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Vector population control using insecticides is a key element of current strategies to prevent malaria transmission in Africa. The introduction of effective insecticides, such as the organophosphate pirimiphos-methyl, is essential to overcome the recurrent emergence of resistance driven by the highly diverse Anopheles genomes. Here, we use a population genomic approach to investigate the basis of pirimiphos-methyl resistance in the major malaria vectors Anopheles gambiae and A. coluzzii. A combination of copy number variation and a single non-synonymous substitution in the acetylcholinesterase gene, Ace1, provides the key resistance diagnostic in an A. coluzzii population from Côte d'Ivoire that we used for sequence-based association mapping, with replication in other West African populations. The Ace1 substitution and duplications occur on a unique resistance haplotype that evolved in A. gambiae and introgressed into A. coluzzii, and is now common in West Africa primarily due to selection imposed by other organophosphate or carbamate insecticides. Our findings highlight the predictive value of this complex resistance haplotype for phenotypic resistance and clarify its evolutionary history, providing tools to for molecular surveillance of the current and future effectiveness of pirimiphos-methyl based interventions., Competing Interests: The authors have declared that no competing interests exist.

This study explored the potential association between chronic exposure to pesticide mixtures including paraquat and respiratory outcomes among Colombian farmers. Sociodemographic and occupational data, respiratory symptoms and spirometric data were collected. Paraquat in spot urine samples were quantified with solid-phase extraction high-performance liquid chromatography. Multiple Poisson regressions with robust variance were used to determine factors associated with respiratory outcomes. Profiles of pesticide mixtures used were identified among 217 farmworkers, but profenofos and methamidophos-based mixtures were more frequent. Chronic paraquat exposure was slightly associated with self-reported asthma (PR: 1.06; 95% CI 1.00 to 1.13). Different pesticide mixtures were associated with flu, thoracic pain, allergic rhinitis, and obstructive pattern in spirometry. Although acute exposure to paraquat is low among Colombian farmers participating in the study, associations between respiratory outcomes and chronic pesticide mixtures exposure including profenofos, methamidophos or glyphosate require further specific studies.

This work is part two of a three-part series in this issue of a Sweden-United States collaborative effort towards the understanding of the chemical attribution signatures of Russian VX (VR) in synthesized samples and complex food matrices. In this study, we describe the sourcing of VR present in food based on chemical analysis of attribution signatures by liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with multivariate data analysis. Analytical data was acquired from seven different foods spiked with VR batches that were synthesized via six different routes in two separate laboratories. The synthesis products were spiked at a lethal dose into seven food matrices: water, orange juice, apple purée, baby food, pea purée, liquid eggs and hot dog. After acetonitrile sample extraction, the samples were analyzed by LC-MS/MS operated in MRM mode. A multivariate statistical calibration model was built on the chemical attribution profiles from 118 VR spiked food samples. Using the model, an external test-set of the six synthesis routes employed for VR production was correctly identified with no observable major impact of the food matrices to the classification. The overall performance of the statistical models was found to be exceptional (94%) for the test set samples retrospectively classified to their synthesis routes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

To investigate pesticide residue concentrations and potential human health risk, a study was conducted in 118 leafy vegetable samples collected in 2014-2015 from the North Central agricultural areas of Chile. The pesticide residues were determined using the multiresidue QuEChERS method by gas chromatography as well as high-performance liquid chromatography. The results indicated that 27% of the total samples contained pesticide residues above the maximum residue limits of each active ingredient. The maximum estimated daily intake obtained for carbon disulphide (CS 2 ), methamidophos, azoxystrobin and cypermethrin were 0.57, 0.07, 0.06 and 0.05 mg kg -1 , respectively, which was higher than their acceptable daily intake. It is concluded that inhabitants of the North Central agricultural area of Chile are not exposed to health risks through the consumption of leafy vegetables with the exception of methamidophos. Nevertheless, the high levels of methamidophos detected in leafy vegetables could be considered a potential chronic health risk.

