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Di-alkyl phosphate biomonitoring data: assessing cumulative exposure to organophosphate pesticides
Abstract
The 1996 Food Quality Protection Act (FQPA) requires the evaluation of both aggregate and cumulative health risks from pesticides (FFDCA 408(b)(2)(D)(v) and (vi).) Organophosphate (OP) pesticides are the first class of chemicals to undergo FQPA mandated aggregate and cumulative assessments. In this report, summary data on biomonitoring for urinary levels of six alkyl phosphate (AP) metabolites of OPs, as reported in the initial, March 2001, U.S. Centers for Disease Control and Prevention's (CDC) "National Report on Human Exposure to Environmental Chemicals," are compared to EPA modeled estimates of OP exposure reported in Registration Eligibility Decision documents (REDs), Interim REDs and to currently reported cumulative exposure estimates in the EPA's Cumulative Risk Assessment of the Organophosphate Pesticides. This comparison indicates that EPA's aggregate exposure estimates (dietary, drinking water, and non-dietary residential exposures) for many individual OPs were greater than the cumulative estimate for all OPs combined based on the CDC AP biomonitoring data. The results also suggest that EPA's screening level assessments of OPs, while being qualitative indicators of the relative importance of various exposure sources, are not good quantitative indicators of actual exposures. However, the mean biomonitoring estimate of cumulative OP exposure appears to exceed the EPA's subsequent preliminary estimate of cumulative OP exposure by as much as the REDs appear to overestimate the biomonitoring results. While the conservatism, tendency to overestimate exposure, in the individual REDs is readily acknowledged, the conservatism and limitations of applying currently available CDC AP biomonitoring data to evaluate human exposure to OPs are not as readily apparent. We postulate that oral absorption of non-anti cholinergic, pre-hydrolyzed OPs, sources of APs other than pesticides, and the conservative result of summing exposure from each AP at the geometric mean contribute to non-quantified overestimates of absorbed dosage from the CDC biomonitoring data reported in March 2001. CDC AP biomonitoring data may serve a useful purpose in providing an upper bound estimate of absorbed dosage for "ground truthing" aggregate exposure estimated from first tier models used in REDs, but at best may provide only a credible "target" for the complex cumulative exposure assessment models currently under development. The reliability of quantitative estimates of OP exposure levels will improve as cumulative risk exposure models are validated over time and under use conditions prevalent at the time the AP biomonitoring samples are collected. Analyses contained herein should be revisited and compared to the CDC Second National Report on Human Exposure to Environmental Chemicals ( http://www.cdc.gov/exposurereport), released to the public on January 31, 2003, and the final EPA OP Cumulative Risk Assessment.
... The OP pesticides have a short half-life, lasting only a few hours to a few days, and rapidly convert into pesticide-specific metabolites [24].These metabolites, known as dialkyl phosphate (DAP) [25], are converted into six common DAP metabolites when ingested: diethyl phosphate (DEP), diethyl thiophosphate (DETP), diethyl dithiophosphate (DEDTP),dimethyl phosphate (DMP), dimethyl thiophosphate (DMTP) and dimethyl dithiophosphate (DMDTP) [26,27]. The chemical structure of six urinary metabolites has given in Figure S1 (Supplementary). ...
... Monitoring of DAP metabolites is crucial as they serve as potential biomarkers of population exposure to OP pesticides and hence sensitive and selective analytical methods are required. In the past, several analytical methods have been described for the measurement of DAP metabolites in urine and other matrices, including gas chromatography (GC) and liquid chromatography (LC) in combination with different detectors such as flame photometric detector (FPD) [29], nitrogen phosphorus detector (NPD) [30] and mass spectrometry (MS) [27,[31][32][33][34][35][36]. Currently, LC-MS/MS is the main analytical method for monitoring pesticides and their metabolites in urine, with numerous methods published in recent years. ...
To monitor human exposure to pesticides, experts commonly measure their metabolites in urine, particularly dialkyl phosphates (DAPs), which include diethyl phosphate (DEP), Diethyl thiophosphate (DETP), diethyl dithiophosphate (DEDTP), dimethyl phosphate (DMP), dimethyl thiophosphate (DMTP) and dimethyl dithiophosphate (DMDTP)to monitor the metabolites of organophosphates. These DAP metabolites are a urinary biomarker for assessing pesticide exposure and potential health risks. This study presented a new screening method combining ultrafast liquid chromatography with tandem mass spectrometry (UFLC–MS/MS) to detect six DAP metabolites in human urine. The study also compared standard sample extraction methods, namely, liquid–liquid extraction (LLE); quick, easy, cheap, effective, rugged and safe (QuEChERS); and lyophilization. After a comprehensive analysis of the methods used to extract the analytes, including recovery rate, repeatability and reproducibility, the liquid–liquid extraction (LLE) method was found to be the best. It had a high recovery rate, was easy to handle, required less sample volume and had a short extraction time. Therefore, the LLE method was chosen for further analysis. The results showed excellent performance with high recoveries between 93% and 102%, precise repeatability (RSD) between 0.62% and 5.46% and acceptable reproducibility values (RSD) between 0.80% and 11.33%. The method also had limits of detection (LOD) ranging from 0.0201 ng/mL to 0.0697 ng/mL and limits of quantification (LOQ) ranging from 0.0609 ng/mL to 0.2112 ng/mL. Furthermore, the UFLC–MS/MS method was validated based on the SANTE guidance and successfully analyzed 150 urine samples from farmers and non-farmers. This validated method proved useful for biomonitoring studies focusing on OP pesticide exposure. It offers several advantages, such as a reduced need for samples, chemicals and materials, and a shorter analysis time. The method is sensitive and selective in detecting metabolites in human urine, making it a valuable approach for the practical and efficient assessment of pesticide exposure.
... These compounds are widely used worldwide as pesticides due to their low residual power in the environment. Some commercial uses of OPs include plague control (Marselos and Vainio, 1991), industrial disinfection of hospitals and schools, or fumigants for flower production and maintenance of golf courts or football pitches (Duggan et al., 2003). Due their widespread use, it has been proposed that all living organisms are continually exposed to these compounds. ...
... It is important to mention that the primary mechanism of OP toxicity is the inhibition of acetylcholinesterase (AChE) (Edwards and Tchounwou, 2005;Nolan et al., 1984). OPs such as Disulfothon, Ethion, Phorate, Phosalone and Terbufos, generate metabolites called dialkyl phosphates (DAPs) like diethyl dithiophosphate (DEDTP), diethyl thiophosphate (DETP), diethyl phosphate (DEP), dimethyl dithiophosphate (DMDTP), dimethyl thiophosphate (DMTP) and dimethyl phosphate (DMP) (Duggan et al., 2003). These metabolites are formed once the OPs are absorbed by organisms like plants, insects or mammals. ...
Glutamate is the major excitatory neurotransmitter in the vertebrate central nervous system. During synaptic activity, glutamate is released and binds to specific membrane receptors and transporters activating, in the one hand, a wide variety of signal transduction cascades, while in the other hand, its removal from the synaptic cleft. Extracellular glutamate concentrations are maintained within physiological levels mainly by glia glutamate transporters. Inefficient clearance of this amino acid is neurotoxic due to a prolonged hyperactivation of its postsynaptic receptors, exacerbating a wide array of intracellular events linked to an ionic imbalance, that results in neuronal cell death. This process is known as excitotoxicity and is the underlying mechanisms of an important number of neurodegenerative diseases. Therefore, it is important to understand the regulation of glutamate transporters function. The transporter activity can be regulated at different levels: gene expression, transporter protein targeting and trafficking, and post-translational modifications of the transporter protein. The identification of these mechanisms has paved the way to our current understanding the role of glutamate transporters in brain physiology and will certainly provide the needed biochemical information for the development of therapeutic strategies towards the establishment of novel therapeutic approaches for the treatment and/or prevention of pathologies associated with excitotoxicity insults.
... Diethyldithiophosphoric acid, diethylphosphorodithioate or diethyldithiophosphate (DEDTP) is a partial ester of dithiophosphoric acid that belongs to the group of dialkyldithiophosphoric acids or dialkylphosphates (DAPs). DAPs are metabolites that result from the biotransformation of some organophosphate (OP) pesticides, such as disulfoton, ethion, phorate, phosalone or terbufos (Duggan et al., 2003), in hepatic cells. However, it is also synthesized via the reaction of phosphorus pentasulfite with ethanol (Cowsik and Srinivasan, 1973), and this strong acid is used as a chelating agent (Maltez et al., 2008). ...
... Synthetic DEDTP is used for several purposes, such as an additive in lubricants, flame retardants, and plasticizers (Marklund et al., 2005), in corrosion and oxidation inhibitors, as an oil additive (Becker et al., 1997;Hamawand et al., 2013), a collector in the flotation of minerals (McFadzean et al., 2013), surfactants in detergents (Cooper and Urfer, 1964) and in analytical determinations (Ferreira et al., 2007). Exposure to DEDTP in general population occurs via contaminated food (Duggan et al., 2003;Lu et al., 2005), which increases the risk of chronic exposure. Several studies demonstrated detectable levels of up to 260 ppb in urine of the general population, who are not occupationally exposed (Bradman et al., 2005;Bouchard et al., 2010;Kavvalakis and Tsatsakis, 2012). ...
... These compounds are widely used worldwide as pesticides due to their low residual power in the environment. Some commercial uses of OPs include plague control (Marselos and Vainio, 1991), industrial disinfection of hospitals and schools, or fumigants for flower production and maintenance of golf courts or football pitches (Duggan et al., 2003). Due their widespread use, it has been proposed that all living organisms are continually exposed to these compounds. ...
... It is important to mention that the primary mechanism of OP toxicity is the inhibition of acetylcholinesterase (AChE) (Edwards and Tchounwou, 2005;Nolan et al., 1984). OPs such as Disulfothon, Ethion, Phorate, Phosalone and Terbufos, generate metabolites called dialkyl phosphates (DAPs) like diethyl dithiophosphate (DEDTP), diethyl thiophosphate (DETP), diethyl phosphate (DEP), dimethyl dithiophosphate (DMDTP), dimethyl thiophosphate (DMTP) and dimethyl phosphate (DMP) (Duggan et al., 2003). These metabolites are formed once the OPs are absorbed by organisms like plants, insects or mammals. ...
Glutamate, the main excitatory neurotransmitter in the vertebrate Central Nervous System, is involved in almost every aspect of brain physiology, and its signaling properties are severely affected in most neurodegenerative diseases. This neurotransmitter has to be efficiently removed from the synaptic cleft in order to prevent an over-stimulation of glutamate receptors that leads to neuronal death. Specific sodium-dependent membrane transporters, highly enriched in glial cells, elicit the clearance of glutamate. Once internalized, it is metabolized to glutamine by the glia-enriched enzyme Glutamine synthetase. Accumulated glutamine is released into the extracellular space for its uptake into pre-synaptic neurons and its conversion to glutamate that is packed into synaptic vesicles completing the glutamate/glutamine cycle. Diverse chemical compounds, like organophosphates, directly affect brain chemistry by altering levels of neurotransmitters in the synaptic cleft. Organophosphate compounds are widely used as pesticides, and all living organisms are continuously exposed to these substances, either in a direct or indirect manner. Its metabolites, like the diethyl dithiophosphate, are capable of causing brain damage through diverse mechanisms including perturbation of neuronal-glial cell interactions and have been associated with attention-deficit disorders and other mental illness. In order to characterize the neurotoxic mechanisms of diethyl dithiophosphate, we took advantage of the well characterized model of chick cerebellar Bergmann glia cultures. A significant impairment of [3H] d-Aspartate transport was found upon exposure to the metabolite. These results indicate that glia cells are targets of neurotoxic substances such as pesticides and that these cells might be critically involved in the associated neuronal death.
... 1,2 Exposure to OPs is usually assessed through analysis of blood and urine biomarkers to determine acetylcholinesterase levels. [5][6][7][8] Depression of plasma acetylcholinesterase activity in the blood is indicative of OP exposure. Biomarkers that measure concentrations of erythrocyte cholinesterase are used to assess chronic exposure and acute poisoning. ...
... Biomonitoring studies of urinary dialkyl phosphate metabolites may reflect exposure to OP pesticides in farmworkers, and their use is suggested to detect low doses of pesticides. [5][6][7][8] However, if commonly used pesticides can be identified via questionnaire, specific biomarkers according to the type of pesticide are recommended, similar to studies conducted by Steenland et al. 38 and Berent et al. 54 While these two studies found no association, they are not sufficient to guide conclusions regarding workers. Chronic exposure to OP pesticide assessment requires consecutive urinary dialkyl phosphates measurements, which was not clearly developed in any of the studies reviewed. ...
Background:
Previous studies have demonstrated that acute poisoning from exposure to organophosphate (OP) pesticides in agricultural workers causes adverse health effects. However, neuropsychological and cognitive effects of chronic occupational exposure to OP pesticides remain controversial.
Objective:
To identify, evaluate, and systematize existing evidence regarding chronic exposure to OP pesticides and neuropsychological effects in farmworkers.
Methods:
Using the PubMed search engine, a systematic review process was implemented and replicated according to the PRISMA statement. Eligibility criteria included workers over 18 years of age exposed to OP pesticides as well as assessment of neuropsychological and cognitive functioning. Search terms were in English and Spanish languages and included organophosphate and workers.
Results:
Of the search results, 33 of 1,256 articles meet eligibility criteria. Twenty-four studies found an association between chronic occupational exposure to OP pesticides and low neuropsychological performance in workers. We classified nine of the studies to have study design limitations. Studies indicated occupational exposure to OP pesticides is linked to difficulties in executive functions, psychomotor speed, verbal, memory, attention, processing speed, visual-spatial functioning, and coordination. Nine studies find no relationship between OP pesticides exposure and neuropsychological performance.
