staff of the Worker Health and Safety Branch of the California Department of Pesticide Regulation, California Environmental Protection Agency (Cal/EPA). The crucial determination is assessment of the degree of relationship between the exposure and subsequent disease: definite, probable, possible, unlikely, or unrelated. In most years, the number of cases investigated has been between 2,500 and 3,000. Excluding antimicrobials, the number of cases found after investigation to have a definite, probable, or possible relationship with pesticide exposure has ranged from 970 (in 1989) to 1,372 (in 1988). Cases involving antimicrobials rarely were reported prior to 1987. In that year, surveillance staff began reviewing workers' compensation records personally, with the specific goal of identifying antimicrobial cases. Since then, antimicrobials have been found to account for 746-813 cases annually, primarily involving splashes and squirts to the eye and inhalation of fumes or vapors. Numbers of case reports from agricultural situations have varied irregularly, driven by small numbers of episodes concerning multiple individuals. Variability in numbers of cases involving the skin has depended almost entirely on variation in numbers of field worker dermatitis. The most common situation for field worker dermatitis has been summer work in table grapes grown in the southern San Joaquin valley. In the two years since reentry intervals for the acaricide propargite were lengthened, there have been no more major clusters of field worker dermatitis. Although the cases collected by the surveillance program are predominantly occupational, because of dependence on workers' compensation for case identification, most recorded deaths are nonoccupational. Nonoccupational fatalities include suicides, mistaken ingestion of pesticides (especially if stored in food containers), and entry into structures being fumigated. Occupational deaths are less common and more varied. The circumstances of each reported occupational death are summarized above.

Pesticide exposure assessment.

Unintended, accidental, or unavoidable human exposures may result from pesticide use. Risk Characterization provides registrants, regulators, and the public a means to assess relative risks of pesticide use. Exposure Assessments are less standardized. Potential Dermal Exposure (PDE; mg/kg) is the amount of contact with the potential for dermal absorption (DA). Mixer/loader/applicator data developed using passive dosimetry and skin washing forms a Tier 1 Generic Database. If disqualifying estimates are obtained a more accurate estimate (Tier 2) may be developed from measurements of DA, clothing protection, and PDE under use conditions. Direct estimates of absorbed dose (Tier 3) require metabolic and kinetic data and biological monitoring. Harvesters and other persons who contact treated surfaces need reentry intervals to minimize acute and chronic exposure. Work tasks, dislodgeable foliar residue, and duration of exposure are the foundations for exposure-based, generic estimates of harvester PDE.

Chlorothalonil exposure of workers on mechanical tomato harvesters.

Worker exposure to chlorothalonil (tetrachloroisophthalonitrile, Bravo during mechanical tomato harvester operations of fruit for processing was estimated from passive dermal dosimetry monitoring (gauze pad and undershirt dosimetry), air concentration measurements and hand washes. Gauze pad dosimeters placed outside of workers' clothing gave an average potential dermal exposure of 499.6 micrograms/h. Dermal exposure based on undershirt dosimetry averaged 43.4 micrograms/h. Air concentrations ranged from 0.002-0.02 microgram/l. Dislodgeable fruit residues were measured and used to develop transfer factors (cm2 h) for both the pad dosimetry (450) and shirt dosimetry (40). Study results indicate that normal work clothing provides a 90% reduction in dermal exposure to chlorothalonil and that contribution of inhalation to total exposure ranges from 8.1-28%.

Long vs. short monitoring intervals for peach harvesters exposed to foliar azinphos-methyl residues.

A dermal monitoring study of peach harvesters exposed to azinphos-methyl (AM) residues was conducted in Sutter County, California. Harvesters were paid by piecework, which allowed characterization of the relationship between dermal exposure (DE) and time or production. Workers wore 2 long-sleeved knit T-shirts for each monitoring interval and also provided a hand residue sample. Dislodgeable foliar residue (DFR) samples were also collected. The highest correlations were found for inner shirts vs. production and DE vs. time worked (r2 = 0.67, P < 0.01). DE was greatest after 2-h exposures and reached equilibrium after 3 h, indicating that exposure estimates from shorter intervals would overestimate exposure.