Organophosphorus pesticides acephate and chlorpyrifos in foods have potential to impact human health. The aim of the current study was to investigate the pharmacokinetics of acephate and chlorpyrifos orally administered at lowest-observed-adverse-effect-level doses in chimeric mice transplanted with human hepatocytes. Absorbed acephate and its metabolite methamidophos were detected in serum from wild type mice and chimeric mice orally administered 150mg/kg. Approximately 70% inhibition of cholinesterase was evident in plasma of chimeric mice with humanized liver (which have higher serum cholinesterase activities than wild type mice) 1day after oral administrations of acephate. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated plasma concentrations of acephate and chlorpyrifos in humans were consistent with reported concentrations. Acephate cleared similarly in humans and chimeric mice but accidental/incidental overdose levels of chlorpyrifos cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in mice. The data presented here illustrate how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of toxicological potential of organophosphorus pesticides., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In Costa Rica, thousands of tones of agricultural pesticides have been used for decades and their use is continuously increasing due to intensive and expanding production of coffee, pineapple, rice, ornamental plants and bananas. The objective of this study was to evaluate whether choline esterase (ChE) activity could be used as a biomarker of exposure to pesticides in the Costa Rican native fish Astyanax aeneus (characidae). Three methods used in order to evaluate the ChE biomarker were as follows: Laboratory studies where A. aeneus was exposed to organophosphate pesticide (ethoprophos); In situ 48 hr exposure assessment using caging experiments with fish exposed upstream and downstream of banana plantations and ChE activity estimation of in fish captured directly at sites with different degrees of pesticide exposure. Results from the laboratory studies showed that ChE activity in both brain and muscle tissue was significantly lower in fish exposed to ethoprophos than in controls. Fish from the caging experiments showed no difference in ChE activity neither in brain nor in muscle tissue between the four tested sites and was attributed to the short duration of the exposure. Asignificant difference in ChE activity was determined in muscle of fish captured from Laguna Madre de Dios compared to fish from Canal Batán. Although our laboratory results revealed that ChE activity in A. aeneus was highly responsive to ethoprophos, results from field experiments were less conclusive and showed that the captured fish showed large variability in ChE activity and that more research is needed before ChE activity can be used as reliable biomarker of pesticide exposure.

Nucleic acid oligodeoxynucleotides (ODN) are increasingly used in biological research and in clinics where they are used for both diagnostic and therapeutic purposes. In order to increase the stability and efficacy of ODNs, various chemical modifications have been applied to create nucleic acid derivatives that are not recognized by endogenous nucleic acid cleavage mechanisms. One of the most common and cost-effective modifications is the phosphothioate (PTO) modification. The PTO modification is implemented mainly in antisense ODN, but also in ODN that were shown to activate members of the toll-like receptor (TLR) family such as TLR3 (poly-I:C), TLR8 (ssRNA) and TLR9 (CpG). We recently found that PTO-ODN aimed at activating TLR9 induce a non-TLR9-specific detachment phenotype in a growth-substrate dependent manner. Moreover, we found that unmodified and PTO-modified TLR ligands induce distinct patterns of gene expression in cultured neural cells. These findings suggest that PTO-ODN can cause nonspecific effects on cell adhesion that could compromise interpretation of data from experiments using PTO-ODN.

Background: Organophosphate insecticides represent one of the most widely used classes of pesticides with high potential for human exposure in both rural and residential environments., Objective: In the present study, we investigated the effects of pirimiphos-methyl (0, 2-diethylamino-6-methylpirimidin-4-yl O, O-dimethyl phosphorothioate), an organophosphothioate pesticide, on male rat reproductive performances., Methods: A total of 24 adult Wistar rats were divided into 4 groups of 6 animals each and orally treated with 0, 41.67, 62.5 or 125 mg/kg of pirimiphos-methyl for 90 days., Results: Results from the study showed a significant increase (p<0.05) in feed consumption, body weight gain, relative testis and epidiydimis weights and intra-testicular cholesterol level in rats receiving the test substance at doses of 62.5 or 125 mg/kg whereas a significant decrease (p<0.05) in serum total protein, sperm density and motility, fertility and parturition indices and pups sex-ratio (M/F) was recorded in animals treated with 125 mg/Kg of pirimiphos methyl. Histological findings also indicated enlargement of interstitial space, inhibition of spermatogenesis, rarefaction of Leydig cells and oedema in testes compared to control animals., Conclusion: It could then be concluded that pirimiphos-methyl (62.5 and 125 mg/kg) is detrimental to the reproductive potentials of male rats.

It has been suggested that, in some cases, exposure to environmental contaminants affects children more profoundly than adults. It is important to evaluate adverse health outcomes in children, a population susceptible to toxic chemicals and mixtures. We examined the effects that maternal exposure to two pesticides had on maturational aspects of offspring development during the nursing period. Nursing female rats were exposed to 1-4mg/kg of intraperitoneal methamidophos, 200-800mg/kg of chlorothalonil, or both. The higher doses of methamidophos affected pup viability by day 21 of life. Both pesticides, alone or together, affected body weight gain of dams and offspring. Developmental milestones evaluated in the pups were incisor eruption, ear unfolding, eye opening and testis descent. Although no clear dose-response relationship was established between these milestones and exposure to methamidophos or chlorothalonil, incisor eruption was accelerated in many groups, and the majority of rat offspring exposed to methamidophos presented later ear unfolding and eye opening than did the control group offspring. Sexual maturation (testis descent) was significantly delayed in some groups. For dams and pups alike, simultaneous exposure to both pesticides was not found to have a greater toxic effect than that resulting from exposure to only one of the two. Taken together, these results demonstrate exposure-related influences on several developmental measures. Detection of more subtle effects may be improved through the use of the developmental temporal response protocols utilized in this study.