Conclusions:
Overall, evidence suggests an association between chronic occupational exposure to OP pesticides and neuropsychological effects. However, there is no consensus about the specific cognitive skills affected.
... " The authors reported that children who consumed organic diets eliminated (via urine) nondetectable amounts of organophosphorous (OP) insecticide metabolites. The finding supports the consensus that the diet is the predominant source of OP compounds and OP metabolites excreted in urine (Barr et al. 2004; Duggan et al. 2003; Krieger et al. 2003). Lu et al. (2006a) claimed " a convincing demonstration of the ability of organic diets to reduce children's OP pesticide exposure and the health risks that may be associated with these exposures. ...
... If risk is defined as the likelihood of an adverse effect in an exposed population, the risk of neurotoxicity caused by these dietary OP exposure(s) is zero; that is, disease has not been observed in the population who consumes food that sometimes contains OP pesticides or OP metabolite residues (Krieger et al. 2003). Back-calculated OP exposures are well below the experimental lowest observed adverse effect level (LOAEL), the estimated no observed adverse effect level (NOAEL), and the regulatory reference dose (RfD) for neurotoxicity of any OP insecticide used in crop protection (Barr et al. 2004; Duggan et al. 2003; Fenske et al. 2000). The research is misrepresented with respect to its relevance to risk reduction (that is the point of the fundamental " observed " in the LOAEL and the NOAEL upon which RfDs are based). ...
... After intake, most organophosphate (OP) pesticides are rapidly metabolized to one or more of six dialkyl phosphate (DAP) metabolites. 1 Due to the short half-life, these are mostly excreted in urine within 24 h. 2 Therefore, levels of DAP metabolites in urine reflect recent exposure to one or more OP pesticides. 1,3,4 Furthermore, OP pesticides can degrade in the environment, be metabolized by plants or broken down during food processing, leading to the presence of those metabolites in food and the environment. ...
... After intake, most organophosphate (OP) pesticides are rapidly metabolized to one or more of six dialkyl phosphate (DAP) metabolites. 1 Due to the short half-life, these are mostly excreted in urine within 24 h. 2 Therefore, levels of DAP metabolites in urine reflect recent exposure to one or more OP pesticides. 1,3,4 Furthermore, OP pesticides can degrade in the environment, be metabolized by plants or broken down during food processing, leading to the presence of those metabolites in food and the environment. 5 Thus, urinary OP metabolite levels represent exposure to parent OP pesticides as well as their metabolites and are considered to be non-specific markers of OP pesticide exposure. ...
The widespread use of organophosphate (OP) pesticides has resulted in ubiquitous exposure in humans, primarily through their diet. Exposure to OP pesticides may have adverse health effects, including neurobehavioral deficits in children. The optimal design of new studies requires data on the reliability of urinary measures of exposure. In the present study, urinary concentrations of six dialkyl phosphate (DAP) metabolites, the main urinary metabolites of OP pesticides, were determined in 120 pregnant women participating in the Generation R Study in Rotterdam. Intra-class correlation coefficients (ICCs) across serial urine specimens taken at <18, 18–25, and >25 weeks of pregnancy were determined to assess reliability. Geometric mean total DAP metabolite concentrations were 229 (GSD 2.2), 240 (GSD 2.1), and 224 (GSD 2.2) nmol/g creatinine across the three periods of gestation. Metabolite concentrations from the serial urine specimens in general correlated moderately. The ICCs for the six DAP metabolites ranged from 0.14 to 0.38 (0.30 for total DAPs), indicating weak to moderate reliability. Although the DAP metabolite levels observed in this study are slightly higher and slightly more correlated than in previous studies, the low to moderate reliability indicates a high degree of within-person variability, which presents challenges for designing well-powered epidemiological studies.
... Today, organophosphorous (OP) compounds are widely used as pesticides due to their low residual power into the environment and have replaced chlorinated compounds as the famous DDT. Some commercial uses of OP compounds are as control of farm plagues and transmissible diseases like malaria, yellow fever, dengue and chagas [1], disinfection and safety of private industry, hospitals and schools, or as fumigants for flower production and maintenance of golf or football stadiums gardens [2]. In fact, it is recently proposed that all beings are exposed directly or indirectly to OP [3]. ...
... Finally, DAPs have been reported as widely detected compounds in cultures, waste water, flowers, fruit, etc. In fact, one report in the United States shows that all children tested in one elementary school excreted all six DAPs without referring previous exposure to OP compounds [2], so it is not surprising that in the future, this kind of metabolites would be on the agenda of immunotoxicologist. ...
Background: We have previously shown that Diethyldithiophosphate (DEDTP), a metabolite of Organophosphorous (OP) compounds biotransformation with longer half life than its parental compound, can modulate T CD4 lymphocyte functions. To explore if DEDTP can also alter T CD8 homeostasis and proliferation we evaluated cellular viability and proliferation by propidium iodide (PI) incorporation and carboxyfluorescein succinimidyl ester (CFSE) assay by flow cytometry, respectively, in peripheral blood mononuclear cells (PBMCs) and T CD8 cells from healthy male donors. Results: In vitro exposure to 1-50 μM DEDTP decreased T CD4 vs. T CD8 proportion on resting T CD3 lymphocytes. DEDTP decreased T CD8 viability in a dose-dependent manner after 24 h without affecting the rest of T CD3 lymphocytes. DEDTP also decreases CFSE dilution in T CD8 cells stimulated with anti-CD3/CD28 by arresting cells at the first round of division (M1). Decrease in cell proliferation was not only due to cellular arrest, but also to a consequence of cell death. Although cell death and cell cycle arrest were observed in the majority of the T CD8 cells, some particular T CD8 subset clones presented a high proliferative rate in the presence of DEDTP. Conclusion: DEDTP showed higher toxicity and cytostaticity in T CD8 cells than in T CD4 lymphocytes. This is relevant in exposed individuals as their ability to deal with viral infections and cancer cells could be limited by exposure to OP pesticides.
... In December 2004, NEJAC reported, at length, on cumulative risks and impacts [2]. Much remained tentative, with a search still on for cumulation criteria intuitively sensible and experimentally verifiable [128][129][130][131]. ...
Toxic chemicals — “toxicants” — have been studied and regulated as single entities, and, carcinogens aside, almost all toxicants, single or mixed and however altered, have been thought harmless in very low doses or very weak concentrations. Yet much work in recent decades has shown that toxicants can injure wildlife, laboratory animals, and humans following exposures previously expected to be harmless. Additional work has shown that toxicants can act not only individually and cumulatively but also collectively and even synergistically and that they affect disadvantaged communities inordinately — and therefore, as argued by reformers, unjustly. As late as December 2016, the last full month before the inauguration of a president promising to rescind major environmental regulations, the United States federal environmental-health establishment, as led by the Environmental Protection Agency (EPA), had not developed coherent strategies to mitigate such risks, to alert the public to their plausibility, or to advise leadership in government and industry about their implications. To understand why, we examined archival materials, reviewed online databases, read internal industry communications, and interviewed experts. We confirmed that external constraints, statutory and judicial, had been in place prior to EPA’s earliest interest in mixture toxicity, but we found no overt effort, certainly no successful effort, to loosen those constraints. We also found internal constraints: concerns that fully committing to the study of complex mixtures involving numerous toxicants would lead to methodological drift within the toxicological community and that trying to act on insights from such study could lead only to regulatory futility. Interaction of these constraints, external and internal, shielded the EPA by circumscribing its responsibilities and by impeding movement toward paradigmatic adjustment, but it also perpetuated scientifically dubious policies, such as those limiting the evaluation of commercial chemical formulations, including pesticide formulations, to only those ingredients said by their manufacturers to be active. In this context, regulators’ disregard of synergism contrasted irreconcilably with biocide manufacturers’ understanding that synergism enhanced lethality and patentability. In the end, an effective national response to mixture toxicity, cumulative risk, and environmental injustice did not emerge. In parallel, though, the National Institute of Environmental Health Sciences, which was less constrained, pursued with scientific investigation what the EPA had not pursued with regulatory action.
... There are many studies where people exposed to pesticides, such as those working in agriculture and in factories or due to their geographic location, were found to have higher levels (e.g.in breast milk, maternal blood, serum, urine, hair, umbilical cord blood) than those not exposed [79][80][81][82][83][84] . ...
Objective:
Chemicals that disrupt the endocrine homeostasis of the human body, otherwise known as endocrine disruptors (EDCs), are found in the blood, urine, amniotic fluid, or adipose tissue. This paper presents the current knowledge about EDCs and the reproductive system.
Materials and methods:
The article is an overview of the impact of EDCs and their mechanism of action, with particular emphasis on gonads, based on the information available on medical databases (PubMed, Web of Science, EMBASE and Google Scholar, EMBASE and Web of Science) until May 2021.
Results:
EDCs occur in everyday life, e.g., they are components of adhesives, brake fluids, and flame retardants; they are used in the production of polyvinyl chloride (PVC), plastic food boxes, pacifiers, medicines, cosmetics (bisphenol A, phthalates), hydraulic fluids, printing inks (polychlorinated biphenyls - PCBs), receipts (bisphenol A, BSA) and raincoats (phthalates); they are also a component of polyvinyl products (e.g. toys) (phthalates), air fresheners and cleaning agents (phthalates); moreover, they can be found in the smoke from burning wood (dioxins), and in soil or plants (pesticides). EDCs are part of our diet and can be found in vegetables, fruits, green tea, chocolate and red wine (phytoestrogens). In addition to infertility, they can lead to premature puberty and even cause uterine and ovarian cancer. However, in men, they reduce testosterone levels, reduce the quality of sperm, and cause benign testicular tumors.
Conclusions:
Therefore, this article submits that EDCs negatively affect our health, disrupting the functioning of the endocrine system, and particularly affecting the functioning of the gonads.
... some PBDEs (Trudel et al., 2011) and some phthalates (Wilson et al., 2003). However, several authors who have performed exposure assessments on both indoor and diet exposure found that dietary ingestion was not the main route of exposure for chlorpyrifos (Beamer et al., 2012;Duggan et al., 2003), DEP, BBP and DiNP (Wormuth et al., 2006), some PBDEs (Lorber, 2007), some PCBs and some OCs (Wilson et al., 2003). For certain compounds, exposure via dietary ingestion could also equal exposure via non-dietary ingestion: e.g. ...
La qualité de l’environnement intérieur est aujourd’hui un sujet de préoccupation majeur en santé publique. Les populations passent près de 90 % de leur temps en environnement intérieur où elles sont exposées à des polluants comme les composés organiques semi-volatils (COSV) suspectés d’effets néfastes pour la santé. L’ingestion de poussières est une voie d’exposition non négligeable à certains de ces COSV, en particulier chez les enfants. Pour caractériser cette exposition, il est nécessaire de prendre en compte la bioaccessibilité orale des COSV, définie comme la fraction de polluant libérée dans le tractus gastro-intestinal et disponible à l’absorption. Dans ce contexte, les objectifs de cette thèse sont de (i) développer et valider une méthode simple à mettre en œuvre pour la mesure de la bioaccessibilité orale des COSV dans les poussières et (ii) produire des données de bioaccessibilité pour des COSV d’intérêt sanitaire. Cette thèse sur articles est constituée de trois chapitres : un contexte scientifique, qui présente les sources et la toxicité des COSV, puis décrit leur présence dans l’air et les poussières des écoles, avant d’aborder les différentes voies d’exposition humaine ; un état de l’art sur la bioaccessibilité orale des COSV dans les poussières ; la proposition d’une méthode simplifiée pour la mesure de cette bioaccessibilité, sa validation et son application à de premiers échantillons. Ces travaux se concluent sur un contexte plus large que l’ingestion en établissant des perspectives considérant également la bioaccessibilité par inhalation et par contact cutané, afin de caractériser de manière globale l’exposition aux COSV en environnement intérieur.
... Six analytes were measured in each specimen: dimethylphosphate (DMP), dimethylthiophosphate (DMTP), dimethyldithiophosphate (DMDTP), diethylphosphate (DEP), diethylthiophosphate (DETP), and diethyldithiophosphate (DEDTP). Almost all OP are metabolized to at least one of six possible DAP metabolites, as shown in Table S1 (Duggan et al. 2003). ...
Background:
Animal studies suggest that pesticide exposure elicits endocrine changes, increases embryo implantation failure, and decreases litter size. However, only a few epidemiological studies have evaluated the effects of pesticides on the outcomes of in vitro fertilization (IVF) pregnancies.
Objectives:
This study examined the associations between preconception organophosphate pesticides (OP) exposure and pregnancy outcomes among women undergoing IVF in a Chinese population.
Methods:
This study included 522 women with infertility who underwent IVF. Women were recruited from a prospective study, the China National Birth Cohort (CNBC), from Shanghai, China, between July 2017 and December 2018. Demographic and clinical information were collected from medical records and through questionnaires. Preconception exposure to OP was assessed by measuring six nonspecific dialkylphosphate (DAP) metabolites [diethylthiophosphate (DETP), diethylphosphate (DEP), diethyldithiophosphate (DEDTP), dimethylthiophosphate (DMTP), dimethylphosphate (DMP), dimethyldithiophosphate (DMDTP)] in urine samples collected at recruitment. Generalized estimating equation (GEE) models were used to evaluate the associations between OP and pregnancy outcomes.
