Search

Epidemiologic studies of pesticides have been subject to important biases arising from exposure misclassification. Although turf applicators are exposed to a variety of pesticides, these exposures have not been well characterized. This paper describes a repeated measures study of 135 TruGreen applicators over three spraying seasons via the collection of 1028 urine samples. These applicators were employed in six cities across the United States. Twenty-four-hour estimates (μg) were calculated for the parent compounds 2,4-D, MCPA, mecoprop, dicamba, and imidacloprid and for the insecticide metabolites MPA and 6-CNA. Descriptive statistics were used to characterize the urinary levels of these pesticides, whereas mixed models were applied to describe the variance apportionment with respect to city, season, individual, and day of sampling. The contributions to the overall variance explained by each of these factors varied considerably by the type of pesticide. The implications for characterizing exposures in these workers within the context of a cohort study are discussed.

This article is a review of blood cholinesterase activity in a cohort of urban pesticide applicators ranging from 1680 to over 3800 workers. During the period 1981-1991, 208, 788 blood samples were taken for measurement of cholinesterase activity with an average of 6 samples per year from each worker. A total of 150 workers or 0.44% of the cohort was removed from exposure to cholinesterase-inhibiting insecticides because of decreased cholinesterase activity. No worker required treatment for signs of cholinesterase inhibition.

The effects of reducing plasma bilirubin concentrations, by feeding activated charcoal, on embryonic survival in the jaundiced female Gunn rat was studied. The feeding of charcoal was effective in reducing plasma bilirubin levels by as much as 40%. Improved embryonic survival was observed in the charcoal-fed female rats in which 58% of the time-mated females were pregnant at necropsy. This was compared to 0% for the control females. Forty-eight percent of the charcoal fed and 7% of the control females that were continuously mated produced a live litter. Necropsy observations showed that 41-58% of the fetuses were in some stage of resorption. These findings support the hypothesis of an adverse bilirubin effect on reproduction in the female Gunn rat. It is suggested that jaundice during pregnancy may result in a risk to the unborn fetus.

Aspirin dosages calculated from published pharmacokinetic data were tested in 3 male and 3 female Basset Hounds. Emesis occurred frequently after dosing at the rate of 50 mg/kg of body weight, a dosage that would be required for a convenient 12-hour dosing interval. A dosage of 25 mg/kg every 12 hours avoided emesis but did not maintain serum salicylate concentrations within the desired range of 10 to 30 mg/100 ml. A dosage of 25 mg/kg every 8 hours resulted in serum salicylate concentrations varying from 12.5 to 17.8 mg/100 ml. It was concluded that a maintenance dosage of 25 to 35 mg/kg every 8 hours in optimal for the dog, based on extrapolation of data obtained in man.

Diphenylhydantoin was found to have a short half life and poor gastrointestinal absorption in dogs. Consequently, serum content after single or repeated oral dosage of 10 mg/kg of body weight did not exceed a concentration of 2 microgram/ml. To achieve a postulated effective plasma concentration of diphenylhydantoin, oral dosage of at least 35 mg/kg of body weight 3 times daily seems necessary.

Phototherapy has been widely used in the treatment of neonatal hyperbilirubinemia. Recent reports, however, have indicated that fluorescent light may be toxic and mutagenic to mammalian cells. these findings suggest possible long-term side effects with the use of phototherapy. This study was undertaken to determine the effects of phototherapy on hepatic microsomal enzyme activity. The exposure of Sprague-Dawley and Gunn rats to special blue fluorescent light at an average irradiance of 1,200 microW/cm2 resulted in no significant changes in liver microsomal enzyme activity for aniline hydroxylase, p-nitroanisole-O-demethylase, ethylmorphine-N-demethylase, cytochrome c reductase or the quantity of cytochrome P-450. A significant decrease in aniline hydroxylase and p-nitroanisole-O-demethylase activity was observed when liver microsomes were exposed in vitro to special blue fluorescent light. Photoactivated bilirubin did not effect the activity of the mixed-function oxidase enzymes measured under the conditions of this study.