Objective: To analyze the relationship between the chronic exposure (EC) to organophosphated insecticides (IOF) with the presence of peripheral neuropathy (NP) and the deterioration of cognitive functions (DFC)., Design of the Study: Cross-section, comparative and observational., Material and Methods: Workers with more than three months of seniority, who participated in any stage of the process of production of IOF were included, and those with alterations in the neurological function were excluded. Two control groups were made up: the first one, without direct exposure to IOF, and the second one, without any exposure whatsoever to IOF. A physical examination was practiced on inferior limbs and a motor neuroconduction of the fibular nerves was carried out. The Minimum Exam of the Mental State was set (Mental Mini). The sampling was not random., Results: It was found that the presence of DFC and the clinical data for NP were greater in the exposed group than in the controls, (p < 0.05). Besides, data with a tendency to the continuation in the parameters of latencies, widths and waves F for the motor neuroconduction of inferior limbs were presented., Conclusions: The long term exposure to IOF is related to deterioration in the cognitive function; as well as to the neurological manifestations in inferior limbs that condition an injury in the peripheral nerve, without being conclusive about the loss of its function.

Organophosphorous pesticides (OPs) are suspected of altering reproductive function by reducing brain acetylcholinesterase activity and monoamine levels, thus impairing hypothalamic and/or pituitary endocrine functions and gonadal processes. Our objective was to evaluate in a longitudinal study the association between OP exposure and serum levels of pituitary and sex hormones. Urinary OP metabolite levels were measured by gas-liquid chromatography, and serum pituitary and sex hormone levels by enzymatic immunoassay and radioimmunoassay in 64 men. A total of 147 urine and blood samples were analyzed for each parameter. More than 80% of the participants had at least one OP metabolite in their urine samples. The most frequent metabolite found was diethylthiophosphate (DETP; 55%), followed by diethylphosphate (DEP; 46%), dimethylthiophosphate (DMTP; 32%), and dimethyldithiophosphate (DMDTP; 31%). However, the metabolites detected at higher concentrations were DMTP, DEP, DMDTP, and dimethylphosphate. There was a high proportion of individuals with follicle-stimulating hormone (FSH) concentrations outside the range of normality (48%). The average FSH serum levels were higher during the heavy pesticide spraying season. However, a multivariate analysis of data collected in all periods showed that serum FSH levels were negatively associated with urinary concentrations of both DMTP and DMDTP, whereas luteinizing hormone (LH) was negatively associated with DMTP. We observed no significant associations between estradiol or testosterone serum levels with OP metabolites. The hormonal disruption in agricultural workers presented here, together with results from experimental animal studies, suggests that OP exposure disrupts the hypothalamic-pituitary endocrine function and also indicates that FSH and LH are the hormones most affected.

The drug-toxicant interaction between the antidepressant imipramine (IMI) and three organophosphorothionate pesticides (OPTs), to which humans may be chronically and simultaneously exposed, has been investigated in vitro. Concentrations of IMI (2-400 microM) and OPTs (< or =10 microM) representative of actual human exposure have been tested with recombinant human CYPs and human liver microsomes (HLM). The different CYPs involved in IMI demethylation to the pharmacologically active metabolite desipramine (DES) were CYP2C19 > CYP1A2 > CYP3A4. The OPTs significantly inhibited (up to >80%) IMI bioactivation catalyzed by the recombinant CYPs tested, except CYP2D6, and by HLM; the inhibition was dose-dependent and started at low pesticide concentrations (0.25-2.5 microM). The OPTs, having lower K(m) values, efficiently competed with IMI for the enzyme active site, as in the case of CYP2C19. However, with CYP1A2 and CYP3A4, a time- and NADPH-dependent mechanism-based inactivation also occurred, consistently with irreversible inhibition due to the release of the sulfur atom, binding to the active CYP during OPT desulfuration. At low IMI and OPT concentrations, lower IC50 values have been obtained with recombinant CYP1A2 (0.7-1.1 microM) or with HLM rich in 1A2-related activity (2-10.8 microM). The K(i) values (2-14 microM), independent on substrate concentrations, were quite low and similar for the three pesticides. Exposure to OPTs during IMI therapeutic treatments may lead to decreased DES formation, resulting in high plasma levels of the parent drug, eventual impairment of its pharmacological action and possible onset of adverse drug reactions (ADRs).

By the methods of CFU and rDNA-PCR-DGGE, this paper studied the dynamic changes of culturable fungal populations, community structure, and population richness in black soil under stress of acetochlor and methamidophos. The results showed that the growth of fungi was promoted under lower concentration acetochlor (50 mg x kg(-1)), but long-standing inhibited under its higher concentration (250 mg x kg(-1)). 250 mg kg(-1) methamidophos promoted the growth of culturable fungi intensively during 8-week period, resulting in 10 times increase in CFU of fungi than the control, while low concentration methamidophos (50 mg x kg(-1)) had no evident effect. The richness of culturable fungi in soil treated by medium and high concentration acetochlor was decreased irreversibly. Cluster analysis of fungal rDNA-PCR-DGGE fingerprints profile showed that acetochlor and methamidophos could change the culturable fungal community structure diversely, and the effect of methomidophos was more obvious.