Results:
Compared with women in the lowest quartile (
Q
1
) of individual DEP and
Σ
4
DAP
(the sum of DMP, DMTP, DEP, and DETP), women in the highest quartile (
Q
4
) had lower odds of successful implantation, clinical pregnancy, and live birth, and most of the negative trends were significant (
p
-trends
<
0.05
). There were no significant associations between urinary DAP concentrations and early IVF outcomes, including total and mature oocyte counts, best embryo quality, fertilization,
E
2
trigger levels, and endometrial wall thickness.
Conclusion:
Preconception OP exposure was inversely associated with successful implantation, clinical pregnancy, and live birth in women who underwent IVF. https://doi.org/10.1289/EHP7076.
... This study has several limitations. First, urinary DAP metabolite concentrations provide information regarding the joint exposure to multiple OP pesticides instead of providing specific information regarding the exact OP pesticide exposure (Duggan et al., 2003;Margariti et al., 2007;Wessels et al., 2003). It is therefore unknown to which specific OP parent pesticide(s) our study population was exposed. ...
... Some of the active OP pesticides may remain on or in food after they are applied to food crops (Eaton et al., 2008) and the exposure of non-occupationally exposed individuals occurs most likely through their diet (Llop et al., 2017;Lu et al., 2008;Sokoloff et al., 2016;van den Dries et al., 2018). After ingestion, most OP pesticides undergo bioactivation, during which the toxic oxon form is established, followed by detoxification, which produces up to 6 non-specific dialkyl phosphate (DAP) metabolites (Duggan et al., 2003). Preformed DAP metabolites also exist in the food supply (Clune et al., 2012;Lu et al., 2005;Quirós-Alcalá et al., 2012). ...
Background:
Prenatal exposure to organophosphate (OP) pesticides has been associated with altered neuronal cell development and behavioral changes in animal offspring. However, the few studies investigating the association between prenatal OP pesticide exposure and neurodevelopmental outcomes such as Attention-Deficit Hyperactivity Disorder (ADHD) and autistic traits in children produced mixed findings.
Objective:
The objective of the present study was to examine whether maternal urinary concentrations of OP pesticide metabolites are associated with ADHD and autistic traits in children participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands.
Method:
Maternal concentrations of 6 dialkylphosphates (DAPs) were measured using gas chromatography coupled with tandem mass spectrometry in urine samples collected at <18 weeks, 18-25 weeks, and > 25 weeks of gestation in 784 mother-child pairs. DAP metabolite concentrations were expressed as molar concentrations divided by creatinine levels and log10 transformed. ADHD traits were measured at ages 3, 6, and 10 years using the Child Behavior Checklist (CBCL) (n = 781) and autistic traits were measured at age 6 years using the Social Responsiveness Scale (SRS) (n = 622). First, regression models were fit for the averaged prenatal exposure across pregnancy. Second, we investigated associations for each collection phase separately, and applied a mutually adjusted model in which the effect of prenatal DAP concentrations from each time period on ADHD and autistic traits were jointly estimated. All associations were adjusted for relevant confounders.
Results:
Median DAP metabolite concentration was 309 nmol/g creatinine at <18 weeks, 316 nmol/g creatinine at 18-25 weeks, and 308 nmol/g creatinine at >25 weeks of gestation. Overall, DAP metabolite concentrations were not associated with ADHD traits. For instance, a log10 increase in averaged total DAP concentrations across gestation was not associated with a lower ADHD score (-0.03 per SD 95 CI: -0.28 to 0.23). Similarly, no associations between maternal DAP concentrations and autistic traits were detected.
Conclusions:
In this study of maternal urinary DAP metabolite concentrations during pregnancy, we did not observe associations with ADHD and autistic traits in children. These are important null observations because of the relatively high background DAP concentrations across pregnancy, the relatively large sample size, and the 10-year follow-up of the offspring. Given the measurement error inherent in our OP pesticide exposure biomarkers, future studies using more urine samples are needed to accurately measure OP pesticide exposure over pregnancy in relation to ADHD and autistic traits.
... One potential explanation is that alkyl phosphate sources include pesticides used in agriculture [51,52]. Presence of alkyl phosphate can be used to measure exposure to pesticides [53,54] and other processed material such as flame retardants [55]. High alkylphosphate utilization sites in the study are all associated with significant wastewater discharge. ...
Phosphorus (P) is a nutrient of primary importance in all living systems, and it is especially important in streams and rivers which are sensitive to anthropogenic P inputs and eutrophication. Microbes are accepted as the primary mineralizers and solubilizers of P improving bioavailability for organisms at all trophic levels. Here, we use a genomics approach with metagenome sequencing of 24 temperate streams and rivers representing a total P (TP) gradient to identify relationships between functional genes, functional gene groupings, P, and organisms within the P biogeochemical cycle. Combining information from network analyses, functional groupings, and system P levels, we have constructed a System Relational Overview of Gene Groupings (SROGG) which is a cohesive system level representation of P cycle gene and nutrient relationships. Using SROGG analysis in concert with other statistical approaches, we found that the compositional makeup of P cycle genes is strongly correlated to environmental P whereas absolute abundance of P genes shows no significant correlation to environmental P. We also found orthophosphate (PO4³⁻) to be the dominant factor correlating with system P cycle gene composition with little evidence of a strong organic phosphorous correlation present even in more oligotrophic streams.
... After absorption, most OP pesticides undergo bioactivation, during which the toxic oxon form is formed, followed by detoxification, which produces up to six dialkyl phosphate (DAP) metabolites (Barr et al., 2006;Duggan et al., 2003). These DAP metabolites have a short halflife and are mostly excreted in urine within 24 h (Huen et al., 2012). ...
Background:
In the Netherlands organophosphate (OP) pesticides are frequently used for pest control in agricultural settings. Despite concerns about the potential health impacts of low-level OP pesticides exposure, particularly in vulnerable populations, the primary sources of exposure remain unclear. The present study was designed to investigate the levels of DAP metabolites concentrations across pregnancy and to examine various determinants of DAP metabolite concentrations among an urban population of women in the Netherlands.
Method:
Urinary concentrations of six dialkyl phosphate (DAP) metabolites, the main urinary metabolites of OP pesticides, were determined at <18, 18-25, and >25 weeks of pregnancy in 784 pregnant women participating in the Generation R Study (between 2004 and 2006), a large population-based birth cohort in Rotterdam, the Netherlands. Questionnaires administered prenatally assessed demographic and lifestyle characteristics and maternal diet. Linear mixed models, with adjustment for relevant covariates, were used to estimate associations between the potential exposure determinants and DAP metabolite concentrations expressed as molar concentrations divided by creatinine levels.
Results:
The median DAP metabolite concentration was 311 nmol/g creatinine for the first trimester, 317 nmol/g creatinine for the second trimester, and 310 nmol/g creatinine for the third trimester. Higher maternal age, married/living with a partner, underweight or normal weight (BMI of <18.5 and 18.5-<25), high education, high income, and non-smoking were associated with higher DAP metabolite concentrations, and DAP metabolite concentrations tended to be higher during the summer. Furthermore, fruit intake was associated with increased DAP metabolite concentrations. Each 100 g/d difference in fruit consumption was associated with a 7% higher total DAP metabolite concentration across pregnancy. Other food groups were not associated with higher DAP metabolite concentrations.
Conclusions:
The DAP metabolite concentrations measured in the urine of pregnant women in the Netherlands were higher than those in most other studies previously conducted. Fruit intake was the main dietary source of exposure to OP pesticides in young urban women in the Netherlands. The extent to which DAP metabolite concentrations reflect exposure to the active parent pesticide rather than to less toxic metabolites remains unclear. Further research will be undertaken to investigate the possible effects of this relatively high level OP pesticides exposure on offspring health.
... Fourteen of the tested samples contained chromium (ranging from 1.30 to 15.75 ppm) where 70% of the samples contained chromium with a concentration more than 5 ppm. Some directives banned the use of heavy metals, Cd, Co, Cr, Ni, and Pb as impurities in the preparation of cosmetics [40,60,61]. ...
Abstract
Background:
The plant Henna (Lawsonia inermis, family Lythraceae) is a naturally grown or cultivated plant allover Africa and Asia. Marketed Henna is a natural powdered material derived from dried and crushed leaves of the plant. Henna is very popular in many parts of Egypt as it is part of the culture and traditions, and it recently became very popular in touristic areas as Sharm El Sheikh-Egypt being used as a tattooing agent. This makes detection of heavy metal content and, other toxic ingredients in Henna marketed in Egypt of crucial importance.
Objectives:
To investigate heavy metal content and, other toxic ingredients as para-phenylenediamine (PPD) in Black Henna marketed in Egypt.
Methods:
Fifteen Black Henna samples were collected randomly from Sharm El Sheikh-Egypt market and, analyzed for metal content by atomic absorption spectrophotometry (ICP-MS) after microwave acid digestion, also the presence of PPD in henna samples was determined qualitatively and quantitatively using High Performance Liquid Chromatography (HPLC).
Results:
PPD was detected in all the black henna samples at concentrations ranging between 1.75% and 32.1%, which is higher than that recommended for hair dyes. The mean concentration of some studied metals as Aluminium, Lead, copper, nickel, and zinc were higher than permissible levels for cosmetics in some of the studied samples.
Conclusion:
In conclusion, PPD is a common ingredient in black henna dye in the developing world. Physicians must be aware of the potential toxicity of this chemical and of the clinical signs of systemic poisoning. High concentration of some metals as Aluminium, lead, copper, nickel, and zinc might be encountered in some Henna products. Considering popular use of henna, the hazardous cumulative effects of prolonged exposure to low concentrations of such metals, especially in children, cannot be ruled out.
Further studies are recommended
... The increasing health awareness and, the increased availability of cosmetic products in different markets draws the attention of researchers and clinicians to find adverse effects 4/5 related to heavy metal contamination [18,19]. Although some cosmetics are benign; others can cause or are supposed to cause harmful effects such as cancer, allergic reaction, mutations, as well as respiratory, developmental and reproductive problems [20]. High levels of cadmium have been linked to DNA mismatches. ...
Cosmetics' use is very popular all over the world including Arabian countries. The use of some cosmetics as Kohl is part of culture and traditions in some countries, and is used since very young ages. This makes detection of heavy metal content in cosmetics marketed in Egypt and other Arabian markets of crucial importance. Objective: To evaluate the levels of heavy metals content among different cosmetic products in the Arabian market. Methods: Different brands of anti-freckle creams, eye shadows, eyeliners, facial powders, foundation, henna and lipsticks were purchased from open markets in Egypt and Saudi Arabia. Sample preparation and analysis was conducted, to estimate levels of twelve different metals (Pb, As, Cd, Ag, Ba, Al, Cr, Mn, Co, Ni, Cu, and Zn) using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Results: The mean concentration of some studied metals as Aluminium, lead, arsenic, copper and nickel were higher than permissible levels for cosmetics in some of the studied samples. Conclusion: In conclusion, cosmetics' contamination with metals above permissible levels is very common in most of the products available in the developing world and Arabian markets. Physicians and users must be aware of the probable toxicity of these elements and of the clinical signs of systemic poisoning. Considering popular use of cosmetics by different age groups, the hazardous cumulative effects of prolonged exposure to low concentrations of metals like; Aluminium, lead, Arsenic, nickel and copper especially in children, cannot be ruled out. Further studies are recommended in addition, cosmetic market control and legislation procedures should be thoroughly implemented.
... Fourteen of the tested samples contained chromium (ranging from 1.30 to 15.75 ppm) where 70% of the samples contained chromium with a concentration more than 5 ppm. Some directives banned the use of heavy metals, Cd, Co, Cr, Ni, and Pb as impurities in the preparation of cosmetics [40,60,61]. ...
Background: The plant Henna (Lawsonia inermis, family Lythraceae) is a naturally grown or cultivated plant allover Africa and Asia. Marketed Henna is a natural powdered material derived from dried and crushed leaves of the plant. Henna is very popular in many parts of Egypt as it is part of the culture and traditions, and it recently became very popular in touristic areas as Sharm El Sheikh-Egypt being used as a tattooing agent. This makes detection of heavy metal content and, other toxic ingredients in Henna marketed in Egypt of crucial importance.
Objective: To investigate heavy metal content and, other toxic ingredients as para-phenylenediamine (PPD) in Black Henna marketed in Egypt.
Methods: Fifteen Black Henna samples were collected randomly from Sharm El Sheikh-Egypt market and, analyzed for metal content by atomic absorption spectrophotometry (ICP-MS) after microwave acid digestion, also the presence of PPD in henna samples was determined qualitatively and quantitatively using High Performance Liquid Chromatography (HPLC).
Results: PPD was detected in all the black henna samples at concentrations ranging between 1.75% and 32.1%, which is higher than that recommended for hair dyes. The mean concentration of some studied metals as Aluminium, Lead, copper, nickel, and zinc were higher than permissible levels for cosmetics in some of the studied samples.
Conclusion: In conclusion, PPD is a common ingredient in black henna dye in the developing world. Physicians must be aware of the potential toxicity of this chemical and of the clinical signs of systemic poisoning. High concentration of some metals as Aluminium, lead, copper, nickel, and zinc might be encountered in some Henna products. Considering popular use of henna, the hazardous cumulative effects of prolonged exposure to low concentrations of such metals, especially in children, cannot be ruled out. Further studies are recommended.
... First, the cross-sectional nature of the present study does not allow us to infer causation. Second, although several previous studies support the use of these six types of dialkyl phosphate metabolites as an indication of OP pesticide exposure [9,46,47], questions on the ability to attribute the source of urinary OP metabolites remain [48,49]. Further, individual differences in the metabolism of and sensitivity towards OP pesticides due to variations in PON1 polymorphisms and enzymatic efficiency [4,36,38] may have also influenced our results. ...