Human disodium octaborate tetrahydrate exposure following carpet flea treatment is not associated with significant dermal absorption.

Disodium octaborate tetrahydrate is used for indoor flea control on carpets and furniture. Disodium octaborate tetrahydrate was applied to a 100% nylon carpet as a solution using a powered rug brush at a rate of approximately 200 micrograms/cm2 carpet. Two randomly chosen groups of volunteers (18 females, 4 males) wore either bathing suits which provided 75% or more skin exposure or whole-body, cotton dosimeters consisting of socks, union suits, and gloves. The volunteers performed a 20-minute set of Jazzercise routines. The availability of boron was demonstrated by covering portions of the carpet with a cotton dosimeter and rolling it with a weighted roller. Additionally, disodium octaborate tetrahydrate was transferred to the whole-body dosimeter. Volunteers also collected 24-hour urine specimens prior to and following the exercise period. The specimens were analyzed for total boron by inductively coupled plasma emission spectroscopy. No evidence of contact transfer and dermal absorption was obtained. The mean daily boron levels (mg/g creatinine) were 1.17, 1.33, and 1.31 for the group with exposed skin and 1.26, 1.12, and 1.26 for those who wore dosimeters which prevented contact. Daily urine boron levels were not significantly different when compared using a two sample t-test assuming equal variances (P > 0.05). Direct dermal contact with disodium octaborate tetrahydrate-treated carpet at a nominal rate of 200 micrograms/cm2 did not produce any adverse effects or change urinary boron clearance.

Biomonitoring and whole body cotton dosimetry to estimate potential human dermal exposure to semivolatile chemicals.

Current methods of estimating absorbed dosage (AD) of chemicals were evaluated to determine residue transfer from a carpet treated with chlorpyrifos (CP) to humans who performed a structured exercise routine. To determine the dislodgeability of residue, a California Department of Food and Agriculture (CDFA) roller was applied to a flat cotton cloth upon a treated carpet. Levels ranged from 0.06 to 0.99 microg CP/cm2. Cotton whole body dosimeters (WBD) were also used to assess residue transfer. The dosimeters retained 1.5 to 38 mg CP/person. Urine biomonitoring (3 days) for 3,5,6-trichloro-2-pyridinol (TCP) of persons who wore only swimsuits revealed a mean AD of 176 microg CP equivalents/person. The results show that the AD depends on the extent of contact transfer and dermal absorption of the residue. Default exposure assessments based upon environmental levels of chemicals and hypothetical transport pathways predict excessive exposure. The cotton WBD retains chemical residues and may be effectively used to predict dermal dose under experimental conditions.

Metabolism and excretion of dimethoate following ingestion of overtolerance peas and a bolus dose.

Data to guide an exposure assessment were obtained by giving sugar peas containing overtolerance dimethoate residues (17 ppm; 8% oxon) and a bolus dose of dimethoate to a healthy adult male. The dimethoate tolerance on peas was and remains 2 ppm. Serial total urine samples were collected and analysed for dimethoate and its oxon, dimethylphosphate, dimethylphosphorothioate (DMTP) and dimethylphosphorodithioate. The dose of dimethoate administered was approx. 0.1 mg/kg body weight and produced no symptoms of toxicity. Dimethylphosphates appeared in the urine within 2 hr. The major metabolite (about 60%) was DMTP. Only traces (< 0.5%) of dimethoate and oxon were recovered from urine. Acetylcholinesterase inhibition was not observed although urinary metabolites were prominent, indicating that they are better indicators of acute exposure than cholinesterase inhibition. The results obtained using a bolus dose were virtually identical to those from the trial with overtolerance peas, and indicated that dimethoate is readily absorbed and its urinary metabolites are readily eliminated following exposures to low doses (0.1 mg/kg body weight).