Background: Irritant contact dermatitis and allergic contact dermatitis (ACD) are frequent among agricultural workers and require targeted interventions. Patch testing is necessary for differential diagnosis, but patch testing with pesticides is uncommon., Objective: This study explores the frequency of ACD and sensitization to pesticides among highly exposed banana plantation workers., Methods: Frequently and recently used pesticides on banana plantations in Divala, Panama, were documented. A pesticide patch test tray specific for this population was prepared. A structured interview was administered to 366 participants, followed by a complete skin examination. The pesticide patch test series, as well as a standard patch test series, was applied to 37 workers with dermatoses likely to be pesticide related and to 23 control workers without dermatoses., Results: The pesticide patch tests identified 15 cases (41%) of ACD (20 positive reactions) among the 37 workers diagnosed with pesticide dermatosis. Three controls had allergic reactions to pesticides (4 positive reactions). The pesticides were carbaryl (5 cases), benomyl (4 cases), ethoprophos (3), chlorothalonil (2), imazalil (2), glyphosate (2), thiabendazole (2), chlorpyrifos (1), oxyfluorfen (1), propiconazole (1), and tridemorph (1). Ethoprophos and tridemorph had not been previously identified as sensitizers. Thus, the prevalence of ACD was 0.03 (15 of 366). On the basis of observed prevalences of positive patch-test reactions among the subgroups with and without dermatoses, we estimated that > or = 16% of the entire population may be sensitized to pesticides., Conclusion: Sensitization to pesticides among banana plantation workers is a frequent occupational health problem. Pesticide patch test trays should be used in assessing skin diseases in highly exposed workers.

Human lymphocytes were exposed to the leukemogenic pesticide isofenphos (IFP) to investigate its effects on chromosomal DNA and cholinergic homeostasis using cholinesterase activity as a marker. Isolated peripheral lymphocytes were administered concentrations of IFP ranging from 0.1 ng/ml to 10 microg/ml. The absence (Group 1) and presence (Group 2) of DNA repair inhibitors 4 mM hydroxyurea (HU), 40 microM cytosine arabinoside (ARA-C) and an NADPH regenerating system (NRS) (Group 3) were analyzed at 1, 6 and 24 h by single cell gel electrophoresis using the comet assay. Significant damage to DNA directly from IFP at 1 h by remarkably low concentrations was observed in Group 1, escalating in Group 2 with DNA repair inhibition, while Group 3 disruptions were highest due to the presence of the NRS P-450 microsomal fraction conducive to producing reactive IFP-oxon and N-desalkyl metabolites. The extent of DNA aberrations increased further in parallel within the groups at 6 and 24 h. Male and female chemical sensitivities were similar on average (P < 0.01). Cholinesterase activity measured in a satellite group was inhibited with 0.1 microg/ml IFP by 69, 62, and 48% at 1, 6, and 24 h, respectively, indicating gradual induction of compensatory synthesis. Restoration of cholinergic homeostasis may be exceptionally impaired at higher IFP concentrations from acetyl-CoA depletion [Leuk. Res. 25 (2001) 883]. In summary, these studies reveal that exposure to the organophosphate pesticide isofenphos induces human DNA mutation beyond endogenous repair capacity and disrupts cholinergic nuclear signaling affectively constructing the mutator phenotype of leukemogenesis.

The respiratory system plays a major role in the pathogenesis of nerve agent toxicity. It is the major route of entry and absorption of nerve agent vapor, and respiratory failure is the most common cause of death follow-ing exposure. Respiratory symptoms are mediated by chemical irritation,muscarinic and nicotinic receptor overstimulation, and central nervous system effects. Recent attacks have demonstrated that most patients with an isolated vapor exposure developed respiratory symptoms almost immediately. Most patients had only mild and transient respiratory effects, and those that did develop significant respiratory compromise did so rapidly. These observations have significant ramifications on triage of patients in a mass-casualty situation, because patients with mild-to-moderate exposure to nerve agent vapor alone do not require decontamination and are less likely to develop progressive symptoms following initial antidote therapy. Limited data do not demonstrate significant long-term respiratory effects following nerve agent exposure and treatment. Provisions for effective respiratory protection against nerve agents is a vital consideration in any emergency preparedness or health care response plan against a chemical attack.

Edifenphos, an organophosphate fungicide, was administered to hemicastrated albino rats intraperitoneally for 15 consecutive days in graded doses of 2 to 8 mg/kg body weight. In the oil-treated hemicastrated control group, ovarian weight and total number of healthy and atretic follicles were significantly higher than the same parameters in sham-operated control animals, and the estrous cycle was normal. Treatment with 2, 4, 6, or 8 mg/kg/d edifenphos significantly decreased ovarian weight (-6.75, -9.79, -18.71, and -34.13 percent, respectively) below that of the controls. Although treatment with 2 or 4 mg/kg/d edifenphos did not change the number of healthy and atretic follicles, a dosage of 4 mg/kg/d significantly decreased the number and duration of estrous cycles. Treatment with 6 or 8 mg/kg/d, however, significantly decreased the number and duration of different phases of the estrous cycle as well. In all treated groups, the weights of the thymus and uterus were significantly reduced when compared with those of hemicastrated oil-treated control animals.