The objective was to determine whether detectable levels of OP metabolites influence the relationship between BMI and cardiometabolic health. This cross-sectional study was conducted using 2227 adults from the 1999-2008 NHANES datasets. Urinary concentrations of six dialkyl phosphate metabolites were dichotomized to above and below the detection limit. Weighted multiple regression analysis was performed adjusting for confounding variables. Independent of BMI, individuals with detectable metabolites had higher diastolic blood pressure (for dimethylphosphate, diethylphosphate, and diethyldithiophosphate; P < 0.05), lower HDL (for diethyldithiophosphate; P = 0.02), and higher triglyceride (for dimethyldithiophosphate; P = 0.05) than those below detection. Contrarily, those with detectable dimethylthiophosphate had better LDL, HDL, and total cholesterol, independent of BMI. Individuals at a higher BMI range who had detectable diethylphosphate (interaction: P = 0.03) and diethylthiophosphate (interaction: P = 0.02) exhibited lower HDL, while little difference existed between OP metabolite detection statuses at lower BMIs. Similarly, individuals with high BMIs and detectable diethylphosphate had higher triglyceride than those without detectable levels, while minimal differences between diethylphosphate detection statuses were observed at lower BMIs (interaction: P = 0.02). Thus, cardiometabolic health outcome differs depending on the specific OP metabolite being examined, with higher BMIs amplifying health risk.
... The early work to evaluate exposures to compounds within a CAG focussed on the organophosphate pesticides. Urinary levels of dialkyl phosphates (DAP) for the population have also been reported (Barr et al., 2011;Duggan et al., 2003;Heudorf and Angerer, 2001) to assess exposures from all routes. As an example of occupational exposures, Ueyama et al. (2012) reported that urinary DAP levels for a range of workers in Japan, including pesticide applicators, were similar to those reported previously. ...
... One study evaluated dialkylphosphates in first-morning void urine samples to compare OP pesticide exposure of preschool children living near the farm with those children living outside the farm (Patchuay, 2006). In another study, alkyl phosphate metabolites of Ops monitoring in urine to assess cumulative exposure to OP pesticides has been conducted, their result showed variability when compared with Center of Disease Control (CDC) data (Duggan, 2003). Most OPs are rapidly absorbed, metabolized, and excreted in urine within hours. ...
... The most common commercial uses of OPs are for the control of weeds, pests and also of transmissible diseases such as malaria, yellow fever and dengue (Marselos and Vainio, 1991). OPs are also reported to be used from private industries to hospitals and schools, golf and football stadiums gardens for disinfection, and as fumigants for flower production and maintenance (Duggan et al., 2003). The proven excessive use of OPs has side effects for both humans and environment and it is clearly noted that all beings are directly or indirectly exposed to OPs (De Cock et al., 1994;Appenzeller and Tsatsakis, 2012;Kavvalakis and Tsatsakis, 2012). ...
... Although Ops are naturally degradable compounds, due to their heavy use in urban and rural areas, a considerable amount of OPs residues could also be found in soil and water. In addition, unfortunately the numbers of synthetic OPs, whose chemical structure are similar to persistent pesticides; continue to grow [2]. Therefore, defined detection of very low concentration of various types of OPs in the environment as well as different samples poses an exceedingly complicated challenge. ...
A dimeric organophosphorus hydrolase (OPH; EC 3.1.8.1; 72 kDa) was isolated from wild-type bacteria, analyzed for its 16s rRNA sequence, purified, and immobilized on gold nanoparticles (AuNPs) to form the transducer part of a biosensor. The isolated strain was identified as Pseudomonas aeruginosa. The AuNPs were characterized by transmission electron microscopy and localized surface plasmon resonance. Covalent binding of OPH to the AuNPs was confirmed by spectrophotometry, enzymatic activity assays, and FTIR spectroscopy. Coumarin 1, a competitive inhibitor of OPH, was used as a fluorogenic probe. The bioconjugates quench the emission of coumarin 1 upon binding, but the addition of paraoxon results in an enhancement of fluorescence that is directly proportional to the concentration of paraoxon. The gold-OPH conjugates were then used to determine paraoxon in serum samples spiked with varying levels of paraoxon. The method works in the 50 to 1,050 nM concentration range, has a low standard deviation (with a CV of 5.7–11 %), and a detection limit as low as 5 × 10−11 M. FigureCoumarin 1, a competitive inhibitor of organophosphorus hydrolase, was used as a fluorogenic probe in the bioconjugates. The gold nanoparticles contained in the bioconjugates quench the emission of coumarin 1 upon binding, but the addition of paraoxon results in an enhancement of fluorescence leading to its detection.
... OP pesticide exposure can be assessed via questionnaires, environmental measurements, and biomonitoring, the latter of which is increasingly common. Biomonitoring measurements used to assess OP pesticide exposure include AChE activity screening, measurement of specific and non-specific urinary metabolites, and measurement of the parent pesticide in blood CDC, 2009;Duggan et al., 2003;Sudakin and Stone, 2011;Wessels et al., 2003). Blood pesticide measurements provide unequivocal evidence of exposure but are often difficult to obtain because of the biological reactivity of the pesticides. ...
... In addition, exposure to OPs has been linked to effects on the endocrine system (Hodgson and Rose, 2006) and prostate cancer (Koutros et al., 2013). Human biomonitoring of OP exposure may be performed by the determination of the parent OP compounds in blood, by the determination of compound-specific metabolites in urine or by the determination of dialkyl phosphates (DAP) in urine ( Duggan et al., 2003). Since compound-specific biomonitoring methods are available for only few OPs, the determination of urinary DAPs is very common to assess OP exposure in population studies (Kavvalakis and Tsatsakis, 2012). ...
Background:
Fetal exposure to organophosphate (OP) pesticides might lead to fetal metabolic adaptations, predisposing individuals to adverse metabolic profiles in later life.
Objective:
We examined the association of maternal urinary OP pesticide metabolite concentrations in pregnancy with offspring body mass index (BMI) and fat measures at 10 years of age.
Methods:
Between 2002 and 2006, we included 642 mother-child pairs from the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. We measured maternal urinary concentrations of OP pesticide metabolites, namely, dialkyl phosphates, including three dimethyl and three diethyl phosphates in early-, mid- and late-pregnancy. At 10 years of age, child total and regional body fat and lean mass were measured through dual energy X-ray absorptiometry, and abdominal and organ fat through magnetic resonance imaging.
Results:
Higher maternal urinary pregnancy-average or trimester-specific dialkyl, dimethyl, or diethyl phosphate concentrations were not associated with childhood BMI and the risk of overweight. In addition, we did not observe any association of dialkyl, dimethyl, or diethyl phosphate concentrations with total and regional body fat, abdominal visceral fat, liver fat, or pericardial fat at child age of 10 y.
Conclusion:
We observed no associations of maternal urinary dialkyl concentrations during pregnancy with childhood adiposity measures at 10 years of age. Whether these associations develop at older ages should be further studied. https://doi.org/10.1289/EHP12267.
Objective: The aim of this study was to evaluate the association between organophosphorus pesticides (OPPs) exposure and sleep problems. Methods: In this study, data from 6295 participants aged 18 years or older were collected from the National Health and Nutrition Examination Survey (NHANES). The dialkyl phosphate compounds (DAPs) metabolites, OPPs exposure biomarker, were examined using solid phase extraction-high coupled with isotope dilution-ultrahigh performance liquid chromatography-tandem mass spectrometry. Data on short sleep duration (SSD), self-reported trouble sleeping and self-reported sleep disorder were collected from the database. Weighted generalized logistic model, weighted quantile sum (WQS) model, and quantile-based g calculation (QGC) methods were used for analyzing the collected data. Results: The prevalence of SSD, self-reported trouble sleeping and self-reported sleep disorder in this study were 28.91 % (1814/6274), 25.31 % (1593/6294), and 9.05 % (289/3195), respectively. After confounding factors adjustments, the prevalence of SDD in participants with high log-transformed DETP, DMTP, DEDTP, and DMDTP were 1.19 times (OR: 1.11–1.28, P
Organophosphates (OPs) are commonly used pesticides worldwide. Humans are exposed to OPs via different routes viz. the respiratory tract, gastrointestinal tract, and dermal integuments. OPs induce neuropathy by either phosphorylating acetyl cholinesterase or neuropathy target esterase, or by binding specifically to nicotinic or muscarinic receptors of nervous system. Other than neurobehavioral effects in humans, OPs cause cholinergic crisis, intermediate syndrome, OP-induced delayed neuropathy, and Chronic organophosphate-induced neuropsychiatric disorders in time and dosage dependent manner. Biomonitoring of OP markers from body fluids minimizes or measures the severity of the impact, allowing for timely control of the exposure. The standard treatments for OPs poisoning which avoid secondary organ damage are atropine administration, acetylcholine esterase restoration therapy with oximes, and general intensive care. This review summarizes the toxic manifestation data available on humans and discusses potential therapeutic modalities, with the aim to highlight the importance of increasing awareness about its potential risk and reevaluation of exposure level.
Prenatal exposure to nonpersistent chemicals such as phthalates, bisphenols, and organophosphate (OP) pesticides is ubiquitous and occurs in mixtures. So far, epidemiological studies investigating neurodevelopmental consequences of these exposures have mainly been restricted to single-pollutant models. Thus, we studied the association between prenatal exposure to nonpersistent chemical mixtures and child IQ and emotional and behavioral problems. Data came from 782 mother-child pairs. Eleven phthalate, one bisphenol, and five OP pesticide urinary exposure biomarkers were measured three times during pregnancy and averaged. Nonverbal IQ, internalizing and attention problems, aggressive behavior, and autistic traits were assessed at child age 6 years. We used quantile g-computation to estimate the change in each outcome per quartile increase in all chemicals within the mixture. Higher exposure to the mixture was associated with lower nonverbal IQ (-4.0 points (95%CI = -7.0, -1.0), -5.5 points (95%CI = -10.2, -0.9), and -4.6 points (95%CI = -10.8, 1.5) for the second, third, and fourth quartile, respectively, compared to the first quartile). These results were mainly driven by the phthalate mixture. No association was observed with emotional and behavioral problems. Prenatal exposure to nonpersistent chemical mixtures was associated with lower nonverbal IQ in children. Exposure to chemical mixtures during gestation is universal and may impact neurodevelopment.
Short-term biomarkers of toxicity have an increasingly important role in the screening and prioritization of new chemicals. In this study, we examined early indicators of liver toxicity for three reference organophosphate (OP) chemicals, which are among the most widely used insecticides in the world. The OP methidathion was previously shown to increase the incidence of liver toxicity, including hepatocellular tumors, in male mice. To provide insights into the adverse outcome pathway (AOP) that underlies these tumors, effects of methidathion in the male mouse liver were examined after 7 and 28 day exposures and compared to those of two other OPs that either do not increase (fenthion) or possibly suppress liver cancer (parathion) in mice. None of the chemicals caused increases in liver weight/body weight or histopathological changes in the liver. Parathion decreased liver cell proliferation after 7 and 28 days while the other chemicals had no effects. There was no evidence for hepatotoxicity in any of the treatment groups. Full-genome microarray analysis of the livers from the 7 and 28 day treatments demonstrated that methidathion and fenthion regulated a large number of overlapping genes, while parathion regulated a unique set of genes. Examination of cytochrome P450 enzyme activities and use of predictive gene expression biomarkers found no consistent evidence for activation of AhR, CAR, PXR, or PPARα. Parathion suppressed the male-specific gene expression pattern through STAT5b, similar to genetic and dietary conditions that decrease liver tumor incidence in mice. Overall, these findings indicate that methidathion causes liver cancer by a mechanism that does not involve common mechanisms of liver cancer induction.
Organophosphates (OP) are one the most used category of synthetic pesticides after the ban of organochlorine. Due to its ubiquitous mode of action on the nervous system across several animal species, they pose a greater risk to non-target organisms. They have also been used as nerve agents in the chemical warfares. Its industrial application is well established, especially its use as flame retardant and plasticizers. In this chapter, we have discussed the physicochemical features of OP, chemical synthesis, application, and its ecotoxicological footprints on biotic and abiotic components.
Toxicological Effects of Veterinary Medicinal Products in Humans is the first definitive guide to discuss the adverse effects of veterinary medicinal products in humans. The chapters focus on occupational safety and consumer issues and examine the circumstances under which exposure is likely to occur. To be in context, it reviews this against the background of adverse health effects from other sources in the veterinary and farming professions. The book examines adverse drug effects reported to regulatory agencies (mainly the FDAÆs Center for Veterinary Medicine) and then considers a series of individual drugs, including antibiotics, anaesthetics and organophosphorus compounds. The chapters also discuss the fundamental aspects of regulatory issues relating to safety assessment, and examine the manner in which user safety is assessed prior to authorisation/approval and what measures can be taken after authorisation/approval in the light of findings from pharmacovigilance activities. There is growing concern over the issue of antimicrobial resistance and the contribution made by veterinary medicinal products. This too is addressed along with the significance to human health and measures that can be taken to mitigate the effects (if any) of the use of antibiotics in animals e.g. prudent use measures. The book will be an essential resource for medical practitioners in hospitals and general practice, pharmaceutical industry scientists, analysts, regulators and risk managers.