Gel filtration was used to measure drug interaction with protein-bound bilirubin in 0.5 ml samples of Gunn rat serum, human serum and fraction V human serum albumin. Using sulfadimethoxine as a prototype differences in displacement were found in all 3 sera. The differences between human and rat serum were related to the binding characteristics of sulfadimethoxine whereas the differences between human serum and fraction V human serum albumin were attributed to displacement of bilirubin from albumin to other proteins in serum. Gel filtration permitted the use of small samples with bilirubin-albumin ratios less than 1.0 and provided data that were used for analysis of drug displacement of bilirubin using principles of drug-receptor theory. Ten of 14 drugs found to alter serum bilirubin concentrations in icteric Gunn rats had measurable effects on protein binding of bilirubin.

Sulfadimethoxine significantly reduced plasma bilirubin levels and altered the tissue bilirubin distribution in both the newborn and the adult Gunn rat. The majority of the unbound bilirubin appeared to distribute perferentially to the intestine and liver in the newborn, whereas in the adult the unbound bilirubin was taken up primarily by the liver. The bilirubin content of brain tissue from both age groups was significantly higher after sulfadimethoxine treatment.

The effectiveness of phototherapy and activated charcoal feeding for reducing plasma bilirubin concentrations was studied in the hyperbilirubinemic Gunn rat. The feeding of charcoal alone was just as effective in reducing plasma bilirubin concentrations as continuous phototherapy. An additive effect on reducing plasma bilirubin concentration was observed when phototherapy and the feeding of charcoal were administered together. The feeding of a 5% charcoal diet to weanling Gunn rats for 8 wk had no effect on growth rate.

Addition of bilirubin in vitro to hepatic microsomes or 9,333 g supernatant activated UDP glucuronyltransferase activity (UDPGT) for p-nitrophenol of livers from Sprague-Dawley rats, Wistar rats, icteric Gunn rats and nonicteric Gunn rats. However, injection of bilirubin at subtoxic doses using a variety of regimens failed to produce detectable activation of UDPGT in intact or bile duct-ligated rats. Pretreatment with intraperitoneal injections of bilirubin increased the rate of morphine glucuronide excretion in both Sprague-Dawley and icteric Gunn rats. Sulfadimethoxine did not affect morphin e excretion in Gunn rats. The data suggest that activation of UDPGT is of little, if any, significance in hyperbilirubinemia although the basis for increased excretion of morphine following bilirubin pretreatment has not been established.

Sodium salicylate was given intravenously to clinically normal cows, and aspirin (acetylsalicylic acid) was given orally to arthritic and clinically normal cattle. Despite slow absorption (half-time of absorption, 2.91 hours) of orally administered aspirin and rapid elimination (biologic half-life, 32 minutes) of salicylates, oral dosage of 100 mg/kg every 12 hours maintained serum salicylate concentration greater than 30 mug/ml, which was considered to be therapeutically effective.

Intraperitoneal injection of bilirubin in a dosage of 25 mg. per kilogram during the days nine to 15 of gestation in bile duct-ligated heterozygous Gunn rats was embryotoxic. Bile duct ligation per se had no gross observable effects on fetal development. Infertility is found in homozygous female Gunn rats that have unconjugated plasma bilirubin concentrations comparable to those achieved in this study (approximately 6.0 mg. per deciliter).