The biomarkers acetylcholinesterase (AChE) and glutathione S-transferase (GST) were measured in fourth-instar Chironomus riparius Meigen larvae exposed to the organophosphate insecticide pirimiphos methyl (0, 5, 10, and 50ng/g) for 48 or 96h, and at high or low food ration. Larvae exposed to 50ng/g pirimiphos methyl died within 48h. The weight of larvae exposed to 10ng/g pirimiphos methyl was significantly lower than those exposed to 0 and 5ng/g. AChE activity was significantly reduced in larvae exposed to 10ng/g, but GST activity remained unaffected. Lower food ration reduced larval weights across all treatments but did not affect biomarker measurements. Insecticide exposure was associated with a longer time to adult emergence and oviposition, fewer egg masses, a greater proportion of deformed egg masses, and fewer eggs.

Vesicants and nerve agents have been used in chemical warfare for ages. They remain a threat in today's altered political climate because they are relatively simple to produce, transport, and deploy. Vesicants, such as mustard and lewisite, can affect the skin, eyes, respiratory system, and gastrointestinal system. They leave affected persons at risk for long-term effects. Nerve agents, such as tabun, sarin, soman, and VX, hyperstimulate the muscarinic and nicotinic receptors of the nervous system. Physicians need to familiarize themselves with the clinical findings of such exposures and the decontamination and treatment strategies necessary to minimize injuries and deaths.

Fourth-instar Chironomus riparius Meigen larvae were exposed to the organophosphate (OP) insecticide pirimiphos methyl (0, 0.1, 1.0, and 10 microg/L) for 48, 72, or 96 h at three temperatures (3, 12, or 22 degrees C). Two biochemical biomarkers, acetylcholinesterase (AChE) and glutathione S-transferase (GST), were measured in individual larvae from each treatment. AChE activity was inhibited by the OP in a dose-responsive fashion. This response remained similar at all three temperatures, demonstrating that AChE is a robust and specific biomarker. Exposure duration had little effect on AChE activity. In contrast, GST activity was induced at the highest OP insecticide concentration, but induction was also evident at 3 degrees C. There was a significant effect of exposure duration, with an overall decline in GST activity over time. This result agrees with previous work suggesting that GSTs are not particularly suitable for use as a biomarker of pesticide exposure or effect in Chironomus., ((c) 2002 Elsevier Science (USA).)

The U.S. Army has estimated acute lethality guideline levels for inhalation of the chemical warfare agents mustard, GB, and VX. These levels are expressed as dosages measured in milligram-minutes per cubic meter (mg-min/m(3)). The National Advisory Council has also proposed acute emergency guideline levels (AEGLs) for the agents. The AEGLs are threshold exposure limits for the general public for mild effects, serious adverse effects, and lethality. They are expressed as air concentrations (in units of mg/m(3)) and are applicable to emergency exposure periods ranging from 10 min to 8 h. The report discusses strengths and deficiencies in the levels, important parameters (i.e., exposure time, breathing rate) that need to be explicitly addressed in deriving the guideline levels, and possible impacts that could result from using AEGLs instead of guideline dosages in future assessments., (Copyright 2002 Elsevier Science (USA))

This study investigated the association between occupational pesticide exposure and semen quality among Chinese workers. Male workers, 32 who were exposed to organophosphate pesticides and 43 who were not exposed were recruited from two nearby factories and interviewed. Following a work shift, semen and urine samples were collected for pesticide metabolite analysis. Semen samples were analyzed for sperm concentration, percentage of motility, and percentage of normal structure. Within the exposed group, the mean end-of-shift urinary p-nitrophenol levels were 0.22 and 0.15 mg/L for the high- and low-exposure subgroups, respectively. Linear regression analysis of individual semen parameters revealed a significant reduction of sperm concentration (35.9 x 10(6) vs 62.8 x 10(6), p < 0.01) and percentage of motility (47% vs 57%, p = 0.03) but not percentage of sperm with normal structure (57% vs 61%, p = 0.13). Multivariate modeling showed a significant overall shift in the mean semen parameter. Occupational exposure to ethylparathion and methamidophos seems to have a moderately adverse effect on semen quality.

59 workers exposed to different chemicals during the manufacture of quinalphos, an organophosphate pesticide (OP) and 17 control subjects were studied. Despite similar blood acetylcholinestarase (AChE) levels in both the exposed and control subjects, a significant number of exposed subjects had altered plantar and ankle reflexes. Higher nervous functions such as memory, learning and vigilance were also found to be affected in these subjects. These findings were attributed to chronic low dose combined exposure to different chemicals used/formed in the manufacture of quinalphos. The study raises the doubt that monitoring of AChE alone among subjects engaged in the manufacture of OP pesticides may not be an adequate safeguard as regards to their health.