Toxicological Effects of Veterinary Medicinal Products in Humans is the first definitive guide to discuss the adverse effects of veterinary medicinal products in humans. The chapters focus on occupational safety and consumer issues and examine the circumstances under which exposure is likely to occur. To be in context, it reviews this against the background of adverse health effects from other sources in the veterinary and farming professions. The book examines adverse drug effects reported to regulatory agencies (mainly the FDAÆs Center for Veterinary Medicine) and then considers a series of individual drugs, including antibiotics, anaesthetics and organophosphorus compounds. The chapters also discuss the fundamental aspects of regulatory issues relating to safety assessment, and examine the manner in which user safety is assessed prior to authorisation/approval and what measures can be taken after authorisation/approval in the light of findings from pharmacovigilance activities. There is growing concern over the issue of antimicrobial resistance and the contribution made by veterinary medicinal products. This too is addressed along with the significance to human health and measures that can be taken to mitigate the effects (if any) of the use of antibiotics in animals e.g. prudent use measures. The book will be an essential resource for medical practitioners in hospitals and general practice, pharmaceutical industry scientists, analysts, regulators and risk managers.
Background
Prenatal exposure to organophosphate (OP) pesticides associate with impaired neurodevelopment in humans and animal models. However, much uncertainty exists about the brain structural alterations underlying these associations. The objective of this study was to determine whether maternal OP pesticide metabolite concentrations in urine repeatedly measured during gestation are associated with brain morphology and white matter microstructure in 518 preadolescents aged 9-12 years.
Method
Data came from 518 mother–child pairs participating in the Generation R study, a population-based birth cohort from Rotterdam, the Netherlands. Maternal urine concentrations were determined for 6 dialkylphosphates (DAPs) including 3 dimethyl (DM) and 3 diethyl (DE) alkyl phosphate metabolites, collected at early, mid, and late pregnancy. At child’s age 9-12 years, magnetic resonance imaging was performed to obtain T1-weighted images for regional brain volumes and surface-based cortical thickness and surface area, and diffusion tensor images to measure white matter microstructure through fractional anisotropy (FA) and mean diffusivity (MD). Linear regression models were fit for the averaged prenatal exposure across pregnancy.
Results
DE and DM metabolite concentrations were not associated with regional brain volumes, cortical thickness, and cortical surface area. However, a 10-fold increase in averaged DM metabolite concentrations across pregnancy was associated with lower FA (B=-1.00, 95%CI=-1.80, -0.20) and higher MD (B=0.13, 95%CI=0.04, 0.21). Similar associations were observed for DE concentrations.
Conclusions
This study provides the first evidence that OP pesticides may alter normal white matter microstructure in children, which could have consequences for normal neurodevelopment. No associations were observed with structural brain morphology, including regional brain volumes, cortical thickness, or cortical surface area.
Consumer and environmental protection depend on the careful regulation of all classes of chemicals. Toxicology is the key science used to evaluate safety and so underpins regulatory decisions on chemicals. With the growing body of EU legislation involved in chemical regulation, there is a concomitant need to understand the toxicological principles underlying safety assessments
Regulatory Toxicology in the European Union is the first book to cover regulatory toxicology specifically in Europe. It addresses the need for a wider understanding of the principles of regulatory toxicology and their application and presents the relationship between toxicology and legislative processes in regulating chemical commodities across Europe. This title has a broad scope, covering historical and current chemical regulation in Europe, the role of European agencies and institutions, and also the use of toxicology data for important classes of chemicals, including human and veterinary medicines, animal feed and food additives, biocides, pesticides and nanomaterials. This book is therefore extremely pertinent and timely in the toxicology field at present.
This book is an essential reference for regulatory authorities, industrialists, academics, undergraduates and postgraduates working within safety and hazards, toxicology, the biological sciences, and the medicinal and pharmaceutical sciences across the European Union.
In modern societies, humans may be exposed to a wide spectrum of environmental stressors, including mixtures of anthropogenic chemicals. Furthermore, because human exposure does not occur under controlled conditions of dose-response evaluations in animal studies, exposure assessment is complex. Three main tools have been used to assess human exposures: history/questionnaire information, environmental monitoring, and biomonitoring (i.e., measuring concentrations of the chemicals or their metabolites or adducts in human specimens). In this chapter, we will discuss the suitability of biomonitoring data for evaluating exposures to mixtures of environmental chemicals.
Multiple chemicals are emitted in residential accommodation. Aggregate Daily Doses (ADD) (ng/kg-bw/d) were estimated for 32 semivolatile organic compounds (SVOCs) of different chemical families that are frequently detected in French dwellings in both air and settled dust. Daily doses were determined using steady-state models for the population, categorized into 11 age groups covering birth to age 30. Three routes of exposure were taken into account: dust ingestion, inhalation (gaseous and particulate phases) and dermal contact with the gaseous phase of air. Contamination levels were preferentially retrieved from large, nationwide representative datasets. A two-dimensional probabilistic approach was used to assess parametric uncertainty and identify the most influential factors. For children aged 2 to 3years, ADD estimates spanned orders of magnitude, with median values ranging from 8.7pg/kg-bw/d for 2,2',3,4,4'-pentabromodiphenylether (BDE 85) to 1.3μg/kg-bw/d for di-isobutyl phthalate (DiBP). Inhalation, ingestion and dermal pathway contributed at varying levels, and depending on compound, air was the dominant medium for 28 of the 32 compounds (either by inhalation or dermal contact). Indoor exposure estimate variance was mainly driven by indoor contamination variability, and secondarily by uncertainty in physical and chemical parameters. These findings lend support to the call for cumulative risk assessment of indoor SVOCs.
Increasingly, health risk assessment is addressing multiple pathway exposures to multiple contaminants. We reviewed aggregated exposure and cumulative risk approaches for contemporary and ubiquitous semivolatile organic compounds (SVOC). We identified 22 studies aggregating exposure pathways, and 31 cumulating risk. Exposure aggregation is based on the addition of pathway-specific doses, using kinetic modeling where it exists, and classic external dose equations otherwise. In most cases, exposure is dominated by a single route or source of exposure - mainly the oral pathway - via dietary or non-dietary exposure. Preferential routes and sources of exposure are influenced by SVOC physical-chemical properties such as vapor pressure. The cumulative risk approach for contaminants is based on dose addition. Simple sum of hazard quotient (Hazard Index: HI) is the most commonly used cumulative risk assessment approach, while Relative Potency Factor (RPF) appeared to the best suited – although this calls for a level of toxicological information that limits the number of compounds that can be studied simultaneously. Where both were performed, moving from HI to more refined approach produced similar results. In conclusion, both approaches - exposure aggregation and cumulative risk - rely on simple assumptions. Nevertheless, they allow uncertainty to be reduced, in comparison with source-by-source or chemical-by-chemical approaches.
Background
An adequate human biomonitoring is necessary for a valid risk assessment of pesticide exposure in occupational applications as well as in consumers.
Objectives
Identification of existing parameters for human biomonitoring of pesticide exposure, the specificity of the parameters and the performance of analytical procedures used for this purpose.
Methods
Review of publications in toxicology, occupational medicine and analytical chemistry with regard to the metabolism of carbamates, neonicotinoids, organophosphates, phenoxy carboxylic acids, pyrethroids, triazines and glyphosates as well as available analytical methods and assessment values.
Results
After systemic absorption the substances are rapidly excreted via urine either unchanged or after metabolic transformation. Human biomonitoring based on renal elimination of the unchanged agent is feasible for glyphosates, neonicotinoids and phenoxy carboxylic acids. In contrast, a substance-specific biomonitoring of carbamates, organophosphates, pyrethroids and triazines can only be performed by the assessment of specific metabolites in urine. Moreover, the determination of metabolites that can be derived from several pesticides of the same group, demonstrates an alternative biomonitoring approach, which can be used for the assessment of the cumulative exposure to a group of substances.
Conclusions
Human biomonitoring parameters exist for most currently used synthetic pesticides, which can be used for the risk assessment of exposed individuals. Almost all existing analytical procedures enable the determination of pesticide exposure in the occupational as well as environmental exposure range.
Chemicals used as pesticides are both a broad, vital catalyst for the support and advancement of all aspects of our lives, and at the same time targets of extensive suspicion and mistrust. Spectacular beneficial responses to chemical technologies in medicine, agriculture, nutrition, and manufacturing have occurred over long periods of time. Issues and common perceptions of the health and environmental significance of chemical exposure often dominate discussion of pesticide use indoors and in agriculture. As those technologies have been developed and used, adverse effects have been observed from time to time, but that reality is dwarfed by subjective feelings that often outweigh reason.
This chapter presents an overview of the pharmacokinetic principles that are of major importance in understanding the toxicology of organophosphorus (OP) insecticides in animals and humans. Organophosphates constitute a large family of insecticides that are structurally related pentavalent phos-phorus acid esters. Their insecticidal as well as toxicological mode of action is primarily associated with their ability to target and inhibit the enzyme acetylcholinesterase (AChE). The three major classes of organophosphorus insecticides are the phosphorothionates, phosphorodithioates, and phosphoroamidothiolates. Organophosphorus insecticides, like most chemical contaminants, are absorbed into the body, and, based on the detection of low levels of metabolites in urine within humans, there is good evidence for widespread although low-level exposures. This chapter also illustrates a number of current and future applications of pharmacokinetics to assess organophosphorus insecticide dosimetry, biological response, and risk in humans exposed to these insecticides. Pharmacokinetics is concerned with the quantitative integration of absorption, distribution, metabolism, and excretion and can be used to provide useful insight into the toxicological responses associated with these insecticides. Since organophosphorus insecticides share a common mode of action through their capability to inhibit AChE activity, it is feasible to develop pharmacokinetic strategies that link quantitative dosimetry with biologically based pharmacodynamic (PD) response modeling. Pharmacokinetics has been successfully utilized to better understand the toxicological implications of human exposure to organophosphorus insecticides. Nonetheless, there is still a significant need to further develop and refine pharmacokinetic models that can be used to accurately assess the risk associated with insecticide exposures.
The literature regarding basic mechanisms of pesticide toxicity, exposure assessment, and risk characterization has literally exploded over the last decade since publication of the 3rd edition of the IRT. The various information sources referenced in this listing were chosen primarily for their focus on human exposure and epidemiology. However, books and journals also covered references about environmental chemistry and ecotoxicological effects so that the interested reader could have some guidance for initiating a search on environmental aspects of pesticide technology. Notable among the specific journal articles are series of publications by singular university or government entities that have been operating under large, multi- year Federal grants to focus on children and worker health in relation to pesticide exposure. For example, the Federally funded Agricultural Health Study (AHS) has a mandate to elucidate relationships between farmworker health and disease and associations with farm practices, especially pesticide use.
Insecticides are of chemical and biological origins, and are used in agriculture, horticulture, forestry, gardens, homes, and offices. They are also used to control vectors, such as mosquitoes and ticks, that are involved in spreading human and animal diseases. Insecticides constitute a large number of chemical classes and exert toxicity in insects and nontarget mammalian (including humans) and avian species through different mechanisms of action. In nontarget species, insecticides can produce anything from minor pain to severe paralysis and death. The insecticides can bind to different enzymes, receptors, and other proteins, and the binding sites and adducts, along with residue of insecticides and their metabolites, can be used as biomarkers of exposure and effects. Detection of an early exposure to the insecticides will not only help in avoiding any further exposure to the insecticides, but will also provide the opportunity for a timely treatment.
This paper systematically reviews epidemiologic studies related to low-level non-occupational exposures to organophosphorus (OP) insecticides. Many of the studies evaluate levels of maternal OP metabolites and subsequent health outcomes in offspring. The studies focused primarily on birth outcomes (e.g., infant body weight or head circumference) and neurodevelopmental (e.g., mental and psychomotor) testing results. The evidence from these studies was reviewed under the Bradford Hill guidelines. Most of the studies assessing exposure based on urinary levels of OP insecticide metabolites used only one or two measurements during pregnancy. The potential for exposure misclassification with this method is largely due to (1) preformed metabolites that are ingested with food, (2) the short elimination half-life of OP insecticides, and (3) lack of specificity to particular OP insecticides for many of the metabolites. For birth outcomes, the majority of reported results are not statistically significant, and the associations are inconsistent within and across studies. There is more within-study consistency for some of the neurodevelopmental testing results, although few associations were examined across several studies. These associations are generally weak, have been replicated only to a limited extent, and require further confirmation before they can be considered established. The OP insecticide levels measured in the epidemiologic studies are too low to cause biologically meaningful acetylcholinesterase inhibition, the most widely used metric for OP insecticide toxicity. Overall, the available evidence does not establish that low-level exposures to OP insecticides cause adverse birth outcomes or neurodevelopmental problems in humans.
The study reports the effect of mesoporous silica nanoparticles (MSNs) on detoxification of toxic organophorous compounds. Based on gravimetric sensing experiment with resonant microcantilever, rapid adsorption of the organophorous simulant of dimethyl methylphosphonate (DMMP) onto MSNs is confirmed. The experimentally observed irreversible gravimetric-signal implies that substitution-reaction possibly occurs at the nanomaterial surface. By exploring a method of gravimetric detection at different temperatures to obtain two isotherms, high reaction-heat of 97.1 kJ mol−1 is extracted that indicates strong chemical interaction. Characterizations with solid-state NMR and FT-IR to the MSNs are performed during the adsorption/interaction process, revealing that substitution-reaction exactly occurs. GC-MS analysis to the post-reaction vapor exhaust indicates that one or two methyl groups in a DMMP molecule can be substituted by hydrogen atom(s) through substitution-reaction with silanol group(s) of MSNs, thereby, destructing DMMP into two sorts of new molecules. With such comprehensive analyses, the destruction/detoxification mechanism is clearly identified. To evaluate the detoxification performance of the MSNs, real toxic of dichlorvos is experimentally examined, resulting in that organophosphate dichlorvos is detoxified into non-toxic dimethylphosphate. The low-cost and producible MSNs are promising for detoxification to organophorous compounds. Besides, the micro-gravimetric analysis method can be expanding for extensive researches on various functional materials.