The elimination of primidone, phenylethylmalonamide, and phenobarbital (administered IV) was studied in dogs. The elimination half-lives were primidone, 1.85 +/- 0.3 (SEM) hours; phenylethylmalonamide, 7.1 +/- 1.45 hours; and phenobarbital, 40.9 +/- 4.96 hours. Dogs given repeated oral doses of primidone for 14 or 21 days had smaller primidone serum concentrations after each dosing. Dogs given 1.0 g of primidone orally (59.2 decreasing to 50.5 mg/kg of body weight) for 21 days accumulated the phenobarbital metabolite with apparent steady-state concentrations of 10 to 20 micrograms/ml and phenylethylmalonamide in concentrations of 2 to 5 micrograms/ml. Serum primidone concentrations decreased after repeated dosing and were measurable in only 1 dog 24 hours after the 21st dose and peak concentrations of 4 to 7 micrograms/ml were measured at 4 hours after the 22nd dose.

The interaction of bilirubin and indocyanine green with sulfobromophthalein (BSP) binding and conjugation by rat liver cytosol proteins was studied. BSP bound to cytosol proteins X, ligandin and Z and the BSP-glutathione conjugate were isolated by sephadex gel chromatography. Neither bilirubin nor indocyanine green affected the binding of BSP to ligandin and Z protein. However, indocyanine green did significantly reduce BSP conjugation in both in vitro and in vivo experiments. Diethyl maleate significantly reduced liver glutathione levels and BSP conjugation. It is suggested that indocyanine gree competitively binds at the ligandin catalytic site whereas the primary binding site for bilirubin is probably a noncatalytic site.

Elimination kinetics of nitrite and nitrate in the dog, sheep, and pony were determined. The elimination half-lives of nitrite were 0.499, 0.475, and 0.566 hours in the dog, sheep, and pony, respectively; those of nitrate were 44.681, 4.233, and 4.821 hours. Apparent specific volumes of distribution (V'd) of nitrite were variable among the 3 species--1,623.7 ml/kg in the dog, 278.0 ml/kg in the sheep, and 191.6 ml/kg in the pony. The V'd of nitrate were less varied--dog, 238.5 ml/kg; sheep, 291.1 ml/kg; and pony, 209.3 ml/kg. In the in vitro studies on protein binding in canine plasma, the extent of nitrite-protein binding varied directly with concentrations of 5 to 25 mug of NO2 minus/ml (4.5 to 13.6% bound), but inversely with concentrations of 50 to 100 mug of NO2 minus/ml (9.8 to 8.8% bound). Less than 1% of nitrate was bound to canine plasma at equimolar concentrations (5 to 100 mug of NO3 minus/ml).

The concentrations of phenytoin (DPH) in the CNS of adult dogs given the drug by IV injection, continuous IV infusion, or repeated daily oral administration and of newborn pups given DPH by IV injection were consistently proportional to serum concentrations of the drug at the time of blood sample collections. Adult dogs injected IV with [14C]DPH failed to show predilection of the drug for the 13 anatomic brain sections sampled. The pharmacokinetics of DPH were studied in adult and neonatal dogs given 15 mg of the drug/kg of body weight as a single IV injection. The mean half-life of the drug in adult dogs injected IV was 4.5 hours. The serum half-life of injected DPH was lowest in pups 30 days of age when compared with that in other age groups. The serum half-life of injected DPH was increased in adult dogs under pentobarbital anesthesia.

The absorption of horseradish peroxidase was estimated in 10-day-old rats by measuring plasma peroxidase levels following intraduodenal admininstration. Peak levels occurred 45 min after injection. Plasma peroxidase levels, 45 min after injection into five ligated segments along the small intestine, were significantly lower in rats with distal segments than in rats with proximal segments. This indicates that the proximal small intestine, including the duodenum, may play a significant role in nonantibody macromolecular transport as well as in immunoglobulin absorption.