Background: A study of the prevalence of sperm aneuploidy among pesticide factory workers was conducted in Anhui, China., Methods: We recruited 75 men: 32 subjects from a large pesticide-manufacturing plant and 43 subjects from a nearby textile factory free of pesticide exposure. Each subject met the following criteria: age of 20-40 years; continuous work in the plant for 3 months prior to the study, no congenital anomalies or acquired disease of the external genitalia and no history of recent febrile illness or mumps. Within one hour after collection from each subject, semen was evaluated in terms of several parameters and smear slides were prepared., Results: Exposure assessment revealed that workers in the pesticide plant were exposed to ethyl parathion or methamidophos, each of which is a potent organophosphate pesticide, at a median level of 0.02 mg/m3 (8-hour time weighted average as measured by personal pump) while workers in the control plant had no such occupational exposure. Twenty-nine semen slides (13 from the exposed group and 16 from the unexposed group) were randomly chosen for aneuploidy scoring by the three-color fluorescence in situ hybridization (FISH) method with scorers being unaware of exposure status. Median semen parameters were as follows for exposed (and unexposed) men: abstinence period, 3 days (4 days); sperm concentration, 52.8x10(6)/ml (53.1x10(6)/ml); proportion of sperm with normal motility, 50.5% (61.3%); and proportion of sperm with normal morphology, 59% (61.5%). The specific chromosome abnormalities of interest were disomy for chromosome 18 and the three different types of sex chromosome disomy (i.e. XX, XY, YY disomy). The crude proportion of all aneuploidy combined was 0.30% and 0.19% for sperm from exposed and unexposed men, respectively. Poisson regression with overdispersion adjustment yielded significantly different crude risks of aneuploidy - 3.03 and 1.94 per 1,000 sperm from exposed and unexposed men, respectively - giving a rate ratio of 1.56 (95% CI, 1.06-2.31). The regression coefficients remained statistically significant after adjustment for inter-technician variability giving a rate ratio of 1.51 (95% CI, 1. 04-2.20)., Conclusions: We conclude that occupational exposure to organophosphate pesticides moderately increases the prevalence of sperm aneuploidy., (Copyright 1999 Wiley-Liss, Inc.)

Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels, as well as urinary levels of FSH, LH, and E1C, a metabolite of testosterone, were measured to investigate the adverse reproductive effects of organophosphate pesticides among Chinese factory workers who were occupationally exposed to ethylparathion and methamidophos. Thirty-four exposed workers were randomly chosen and recruited from a large pesticide factory, and 44 unexposed workers were selected from a nearby textile factory. A quantitative pesticide exposure assessment was performed among a subset of the exposed and unexposed workers. Information on potential confounders was collected in an interview. A single blood sample was collected at the end of a work shift, when each subject also donated a semen sample. Three first-voided urine samples were collected from each worker on 3 consecutive days. Urinary p-nitrophenol level at 1 hour after the work shift correlated with serum (r = 0.71, P < 0.01) and urinary (r = 0.51, P = 0.04) FSH levels. Stratifying by the subjects' exposure status, we found a significant negative correlation among the exposed group between urinary FSH level and sperm count (r = -0.61, P < 0.01) and between urinary FSH level and sperm concentration (r = -0.53, P = 0.03). Pesticide exposure alone was significantly associated with serum LH level (beta [coefficient of exposure effect] = 0.79; 95% confidence interval [CI] = 0.42, 1.16) but not with serum FSH or testosterone or with any urinary hormone levels. With adjustment for age, rotating shift work, current cigarette smoking, and current alcohol consumption, exposure significantly increased the serum LH level by 1.1 mIU/mL (95% CI = 0.34, 1.82). Meanwhile, the serum FSH level was slightly elevated (beta [coefficient of exposure effect] = 1.38; 95% CI = -0.09, 2.85) and the serum testosterone level was decreased (beta = -55.13; 95% CI = -147.24, 37) with increased pesticide exposure. Age and rotating shift work appeared to act as confounders. We conclude that organophosphate pesticides have a small effect on male reproductive hormones, suggestive of a secondary hormonal disturbance after testicular damage.

Discrepancies in the aging reaction between neuropathy target esterase (NTE) inhibited in vitro and in vivo by racemic mixtures of O-alkyl O-2,5-dichlorophenyl phosphoramidates have been observed. It suggested the existence of differences in the interactions (inhibition and aging) between NTE and each stereoisomers of the above mentioned compounds. In order to verify this hypothesis, stereoisomers of O-hexyl O-2,5-dichlorophenyl phosphoramidate (HDCP) were isolated by chiral column chromatography, followed by the evaluation of NTE inhibition and aging for each stereoisomers. The loss of reactivation capacity by KF was used as criterion of aging. The stereoisomer S-(-)-HDCP inhibited hen brain NTE with an I50 of 7.6 nM for 30 min of incubation, this being similar to the value obtained for the racemic mixture (I50 = 6.2 nM), and much lower than that recorded for R-(+)-HDCP (I50 = 191 nM). NTE inhibited by HDCP racemic mixture and the stereoisomer S-(-)-HDCP was reactivated by KF after 20 h of incubation at 37 degrees C. The NTE inhibited by R-(+)-HDCP could not be fully reactivated after inhibition.