Postapplication exposure assessment related to indoor residential application of pesticide products requires consideration of product use information, application methods, chemical-specific deposition, time-dependent availability and transferability of surface residues, reentry time, and temporal location and macro- and microactivity/behavior patterns (Baker et al., 20008.
Baker , S. ,
Driver , J. H. and
McCallum , D. 2000. Residential exposure assessment: A sourcebook, New York, NY: Kluwer Academic/Plenum. View all references). Children's mouthing behavior results in potential postapplication exposure to available pesticides in treated microenvironments through the nondietary ingestion route, in addition to the dermal or inhalation routes. Children's activities and associated behaviors may result in multiple or repeat contact of dermal areas (clothed and unclothed body areas and hands) with treated surfaces, or surfaces that may have indirect sources of residues. Further, some surfaces contacted may have transferable pesticide residues and others may not. Transfer of residues from the indoor residential environment to the dermal surface (e.g., hands) of an individual has been assumed to be linear as a function of time and number of contacts. However, studies suggest that this transfer process to the hands and other body areas may be rapidly saturable. In the most recent U.S. Environmental Protection Agency (EPA), Office of Pesticide Programs (OPP) “Residential Exposure Assessment Standard Operating Procedures” (U.S. EPA, 2012), the input variable for the number of dermal contacts (with treated surfaces) is an exponent, making the relationship nonlinear. Further, removal processes such as hand washing and transfer to untreated surfaces are important to consider. Predictive algorithms for estimating children's hand-to-mouth-related incidental ingestion exposures post pesticide application have been developed by the EPA/OPP and incorporated into probabilistic models. A review of literature addressing variables used to estimate potential incidental ingestion exposure is presented. Data relevant to input variables for predictive algorithms are discussed, including the results of a multiyear, pesticide transferable residue measurement program conducted by the Non-Dietary Exposure Task Force (NDETF) and the associated distributional characterization for this key variable. Sources of conservative bias in current hand-to-mouth, incidental ingestion exposure estimation and the role of biomonitoring to evaluate predicted exposures are discussed.
A recent study by the Toxic Substances Hydrology Program of the U.S. Geological Survey (USGS) shows that a broad range of chemicals found in residential, industrial, and agricultural wastewaters commonly occurs in mixtures at low concentrations downstream from areas of intense urbanization and animal production. The chemicals include human and veterinary drugs (including antibiotics), natural and synthetic hormones, detergent metabolites, plasticizers, insecticides, and fire retardants. One or more of these chemicals were found in 80 percent of the streams sampled. Half of the streams contained 7 or more of these chemicals, and about one-third of the streams contained 10 or more of these chemicals. This study is the first national-scale examination of these organic wastewater contaminants in streams and supports the USGS mission to assess the quantity and quality of the Nation's water resources. A more complete analysis of these and other emerging water-quality issues is ongoing.
Keywords:
pharmaceuticals;
hormones;
other wastewater contaminants;
steroids;
nonprescription drugs;
veterinary pharmaceuticals
The National Center for Health Statistics collaborated with the National Human Monitoring Program of the U.S. Environmental Protection Agency (EPA) in a four-year study to assess the exposure of the general population to selected pesticides through analysis of blood serum and urine specimens. Specimens were collected on a national probability half sample of persons 12-74 years of age from 64 locations across the United States comprising the sample areas in the Second Health and Nutrition Examination Survey (NHANES II) and analyzed for selected organochlorine, carbamate, chlorophenoxy and organophosphorus pesticides. Medical, nutritional and pesticide usage data are also available for each sample person. Preliminary results of the blood serum and urine analyses indicate that the general population is being exposed to some of these types of pesticides. Since 1970, EPA has conducted a national probability sampling of human adipose tissue. Specimens obtained on a survey design representative of the general population were analyzed for selected organochlorine pesticides and toxic chemicals. Findings from the 1978 survey also indicate exposure of the general population to some of these chemicals. Medical data collected from both surveys have yielded no overt correlations between health effects and residue levels. More intensive statistical analyses are underway to investigate the possible existence of more subtle relationships.
Insecticides are often applied indoors where dermal absorption from surfaces as well as inhalation exposure may occur. Children may also have oral exposure due to hand-to-mouth activities. Poison control centers frequently receive complaints of illness following such applications. These complaints may be coincidental due to odors or to a systemic toxic action from an ingredient. Using an appropriate algorithm, surface exposure and total absorption was calculated for chlorpyrifos, dichlorvos and propoxur. With each of these insecticides, the dose calculated might provide a toxic dose, particularly to an infant. More data are, therefore, needed for these and other insecticides to ensure that the levels in the air and on treated surfaces will not be injurious to health. Such data will include bioavailability of surface residues, rate of transfer from surfaces and dose-response data. Pending such data, risk assessments based upon health-protective assumptions should be used to decide the safety of various components.
Dermal absorption of neat malathion, a 50% emulsifiable concentrate (50% EC), and a 1% and 10% aqueous mixture of the 50% EC formulation was examined in human volunteers. The absorption and elimination profiles of [¹⁴C]-malathion equivalents in the urine of the human were compared with the rat. Constants of absorption and elimination were calculated. Distribution of [¹⁴C]-malathion equivalents in selected tissues were examined in the rat. The 50% EC formulation was absorbed as readily as the neat malathion. The absorption of the organic based formulations was influenced by the increase in the surface area of the site of application. The total cumulative absorption was concentration dependent. The rate of absorption of the neat malathion, the 50% EC formulation, and 10% aqueous mixture was less than the rate of elimination resulting in a depletion of the body burden. The rate of absorption and elimination of the 1% aqueous mixture were coincident The elimination of malathion was efficient and independent of surface area, concentration, and formulation. The disposition of malathion favored organs of metabolism and elimination, liver and kidney. A substantial portion of the dose remained at the site of application. The results suggest that acute human toxicity could occur from handling the concentrate when a substantial portion of the exposed skin is contaminated. Acute toxicity from contact with surfaces treated with the aqueous mixtures would be unlikely. Repeated exposure, however, could burden organs of metabolism and elimination, skin, liver and kidney.
Recently state health and regulatory agencies in California used a PB-PK model to estimate the absorbed doses of malathion in individuals allegedly exposed to aerial sprays during an urban pesticide application. Dose simulation in that study was performed on the results of single urine samples collected within 48 h of a potential exposure, and was based on a model validated with observed values from only a single volunteer. As a continuing effort another case study is presented in this chapter to validate the model with more human literature data. Results from this validation study showed that the time courses of the serial urinary malathion (metabolites) excretion presented in the literature were consistent with those simulated by the PB-PK model. When urine results collected from the literature cases at 8 - 12 h, 12 - 24 h, and 24 - 36 h or 24 - 48 h after initial exposure were postulated as spot samples, the majority (64/85) of the individual total absorbed doses simulated were within two-fold of their measured values, with no simulation doses exceeding three-fold. This validation study further showed that the accuracy would be improved considerably, if the simulation for each literature case were performed on two or more spot samples collected at different time points preferably within the first 24 or 36 h of exposure.
Bidrin, 3-(dimethoxyphosphinyloxy)-N,N-dimethyl-cis-crotonamide, is metabolized to yield trace amounts of 3-(dimethoxyphosphinyloxy)-N-methyl-N-hydroxymethyl-cis-crotonamide and larger amounts of 3-(dimethoxyphosphinyloxy)-N-methyl-cis-crotonamide (SD 9129). SD 9129 is further metabolized to yield 3-(dimethoxyphosphinyloxy)-N-hydroxy-methyl-cis-crotonamide and 3-(dimethoxyphosphinyloxy)-cis-crotonamide. The toxicity to both insects and mammals increased upon successive N-demethylation. Balance studies on the fate of the P32 and C14 from Bidrin-P32, Bidrin-N-methyl-C14, SD 9129-P32, and SD 9129-N-methyl-C14 are considered. Studies on milk residues, urinalysis, and metabolism in houseflies (Musca domestica L.) and bean plants are reported. An unusual pattern of synergism of the toxicity of the Bidrin metabolites in houseflies by sesamex [2-(2-ethoxyethoxy)ethyl-3,4-(methylenedioxy)phenyl acetal of acetaldehyde] was noted.
OBJECTIVES
To derive a method for retrospectively estimating cumulative exposure to organophosphate (OP) pesticides among a cross section of United Kingdom sheep dippers, as part of a wider epidemiological study of neurological abnormality within this group of workers.
METHODS
A hygiene study of dipping sessions at 20 farms using diazinon based dips was carried out by two experienced occupational hygienists. Observations on the exposure of people to concentrate and dilute dip were recorded throughout each dipping session, together with the other relevant factors including the use and condition of protective clothing. Concentrations of urinary metabolites of diazinon were used to measure actual exposure to OPs. To estimate exposure in the subsequent epidemiological study, an occupational exposure history questionnaire was developed using results from the hygiene study and an empirical exposure model.
RESULTS
In the hygiene study, increased urinary metabolites were associated with the handling of concentrate dip and exposure to dilute dip wash through splashing. Very few dippers wore the recommended protective clothing. The handling of concentrate dip was the principal source of exposure to OPs. Dipping task was used as a surrogate for splashing of dilute dip in retrospective exposure estimation. In the epidemiological study, cumulative exposure to OP sheep dips was highly correlated with the total number of dipping days, but not with age.
CONCLUSIONS
Sheep dip concentrate is the most important source of OP exposure among sheep dippers and estimates of exposure to OPs during routine dipping should take due account of exposure to concentrate dip as well as to the dilute dip wash. The observed use of recommended protective clothing by most subjects was insufficient to allow a proper empirical assessment of its effectiveness.
生育程度を変えて栽培した3種類の水稲に32P-Baycid乳剤を散布し,その変化を追跡した。稲体においてBaycidが加水分解される速度はmethyl parathionなどに比較してかなり遅いと考えられる結果を得たが,Baycidの形(PS-sulfide)は散布後急速に消失した。Baycidの酸化物としてはPS-sulfoxide PS-sulfoneが大部分を占め,thiophosphate(PS-型)のphosphate (PO-型)への酸化はきわめて少ないと考えられる。出穂数日前に散布した場合,Baycidの代謝物質は出穂後の穂に移行し,主として“ぬか”に集積する傾向が認められた。乳熟期の“もみ”における水溶性代謝物質をイオン交換樹脂により分離した結果,Phosphoric acid, thiophosphoric acid, O, O-dimethyl phosphoric acid, O, O-dimethyl thiophosphoric acid, O-methyl O-(3-methyl-4-methylmercaptophenyl) thiophosphoric acidおよび一個の未同定物質を検出したが,特にBaycidの脱メチル化合物の割合が高かった。
The behavior of ³²P-labeled Baycid was compared between tea leaves and cabbage leaves, and the residue of Baycid or its metabolites in tea leaves before and after the manufacturing process of green tea was also examined. 1. It was probable that the penetration rate of Baycid into leaf tissues was more rapid in cabbage leaves than in tea leaves, and that the metabolic rate of Baycid was also rapid in cabbage leaves. 2. In tea leaves, PS-sulfoxide and PS-sulfone was detected as the main metabolites of Baycid and the appearance of the other chloroform extractable metabolites was a little, while in cabbage leaves, the distribution of the metabolites was rather different from that of tea leaves, and the appearance of the metabolite which suggested the oxidation of thiophosphate to phosphate was clear. 3. The absolute amount and the distribution of the metabolites in green tea were hardly changed before and after the manufacturing process of green tea. © 1962, JAPANESE SOCIETY OF APPLIED ENTOMOLOGY AND ZOOLOGY. All rights reserved.
Soils of four different types were treated with a relatively high dosage level (15 ppm) of 14C-chlorfenvinphos and were stored at about 22° for four months. After this time the following radio-labelled compounds were detected in the moist soils: unchanged chlorfenvinphos, 1.0-4.7 ppm; 1-(2′4′-dichlorophenyl)ethan-1-ol, 0.06-1.0 ppm; 2,4-dichloroacetophenone, 0.1-0.5 ppm; desethyl chlorfenvinphos, 0.1-0.2 ppm; (2′,4′-dichlorophenyl)ethan-1,2-diol, <0.03 ppm; salts or conjugates of desethyl chlorfenvinphos, 0.05-0.6 ppm; 2,4-dichlorophenyloxirane, <0.005 ppm; 2,4-dichlorophenacyl chloride, <0.005 ppm.
Soils were also treated with 3-4 lb/ac 14C-chlorfenvinphos and cabbages, onions, and carrots were grown to maturity in the soils. The edible part of cabbages at harvest contained no detectable chlorfenvinphos or breakdown products of it when the limit of detectability was about 0.005 ppm. At harvest at 8-10 weeks after soil application of chlorfenvinphos the edible roots of carrots contained 0.12 ppm of unchanged chlorfenvinphos, and onion bulbs contained 0.07 ppm. There was evidence of trace amounts of a compound, probably a salt or conjugate of desethyl chlorfenvinphos, in onions (<0.01 ppm) and in carrots (0.024 ppm or less). Carrots also contained traces (about 0.005 ppm) of 2,4-dichloroacetophenone.