Six Beagle dogs were orally intubated with mixtures of a urea-based fertilizer, 2,4-D, mecoprop (MCPP), dicamba, and either bensulide or chlorpyrifos. The mixtures were formulated as they are used in liquid application to lawns. The dogs were given volumes of 10 ml/kg of body weight, delivering the following quantities of each ingredient: urea--623 mg/kg, inorganic phosphorus (P2O5)--24 mg/kg, potassium (K2O)--66 mg/kg, 2,4-D--6.5 mg/kg, MCPP--3.26 mg/kg, dicamba--0.55 mg/kg, and either bensulide--60.93 mg/kg or chlorpyrifos--6.77 mg/kg. The dogs were given 3 consecutive daily doses of the mixture containing bensulide (round 1) or the mixture containing chlorpyrifos (round 2). The dogs did not exhibit any clinical signs of illness associated with the treatments. Effects on hematologic values or routine clinical chemical analyses did not occur with the round 2 mixture. Serum lactic dehydrogenase activity decreased by approximately 50% after a single dose of the round 1 mixture was given. Plasma cholinesterase decreased to approximately 50% of control values following either the round 1 or the round 2 mixture; this decrease was not accompanied by cholinergic signs of intoxication.

Unconjugated hyperbilirubinemia as occurs in Gunn rats did not affect the plasma disappearance of sulfobromophthalein (BSP) or indocyanine green (ICG). The simultaneous injection of bilirubin and ICG decreased the plasma disappearance of ICG apparently by decreasing hepatic uptake. The data suggest that although bilirubin, ICG and BSP bind to the intracellular hepatic transport protein ligandin one cannot achieve conditions in intact rats to demonstrate effects of competitive interaction with ligandin that affect plasma kinetics of these substances.

Congenital nonhemolytic jaundice as observed in the Gunn rat was transferred successfully to the Sprague-Dawley rat. This jaundice trait occurs as the result of a deficiency of bilirubin glucuronyltransferase and appeared to transfer by simple Mendelian inheritance. A comparison of jaundiced Gunn with jaundiced Gunn-Sprague-Dawley cross rats for plasma bilirubin level, bilirubin glucuronyltransferase activity and female reproductive performance showed no significant difference between the two jaundiced rat groups. The phenotypic expression of the jaundice trait as viewed by the parameters used in this study appeared to be the same for both the Gunn and Gunn-Sprague-Dawley cross rats. The transfer of the jaundice trait to another rat strain enhances the opportunity to characterize this animal model and to determine the possible influence of a long-term closed mating system.

The effectiveness of activated charcoal as an adjunct to phototherapy in reducing plasma bilirubin levels was studied in the jaundiced rat. The administration of charcoal either by feeding or gavage was effective in reducing plasma bilirubin levels in both the adult and suckling jaundiced rat. The combination of charcoal feeding and phototherapy in the adult rat was additive in that the bilirubin levels were significantly lower when compared to levels of the rats given charcoal alone. Plasma bilirubin levels were significantly reduced in the suckling jaundiced rat given either charcoal or charcoal together with phototherapy, however, the combination of treatments did not appear to be additive. These data suggest that charcoal could be a useful adjunct to phototherapy by binding bilirubin in the intestinal lumen and reducing the potential for the enterohepatic circulation of unconjugated bilirubin. Charcoal combined with phototherapy may also reduce the intensity of phototherapy needed to effectively lower plasma bilirubin levels.

The hyperbilirubinemic female Gunn rat has been reported to have impaired fertility. A total of 267 jaundiced (j/j) and 91 nonjaundiced (+/j) female Gunn rats were used in a series of experiments to characterize the nature of this reduced fertility. Sixteen percent of the jaundiced females mated and delivered litters which were characteristically small in number (4.5 pups). A comparison of the gross observations at necropsy of jaundiced and nonjaundiced pregnant rats indicated that the number of implantation sites and live fetuses were significantly lower in the jaundiced females. The number of fetal resorptions in these rats were significantly higher; whereas, the number of corpra lutea was similar for both genotypes. The significantly lower plasma bilirubin levels in the pregnant jaundiced rats compared to the nonpregnant suggested that the observed effect on fertility was related to the concentration of plasma bilirubin.