A proportional mortality study comparing the cotton-growing areas of the San Joaquin Valley with the rest of the State of California was performed by the Office of Environmental Health Hazard Assessment as a continuation of earlier studies related to mercaptan-releasing pesticides. This mortality study found a pattern of increased proportion of "respiratory causes" mortality (ICD codes 460-519), statistically significant at less than the .05 probability level, for 15 of 21 years between 1970 and 1990, for the time period during and immediately following cotton defoliation. Defoliants which have the potential to produce acute symptoms include DEF and Folex, both of which release odorous butyl mercaptan gas as a degradation product. This paper tests the hypothesis that exposure to cotton defoliant breakdown products may be associated with a disproportionate increase in mortality. Prediction of the mortality proportions by pounds of DEF and Folex used was not statistically significant in the unadjusted models or in models adjusted for air pollution variables. One air pollution adjustment factor, total suspended particulates, was a statistically significant independent mortality proportion predictor. This finding suggests that total suspended particulates, not defoliants, may be related to mortality differentials during defoliation season. Possible confounding by demographic variation of the counties was not controlled in the analysis.

Brain cholinesterase (ChE) activities of songbirds collected in pecan groves 6 to 7 hr after separate applications of the organophosphorus pesticides, phosalone and disulfoton, were compared to mean ChE activities of controls (normals) as a measure of insecticide exposure. In general, reduction of brain ChE activity greater than or equal to 2 standard deviations below the control mean indicates exposure to an anticholinesterase compound. Phosalone had little effect on brain ChE activity of birds from treated groves; only slight to moderate (21 to 38%) ChE inhibition was detected in blue jays (Cyanocitta cristata) and red-bellied woodpeckers (Melanerpes carolinus). However, 11 of 15 blue jays from disulfoton-treated groves had moderate to severe ChE depression, ranging from 32 to 72%. Inhibition greater than or equal to 50% of normal may be diagnostic for cause of death. Direct mortality was not observed, but studies have shown that bird carcasses disappear rapidly from agricultural areas, many within 24 hr. We recommend additional field studies of the effects of disulfoton to wildlife, since large wheat-growing areas in the western United States are being considered for disulfoton treatment to control the Russian wheat aphid (Diuraphis noxia).

We investigated the causes of the hypocalcemia associated with WR-2721, an investigational drug that protects normal tissues against the toxic effects of radiation and chemotherapy. Sixteen patients with advanced cancers had serial measurements of serum calcium and other studies of blood chemistry before and after taking the compound. In all 16 patients (18 courses) the mean serum calcium level fell from 2.33 to 1.90 mmol per liter (9.33 to 7.62 mg per deciliter, P less than 0.001) after WR-2721, and in all 8 patients from whom data were obtained, serum calcium levels remained depressed at 24 hours. In 12 patients, ionized calcium levels dropped from 0.98 to 0.80 mmol per liter (P less than 0.01). Serum magnesium values fell from 0.96 to 0.74 mmol per liter (1.91 to 1.48 mg per deciliter, P less than 0.001). There were no changes in arterial pH or serum phosphate concentrations. In nine patients urinary calcium excretion rose from 3.96 to 10.68 mumol per minute (P less than 0.01) after WR-2721. Despite hypocalcemia, parathyroid hormone levels fell in all subjects. WR-2721 also inhibited the release of parathyroid hormone from bovine parathyroid cells incubated in vitro in low (0.5 mM) concentrations of calcium. We conclude that WR-2721 inhibits the secretion of parathyroid hormone and enhances calciuria, thereby leading to hypocalcemia.

Thirty-five workers became ill after they entered a cauliflower field contaminated with residues of three different insecticides, the organophosphates oxydemeton-methyl (Metasystox-R) and mevinphos (Phosdrin), and a carbamate, methomyl (Lannate). One crew member was pregnant with a 4-week-old fetus. At birth, the 3200-g female infant had multiple cardiac defects, bilateral optic nerve colobomas, microphthalmia of the left eye, cerebral and cerebellar atrophy, and facial anomalies. The cardiac defects included ventricular and atrial septal defects, stenosis of the pulmonary artery, and a patent ductus arteriosus. The child died at 14 days of age. There was no family history of birth defects, nor any maternal risk factor present, except that doxylamine (Bendectin) had been prescribed at 9 weeks fetal age. It is unlikely that doxylamine was responsible for the observed anomalies. Of the three chemicals involved, reproductive effects in test organisms have been observed only with oxydemeton-methyl. This case represents the first report of human malformations associated with prenatal exposure to this chemical. Further studies may be warranted to determine if a causal relationship exists.

Of 20 dogs with generalized demodicosis, 18 responded favorably to treatment with 8.5% ronnel solution applied to one-third of the body every 3rd day, in rotation. Duration of treatment was from 5 to 20 weeks. In 2 dogs, the demodicosis recurred and required additional treatment with ronnel. Two dogs died during the study. One death was attributed to ronnel toxicosis; the other was unexplained. Eight of 10 control dogs treated orally and topically for pyoderma associated with demodicosis still had demodicosis 1 year after initiation of the study.