Five groups of male Sprague-Dawley rats were orally administered a mixture of [¹⁴C]- and [¹²C]-glyphosate (N-phosphonomethylglycine) at a dose level of 10 mg/kg body weight. The majority of radioactivity 2 hr after administration was associated with the gastrointestinal contents and small intestinal tissue. Approximately 35–40% of the administered dose was absorbed from the gastrointestinal tract, and urine and feces were equally important routes of elimination. The total body burden 7 days after administration was approximately 1% of the administered dose and was primarily associated with the bone. Total recovery for this study ranged from 95 to 102% of the administered dose. Metabolic profiles of tissues containing greater than 1% of the administered dose at various times after administration indicated that nearly 100% of the body burden of radioactivity was present as unmetabolized parent glyphosate. A minor component constituting <0.1% of the administered dose (<0.4 ppm) was observed in colon tissue from animals 2 hr after the administration of glyphosate and was also present in the GI contents of one animal 28 hr after administration of the radiolabel. The retention time for this metabolite was similar, but not identical, to the retention time for AMPA (aminomethylphosphonic acid), the major bacterial metabolite of glyphosate found in soil. Tissue extraction efficiency was always greater than 90% and stability assays indicated no significant effect of storage on either parent glyphosate or AMPA. The results from this study indicate that virtually no toxic metabolites of glyphosate were produced since there was little evidence of metabolism and essentially 100% of the body burden was parent compound with no significant persistence of material.
O, O-dimethyl O-[4-(methylthio)-m-tolyl] phosphorothioate or Bayer 29493 was oxidized by rats at the phosphoryl sulfur and the thiophenyl group; the sulfoxide and sulfone derivatives of the parent material and its oxygen analog were isolated and identified. Oxidation rather than isomerization was the predominant activation process. The urine and feces contained different percentages of each metabolite. Hydrolysis occurred primarily at the P-O-phenyl bond; cleavage of the P-O-methyl bond was not demonstrated. The percentage of hydrolytic products in the urine decreased as the number of doses increased (10 mg./kg./ day for 10 days). The cholinesterase of the blood and brain of rats was inhibited rapidly and recovered slowly.
The acetonitrile-soluble residues in the liver, kidney, muscle, skin, and heart were negligible at 3 days following oral (100 mg./kg.) or intraperitoneal treatment of rats. About 80% of the administered Bayer 29493 equivalents was eliminated in the excreta regardless of the route of administration.
The differences in the degree in workers’ exposure to organophosphorus pesticides during the spraying of an apple‐orchard were assessed from the urinary content of metabolites: dimethyl phosphorothiolate potassium salt (DMPThK) for Demeton‐S‐methyl and dimethyl phosphorothionate and phosphorodithioate potassium salts (DMTPK and DMDTPK) for Azinphos‐methyl and Methidathion. The highest median concentrations of the metabolites in the urine samples collected after two to three days of work with the pesticides were determined in the mixers preparing pesticide solutions: DMPThK 83ng cm (N = 7) after exposure to Demeton‐S‐methyl; DMTPK 2040 and DMDTPK
The fate of 32P-labeled trichlorfon in lygus bug adults, Lygus hesperus Knight, tobacco budworm larvae, Heliothis virescens F., green lacewing larvae, Chrysopa carnea Stephens, white rats, and cotton plants was investigated. Differences in the susceptibility to trichlorfon among the insect species were influenced primarily by the rates at which the insecticide was absorbed. After treatment with trichlorfon, small amounts of dichlorvos, a highly toxic derivative of trichlorfon, were detected in the extracts of insects and plants, but not in the urine of rats. Both trichlorfon and dichlorvos were metabolized rapidly in all biological materials. Three previously unreported glycosidic conjugates, important in the detoxification of trichlorfon, were detected. One conjugate was a glucuronide found only in the urine of rats. The others were glucosides; one occurred in all insects and plants, and the other was found only in lygus adults.
Relatively small amounts of Geigy GS-13005-[O,O-dimethyl phosphorodithioate S-ester with 4 - (mercaptomethyl) - 2 - methoxy - Δ2 - 1,3,4-thiadiazolin-5-one] were absorbed by cotton plants after foliar, seed, or stem treatments. Only small concentrations of GS-13005 were translocated to new plant growth and none was detected in the fruit. The highly toxic oxygen analog of GS-13005 was found in extracts of treated plants and insects but not detected in the urine of white rats.
Diazinon (14C-ring-labeled) was absorbed and initially accumulated in bean plant roots in higher quantities than in other regions of the plant. It also diffused out of roots when they were rinsed and placed in nutrient solution indicating movement along concentration gradients. Translocation to foliage occurred with small amounts of diazinon present in the primary leaves by two days but not thereafter. Although radioactivity steadily accumulated in the foliage, this was mainly the hydrolysis product (2-isopropyl-4-methylpyrimidin-6-ol) and unextractable metabolites, possibly conjugation products. Thus, the leaves appeared to be the main site for hydrolysis while diazinon persisted in the roots and nutrient solution for several days. Excised primary leaves also hydrolyzed diazinon. Metabolism of the pyrimidinol ring to 14CO2 was very minor, and no 14C-diazoxon was detected at any interval.
The nature and rate of the in vivo metabolism of the experimental systemic insecticide Bidrin were compared in cotton plants, two species of cotton insects, and white rats, through the use of radiometric techniques. Oxidative demethylation of the toxicant to its equally toxic N-methyl derivative occurred in all biological materials, but all toxic products decomposed rapidly. Of nine phosphorus-containing metabolites detected, six hydrolytic and two oxidative products were identified tentatively. A major metabolite that occurred in treated plants was not completely identified, but was shown to contain almost all the original Bidrin molecule.
A rapid, colorimetric method for the determination of small amounts of chromium in human blood, tissues, and urine is described. The method is sensitive to 0.005 microgram of chromium per milliliter of final solution. Samples are ashed in borosilicate glass beakers, using a combination of wet- and dry-ashing methods. The blood and tissue samples are oxidized by bromine in alkaline solution. Oxidation of the urine samples is accomplished by sodium bismuthate in acid solution. Diphenylcarbazide is used as the color reagent. A clear red-violet color is obtained which can be measured colorimetrically or spectrophotometrically. Comparative standardization curves and typical analyses are given.
The objective was to determine percutaneous absorption of cadmium as the chloride salt from water and soil into and through human skin. Soil (Yolo County 65-California-57-8) was passed through 10-, 20-, and 48-mesh sieves. Soil retained by 80 mesh was mixed with radioactive cadmium-109 at 13 ppb. Water solutions of cadmium-109 at 116 ppb were prepared for comparative analysis. Human cadaver skin was dermatomed to 500-μm, and used in glass diffusion cells with human plasma as the receptor fluid (3 ml/hr flow rate) for a 16-hr skin application time. Cadmium in water (5 μl/cm2) penetrated skin to concentrations of 8.8 ± 0.6 and 12.7 ± 11.7% of the applied dose from two human skin sources. Percentage doses absorbed into plasma were 0.5 ± 0.2 and 0.6 ± 0.6%, respectively. Cadmium from soil (0.04 g soil/cm2) penetrated skin at concentrations of 0.06 ± 0.02 and 0.13 ± 0.05% for the two human skin sources. Amounts absorbed into plasma were 0.01 ± 0.01 and 0.07 ± 0.03%. Most of the nonabsorbed cadmium was recovered in the soap and water skin surface wash. Binding of cadmium from water to soil was greater than binding from water to powdered human stratum corneum, supporting the lower absorption from soil than from water. Short-term exposure of cadmium in water to human skin for 30 min (bath or swim) resulted in skin uptake, which upon further perfusion (48 hr), absorbed into the plasma receptor fluid (systemic). Cadmium in soil was increased from 6.5 to 65 ppb. Skin levels correspondently increased, but plasma receptor fluid levels remained constant. Soil capacity was decreased from 40 to 4 mg/cm2. Skin levels correspondingly decreased, suggesting decreased skin contact, but plasma receptor fluid levels remained constant. The above suggest that, with in vitro diffusion, the surface concentration of cadmium will influence skin cadmium concentration, but that absorption into plasma receptor fluid is relatively independent of skin surface concentrations. Calculations suggest that a daily whole body exposure to cadmium at 116 ppb with 0.5% absorption will result in daily systemic intake of about 10 μg cadmium.
Sumario: This paper presents the results of a field study in which exposure to malathion was evaluated simultaneously by biological monitoring and dermal deposition measurements. Malathion metabolites in urine were measured for three days following exposure. Fluorescent tracers and a video imaging system were employed to measure dermal exposure
Blood acetylcholinesterase (ACHE) and pseudocholinesterase (PCHE) activity and urinary dialkyl phosphate (DAP) excretion were measured in a group of 15 male agriculture field workers during a five-day thinning operation in a Northern California peach orchard. Eight men were randomly assigned to work in a Guthion-treated plot, and seven men to work in an adjoining plot free from organophosphate residues. Foliage samples were taken to measure dislodgeable and total Guthion residues. The daily mean percent change in the ACHE and in the PCHE activity was less than -10.0 percent of baseline values for each group of men. Mean ACHE activity of workers in the Guthion treated plot was different from that of workers in the control plot on the fifth exposure day. The mean PCHE activity of workers in the Guthion treated plot was not different from that of workers in the control plot. Daily group-mean urinary metabolite excretion levels for workers exposed to Guthion residues were highly correlated with their daily group-mean percent change in ACHE activity. No urinary metabolites were detected in workers in the control plot. Decay in Guthion residues was markedly slower in this trial than in a comparable study conducted one year previously, emphasizing the difficulty in setting re-entry intervals based on time elapsed from pesticide application. Suggestions were made to extend the time interval of future studies on the human health effects of organophosphate residue exposure, and to further refine urinary metabolite surveillance methods toward the goal of establishing a threshold level of metabolites which would correspond to meaningful exposure to these pesticides residues.
A method for the analysis of the dialkyl phosphate metabolites of organophosphorus pesticides was modified to permit analysis of the monocarboxylic acid (MCA) and dicarboxylic acid (DCA) metabolites of malathion. Recoveries of MCA and DCA from spiked urine are presented, as well as the results of analyses of urine from rats exposed to malathion at five levels. Data from both exposed and unexposed humans are presented.
Studies were done to determine the percutaneous absorption of isofenphos in human volunteers from whom informed consent had been obtained. In vivo absorption in man was 3.6 +/- 3.6% of applied dose for 24-hr exposure and 3.6 +/- 0.5% for 72-hr exposure. Skin wash recovery data show that isofenphos evaporates from in vivo skin during the absorption process; the surface dose is minimal (< 1%) by 24 hr. Skin stripping showed no residual isofenphos in stratum corneum. This explains the similar absorption for 24 and 72-hr dose prewash exposures. Skin surface recovery in vivo with soap and water was 61.4 +/- 10.4 for the first dosing time (15 min). Time-recovery response declined with time to 0.5 +/- 0.2% at 24 hr. In vitro absorption utilizing flow-through diffusion methodology with human cadaver skin and human plasma receptor fluid gave 2.5 +/- 2.0% dose absorbed, an amount similar to in vivo studies. An additional 6.5 +/- 24% was recovered in the skin samples (total of 9%). Skin surface wash at 24 hr recovered 79.7 +/- 2.2% and skin content was 6.5 +/- 2.4% (total dose accountability of 88.7 +/- 4.6%). Thus, isofenphos was available for absorption during the whole dosing period. Neither in vitro absorption nor in vitro evaporation studies predicted the potential skin evaporation of isofenphos. Published dermal studies in the rat had predicted isofenphos absorption at 47% of applied dose (12-fold greater than actual in man). Subsequent toxicokinetic modeling predicted possible concern with the use of isofenphos.(ABSTRACT TRUNCATED AT 250 WORDS)
Five groups of male Sprague-Dawley rats were orally administered a mixture of [14C]- and [12C]-glyphosate (N-phosphonomethylglycine) at a dose level of 10 mg/kg body weight. The majority of radioactivity 2 hr after administration was associated with the gastrointestinal contents and small intestinal tissue. Approximately 35-40% of the administered dose was absorbed from the gastrointestinal tract, and urine and feces were equally important routes of elimination. The total body burden 7 days after administration was approximately 1% of the administered dose and was primarily associated with the bone. Total recovery for this study ranged from 95 to 102% of the administered dose. Metabolic profiles of tissues containing greater than 1% of the administered dose at various times after administration indicated that nearly 100% of the body burden of radioactivity was present as unmetabolized parent glyphosate. A minor component constituting less than 0.1% of the administered dose (less than 0.4 ppm) was observed in colon tissue from animals 2 hr after the administration of glyphosate and was also present in the GI contents of one animal 28 hr after administration of the radiolabel. The retention time for this metabolite was similar, but not identical, to the retention time for AMPA (aminomethylphosphonic acid), the major bacterial metabolite of glyphosate found in soil. Tissue extraction efficiency was always greater than 90% and stability assays indicated no significant effect of storage on either parent glyphosate or AMPA. The results from this study indicate that virtually no toxic metabolites of glyphosate were produced since there was little evidence of metabolism and essentially 100% of the body burden was parent compound with no significant persistence of material.
In order to assess the occupational health risk to workers using pesticides, accurate data on exposure (including knowledge of the primary route of exposure) and on absorption are needed. In addition, a well-defined no-effect level (NOEL) derived from suitable animal data must be available. Biological monitoring, urinary metabolite excretion in particular, frequently is used to indicate whether a worker has been exposed. Interpretation of the toxicological significance of the observed urinary metabolite levels is often difficult because the relationship between these levels and toxic dose are generally unknown. Another complication is the apparent lack of correlation between patch data and urinary metabolite data. The usefulness of a metabolite to predict exposure depends on many things, including detailed knowledge of absorption and excretion characteristics of the parent compound and identification of the metabolites. These data, when combined with appropriate toxicology data, permit an analysis of the potential health risks associated with an occupational exposure to toxic chemicals. This paper will correlate data from a number of studies in which the dermal penetration of azinphosmethyl (AM) was measured in rats, rabbits, monkeys and man; and urinary alkyl phosphate metabolites were measured in orchardists exposed to AM. The feasibility of utilizing metabolite excretion to estimate exposure and ultimate risk will be discussed.