Chloracne is a follicular hyperkeratosis produced by exposure to certain halogenated aromatic compounds. The rabbit ear bioassay has been used successfully for testing the acnegenic activity of compounds, but the lack of reference data in this species limits its usefulness in correlating chloracne to other toxic effects such as skin carcinogenesis. In this study, a prototype chloracnegen, 3,4,3',4'-tetrachloroazoxybenzene (TCAOB), was used. Five strains of mice (hairless, rhino, rhino+, DBA/2J, and C57BL/6) were treated topically with 100 microliters of 0.001, 0.01, or 0.1% TCAOB daily for 3-9 wk. Skin and liver histology were performed and hepatic enzyme activities measured. At the 0.001% TCAOB level, induction of hepatic aniline hydroxylase and cytochrome P-450 occurred in the C57BL/6 mice and induction of cytochrome c reductase occurred in the rhino mice. Dose-dependent gross and histologic skin lesions, characteristic of follicular hyperkeratosis, were observed in the rhino and hairless strains at the 0.01% and 0.1% levels. These two strains also had induction of hepatic cytochrome c reductase, cytochrome P-450, and aniline hydroxylase at TCAOB concentrations of 0.01 or 0.1%. These results suggest that the rhino and hairless strains of mice may be useful in the study of chloracne.

Two dogs that had been given phenytoin for control of seizures for approximately 1 year developed signs of phenytoin toxicosis (postural ataxia an d a hypermetric gait) when chloramphenicol was added to the therapeutic regimen. The signs of toxicosis disappeared within 24 hours after cessation of chloramphenicol treatment. Oral treatment of laboratory dogs with chloramphenicol (50 mg/kg, TID for 3 days) prior to intravenous injection of phenytoin increased the half-life of phenytoin from 3 hours to 15 hours. Dogs infused with phenytoin during pentobarbital anesthesia had little or no change in serum phenytoin concentration during a 2-hour postinfusion observation period, which was unexpected for the intravenous route of administration.

The concentration of procaine in the CSF of 10 adult nonpregnant cows was determined after epidural injection of 5% procaine hydrochloride solution. Samples of CSF were removed through a catheter introduced into the subarachnoid space at the lumbosacral intervertebral space and advanced craniad to the same level as the epidural injection site. The position and the location of the catheter and spinal needle were confirmed radiographically. Segmental analgesia was achieved 8 to 20 minutes after completing the procaine hydrochloride injection and extended between spinal cord segments T12 and L3 on one or both sides of the animal. The average duration of analgesia, as determined by response to superficial and deep muscular pinpricks at the L1 dermatome, was 81.3 +/- 22.8 minutes (min-max, 45-127 minutes). The average subarachnoid concentration of procaine 10 minutes after epidural injection was 120.4 +/- 42.9 microgram/ml. The highest average procaine concentration recorded was 160.7 +/- 63.7 microgram/ml at 25.0 +/- 6.7 minutes after injection. Average procaine concentration was 47.8 +/- 13.5 microgram/ml at cessation of analgesia. A similar concentration of procaine was recovered from the subarachnoid space during either unilateral or bilateral analgesia. Procaine was not found in arterial plasma after the epidural administration of procaine hydrochloride. Subarachnoid threshold concentrations of local anesthetic necessary to produce spinal analgesia were reached after repeated epidural injections, but not after a single administration. It is concluded that segmental epidural analgesia is principally due to anesthesia of dura-covered nerve roots within and outside the epidural space and is minimally, if at all, dependent on the production of analgesia of nerves within the subarachnoid space.

The effects of mineral oil, vegetable oil, and sodium sulfate on the intestinal absorption of a highly lipid soluble pesticide, DDT, were compared in the rat. Intestinal absorption was evaluated by measuring recovery of DDT and metabolites in feces and the concentration of DDT in adipose tissue following oral administration of DDT and each agent. Vegetable oil was shown to significantly increase absorption of DDT when compared to all other treatments.