Dermal and respiratory exposure to pirimiphosmethyl, dimethoate and permethrin were determined for applicators and operators in greenhouse tomato spraying operations. Dermal exposure is several times higher than the degree of respiratory exposure. Dermal exposure in terms of different parts of the body shows significant differences. For applicators the exposure of hands, arms and legs is the greatest, and the operators are the most exposed on their hands and to a small extent on legs. This fact should be taken into account when providing the workers with suitable protective clothing. The carefully selected technology of spraying also has great significance in decreasing the degree of exposure. Because of the chronic toxicity of dimethoate, all possible methods should be taken to reduce exposure.

The effect of WR-2721 on performance maintained by a fixed-ratio 20 (FR-20) schedule for water reinforcement was studied in male Sprague-Dawley rats. Graded doses of WR-2721 (range 25-100 mg/kg) were administered IP immediately prior to a 60 min test session. WR-2721 had a dose dependent monotonic disruptive effect on FR responding, with significant effects at doses of 50, 75 and 100 mg/kg. WR-2721 also decreased postsession water consumption, but only one significant effect at the highest dose (100 mg/kg). Both slopes of the dose-response regression line are parallel in effect. These data indicate that WR-2721 may affect drinking motivation, which could disrupt operant performance, and WR-2721 affects motor behavior at lower doses than those that depress "motivation" to drink. The log dose-probit analysis on the all-or-none disruptive pattern of pause of responding observed from cumulative records disclosed that the slope of this regression line (s = 1.11) was also almost identical to that of reinforcer decrement analyzed from graded dose-response relationship (s = 1.14) and shared the same estimated ED50's (58.5 and 55.6 mg/kg, respectively). A preliminary study using a variety of pharmacological interventions was also carried out to ascertain if the general functional gastrointestinal disorders produced by WR-2721 may subserve the behavioral deficits. Subcutaneous pretreatments with various selective, peripherally active, gastroprotective drugs [cimetidine (30 and 60 mg/kg), pirenzepine (5 and 10 mg/kg) and domperidone (1, 5 and 10 mg/kg)] 30 min prior to challenge with WR-2721 at dose of 100 mg/kg, demonstrated that these drugs did not yield any apparent significant attenuative effects.(ABSTRACT TRUNCATED AT 250 WORDS)

In four patients suffering from allergic contact eczema, the risk of sensitization to a new residue-leaving fungicide (Plondrel) used in spraying roses is considered. Two patients, however, were probably also sensitized to materials from the roses themselves. By gas-liquid chromatography the amount of the fungicide, especially in the leaves of roses, appeared to be rather high. The role of pesticides has to be considered when sensitizing agents of plant dermatitis are investigated.

S-2-(3-Aminopropylamino)ethylphosphorothioic acid (WR-2721) is a promising protectant for radiation-induced lethality. However, treatment with WR-2721 also produces nausea, vomiting, diarrhea, and hypotension, which implies severe functional consequences. Three studies were conducted to assess the effects of WR-2721 on rat motor performance and weight and to assess the ability of WR-2721 to mitigate the early performance decrement (PD) produced by ionizing radiation. In the first study, rats trained on the accelerod motor performance task were give 200, 300, or 400 mg/kg WR-2721 intraperitoneally (ip). The highest dose used referenced the maximum tolerated dose in the rat, which is two-thirds the median lethal dose (590 mg/kg). The subjects were tested immediately after treatment, at 30-min intervals for 3 h, and again at 24 h. All groups (N = 6/group) demonstrated a significant decrease in accelerod performance compared to control levels across the eight test trials, which ranged from 24 to 44% in the 200 and 400 mg/kg dose groups, respectively. Performance returned to baseline levels at 24 h. Some deaths occurred at all dose levels. In the second study, motor performance was measured after exposure to radiation alone or a drug/radiation combination (N = 8/group). WR-2721 was administered 30 min before exposure to 130 Gy of gamma radiation from a 60Co source at a dose rate of 20 Gy/min. Rats were tested on the accelerod immediately after WR-2721 treatment and at 10, 15, 30, 60, and 120 min and 24 h following radiation. Performance was significantly depressed compared to control throughout the 24 h following radiation exposure, with and without WR-2721. The decrement produced by WR-2721 and radiation alone appeared to add up to the combined drug/radiation decrement found over the 15- to 120-min test periods. In the third study assessing the effects of WR-2721 on weight, untrained rats treated with 200 or 400 mg/kg WR-2721 exhibited significant weight loss that lasted up to 3 days. Weight returned to pretreatment levels in 15 days, and no deaths occurred. In summary, the data suggest that in the rat (1) WR-2721 is behaviorally toxic at doses relevant to radioprotection, (2) WR-2721 treatment along with the stress of motor performance may combine to lower the level at which lethalities occur, (3) WR-2721 does not protect for radiation-induced PD, and (4) WR-2721 combined with radiation disrupts performance more severely than either radiation or WR-2721 alone.