Nineteen workers conducting mixing and high-volume airblast applications of the organophosphorus pesticide malathion were monitored simultaneously by biological monitoring and fluorescent tracer evaluation of dermal exposure. Complete 72-hr urine samples were collected and analyzed for dimethylthiophosphate and dimethyldithiophosphate metabolites. Dermal exposure was measured through the addition of a fluorescent tracer to the tank mix, subsequent examination of the skin surface under long-wave ultraviolet light, and fluorescence quantification with a video imaging system. Dermal exposure to applicators was correlated highly with total metabolite excretion (r = 0.91). Mixer exposure was not correlated significantly (r = 0.73) because of wide scatter in the data and the small number of workers monitored. Applicator exposures were more than 3 times higher than mixer exposures, reflecting the high exposure potential inherent in airblast spraying. Exposure to regions protected by gloves or clothing was more than 75% of total exposure for both mixers and applicators. These results provide evidence that the fluorescent tracer technique is a valid methodology for measuring relative levels of dermal exposure during agricultural work activities. The technique also holds promise as a quantitative procedure for evaluating the effectiveness of engineering control strategies and protective clothing performance.
Dermal and respiratory exposure was measured for 15 workers applying a granular diazinon pesticide formulation, using equipment more typical of residential home owner use than large scale or agricultural operations. Urine samples were analyzed for the metabolic product diethylthiophosphate (DETP). The primary determinants of exposure and exposure distribution were job classification and the use of one type of broadcast spreader. Diazinon exposures ranged from 0.1 to 11 mg/day for workers, and from 0.03 to 0.3 mg/day for supervisory personnel, during sampling periods ranging from 3.3 to 7 hr. Individual exposures correlated well with observed duties. An association was found between morning shift diazinon exposure and afternoon urinary DETP levels.
Analytical methods have been developed for the detection of a variety of compounds that are found intact or as metabolites in biological samples from workers exposed to pesticides. Such tests are used primarily in research settings to describe patterns of absorption, metabolism, and excretion, to derive exposure limits for occupational exposure, to evaluate the adequacy of these limits and of work practices in field settings, and to confirm the etiology of poisonings for medicolegal purposes. We review here methods used in studies of occupational pesticide exposure, with particular attention to validation in terms of dose-response relationships, to technical complexity and cost, to the requirements for analytical quality control, and to the utility of these methods for field research purposes. Biological monitoring for intact pesticides or metabolites in agricultural workers is limited to a few chemicals, notably, pentachlorophenol, methyl bromide, and chlordimeform. These programs and their use in regulation and enforcement are described.
Eleven farmers were monitored for dermal and respiratory exposure to terbufos [phosphorodithioic acid, S-(tert-butylthio) methyl O,O-diethyl ester] during a typical working day while planting corn and applying COUNTER 15-G systemic insecticide-nematicide. The average estimated dermal exposure was 72 g/hr while the estimated respiratory exposure was 11 g/hr. The results of urinary alkyl phosphate analyses were all negative showing no detectable absorption of terbufos. Plasma and red blood cell cholinesterase values of exposed farmers showed no significant difference in activity when compared to either preexposure or control values indicating no adverse physiological effects from the exposure. Based on these results, the use of COUNTER 15-G does not present a significant hazard, in terms of acute toxicity, to farmers using this product for the control of corn insects.
Regulators today face complex problems in assessing the health hazards associated with the use of pesticides. Pesticide exposure occurs at manufacturing, application, work area, and consumption situations, and in the air, water, and soil of our daily lives. The skin is the largest organ of the body and thus has become a major environmental port for pesticides to enter the body. In this paper, we review the principles of percutaneous absorption--the rate and extent that chemicals enter the body through the skin--using data currently available for pesticides.
The comparative metabolism and toxicity of organophosphorus and carbamate insecticides are reviewed with the purpose of assessing our present ability to design new toxicants with improved selectivity. The occurrence of quantitative and qualitative differences in metabolism in vertebrates and insects is considered and an assessment is made of the role of metabolic activation and degradation in the complex interactions governing toxicity.
Owing to its high insecticidal activity, systemic properties and relatively low toxicity to mammals, Rogor [O,O-dimethyl S-(N-methyl carba- moylmethyl)phosphorodithioate], also known as dimethoate in the USA and in other countries and as Fosfamide in the Soviet Union, has found a progressively increasing use for the control of several species of phytophagous insects and mites injurious to a great number of cultivated plants. Its spectrum of activity and properties are consistently documented by a wide literature which has been recently reviewed by De
Pietri-Tonelli (1965).
The kinetics of chlorpyrifos, an organophosphorothioate insecticide, and its principal metabolite, 3,5,6-trichloro-2-pyridinol (3,5,6-TCP), were investigated in six healthy male volunteers given a single 0.5 mg/kg po and, 2 or more weeks later, a 0.5 or 5.0 mg/kg dermal dose of chlorpyrifos. No signs or symptoms of toxicity or changes in erythrocyte cholinesterase were observed. Plasma cholinesterase was depressed to 15% of predose levels by the 0.5 mg/kg po dose but was essentially unchanged following the 5.0 mg/kg dermal dose. Blood chlorpyrifos concentrations were extremely low (less than 30 ng/ml), and no unchanged chlorpyrifos was found in the urine following either route of administration. Mean blood 3,5,6-TCP concentrations peaked at 0.93 micrograms/ml 6 hr after ingestion of the oral dose and at 0.063 micrograms/ml 24 hr after the 5.0 mg/kg dermal dose. 3,5,6-TCP was cleared from the blood and eliminated in the urine with a half-life of 27 hr following both the po and dermal doses. An average of 70% of the po dose but less than 3% of the dermal dose was excreted in the urine as 3,5,6-TCP; thus only a small fraction of the dermally applied chlorpyrifos was absorbed. Chlorpyrifos and its principal metabolite were rapidly eliminated and therefore have a low potential to accumulate in man on repeated exposures. Based on these data, blood and/or urinary 3,5,6-TCP concentrations could be used to quantify the amount of chlorpyrifos absorbed under actual use conditions.
Acephate was incubated in distilled water of three different pH's at 37 degrees C for 7 days. Three hydrolytic products were formed: methamidophos, O,S-dimethyl phosphorothiolate (DMPT), and O-methylacetyl phosphoramidothiolate (OMPT). A single dose of acephate was also fed to mice, and their livers were excised and analyzed for metabolic products up to 30 hours. Three products were detected: methamidophos, DMPT, and S-methylacetyl phosphoramidothiolate (SMPT). The anticholinesterase properties of acephate, methamidophos, DMPT, SMPT, and OMPT were determined. Only acephate and methamidophos had measurable inhibitory effects on the mouse erythrocyte enzyme, methamidophos being about ten times more effective than acephate. The amount of methamidophos formed in the water and mouse liver was too low to have any direct effect on the toxicity of acephate. Acephate toxicity to aquatic insects would depend on its persistence in water, its uptake by the insects, its conversion to methamidophos, and the combined inhibitory effect of acephate and methamidophos on the cholinesterase enzyme. The toxicity of acephate to mammals would depend on the direct anticholinesterase effect of the chemical and to a small extent on methamidophos.
The risk to an individual worker from exposure to an organic solvent is more directly related to the uptake of the solvent
than its level in the atmosphere. Uptake varies from worker to worker, depending on exercise, respiratory fitness and the
amount of stored adipose tissue. Clearance and metabolism of a solvent also vary between individuals, being affected by genetic
and environmental factors. Uptake may be estimated by measuring the solvent or its metabolites in breath, blood or urine,
but any sampling strategy must be designed to exclude unnecessary variation introduced by different metabolic handling rates
occurring in individual workers.
An occupational study was conducted for a firm employing 22 pest control operators (PCOs) exposed to three organophosphorus insecticides. Measurements of 8-hour exposure levels were less than: 131.0 microgram/m3 for Vaponite; 41.0 microgram/m3 for Diazinon; and 27.6 microgram/m3 for Dursban. Twenty-four-hour urines analyzed for alkyl phosphates showed the presence of metabolites for these three pesticides. The effect of this exposure is reflected by a statistically significant inhibition of plasma acetylcholinesterase (AChE) among the PCOs as AChE values of either group. Although physical examinations detected no apparent toxic effects in the study group, biological sampling results indicated a need for personal protective equipment during the handling and application of these pesticides.
Chlorpyrifos is a member of the organophosphorus or organophosphate class of insecticides. This class has become one of the most widely used groups of pest control chemicals. In 1989 nearly 40% of the $6.2 billion global insecticide market was comprised of organophosphates (OPs) (Phillips and McDougall 1990). Although Clermont (1854) had first synthesized tetraethylpyrophosphate (TEPP), it was not until much later that the insecticidal properties of this OP were described (Schrader 1942). This milestone led to further synthetic work with insecticidal OPs and thus provided the impetus that would lead to the launch of an entirely new class of insecticides. Early OPs found to be efficacious for insect control and thus brought into widespread use included parathion (1944) and malathion (1952) (Matsumura 1985). These successes stimulated further discovery work on the part of synthetic chemists and entomologists within a number of research organizations.
This paper reviews the process of elimination of creatinine (CRE), and the limitations presented when using it to express urine concentrations. This literature review leads to three conclusions: (1) CRE excretion is subject to wide fluctuations due to specific internal and external factors; (2) the use of CRE to correct chemical concentrations in urine will not necessarily improve the correlation to the exposure dose for all chemicals (it may, in fact, worsen the result); and (3) other means of expressing urine concentration may offer greater accuracy towards estimating individually absorbed dose.
Diazinon is an organophosphorus insecticide which, through general use, comes into contact with human skin. To investigate its percutaneous absorption, human volunteers were exposed for 24 hr to 14C-labelled diazinon applied in acetone solution (2 micrograms/cm2) to the forearm or abdomen, or in lanolin wool grease (1.47 micrograms/cm2) to the abdomen. Complete void urine samples were collected daily for 7 days. Percutaneous absorption ranged from 2.87 +/- 1.16% (mean +/- SD, n = 6) to 3.85 +/- 2.16% of the applied dose, and there were no statistically significant differences with regard to site or vehicle of application. In rhesus monkeys, over the 7 days after iv dosing (2.1 microCi [14C]diazinon, 31.8 micrograms) a total of 55.8 +/- 6.8% (n = 4) of the dose was excreted in the urine, and 22.6 +/- 5.2% was eliminated in the faeces (78.4% total accountability). In in vitro percutaneous absorption studies with human abdominal skin, 14.1 +/- 9.2% of the applied dose accumulated in the receptor fluid over 24 hr of exposure to 0.25 microgram/cm2 (acetone vehicle). The calculated mass absorbed was the same (0.035 microgram/cm2) for both in vitro and in vivo absorption through human skin.
Xenobiotic residues and their metabolites in biological fluids of the general population are an important indicator of exposure to toxic substances dispersed in the environment. Urine samples collected from 124 subjects living in SW Tuscany, Italy were analyzed for alkylphosphates (dimethylphosphate, dimethylthiophosphate, dimethyldithiophosphate, diethylphosphate, diethylthiophosphate, diethyldithiophosphate), aspecific metabolites of organophosphorus insecticides. The compound most frequently found was dimethylthiophosphate which was detectable in 99% of the subjects analyzed, with a geometric mean of 70.7 nmol/g creatinine. The other substances were found in the following percentages of our population, at the following mean concentrations: dimethylphosphate, 87%, 62.8 nmol/g creat.; dimethyldithiophosphate, 48%, 21.1 nmol/g creat.; diethylphosphate, 81%, 27.4 nmol/g creat.; diethylthiophosphate, 73%, 22.8 nmol/g creat.; diethyldithiophosphate, 7%, 13.7 nmol/g creatinine. Subjects eating food (fruit, meat, vegetables) that was not their own produce showed higher urinary concentrations of nearly all the compounds. The other variables considered (sex, age, residence, alcohol, smoking, sampling period) seem to affect the percentages of positive values of the various substances but to different degrees. Age and source of foods were the most important variables for dimethylthiophosphate excretion when mean values were analyzed by Student's t-test and analysis of variance (ANOVA).
Children up to 6 years of age who lived with pesticide applicators were monitored for increased risk of pesticide exposure: 48 pesticide applicator and 14 reference families were recruited from an agricultural region of Washington State in June 1995. A total of 160 spot urine samples were collected from 88 children, including repeated measures 3-7 days apart. Samples were assayed by gas chromatography flame photometric detector for dimethylphosphate metabolites. Dimethylthiophosphate (DMTP) was the dominant metabolite. DMTP levels were significantly higher in applicator children than in reference children (p = 0.015), with median concentrations of 0.021 and 0.005 microg/ml, respectively; maximum concentrations were 0.44 and 0.10 microg/ml, respectively. Percentages of detectable samples were 47% for applicator children and 27% for reference children. A marginally significant trend of increasing concentration was observed with decreasing age among applicator children (p = 0.060), and younger children within these families had significantly higher concentrations when compared to their older siblings (p = 0.040). Applicator children living less than 200 feet from an orchard were associated with higher frequency of detectable DMTP levels than nonproximal applicator children (p =0.036). These results indicate that applicator children experienced higher organophosphorus pesticide exposures than did reference children in the same community and that proximity to spraying is an important contributor to such exposures. Trends related to age suggest that child activity is an important variable for exposure. It is unlikely that any of the observed exposures posed a hazard of acute intoxication. This study points to the need for a more detailed understanding of pesticide exposure pathways for children of agricultural workers.
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