Magnitude of behavioral deficits varies with job-related chlorpyrifos exposure levels among Egyptian pesticide workers.

Chronic occupational exposure to organophosphorus pesticides (OPs) is consistently associated with deficits on behavioral tests when compared to unexposed comparison groups. However, a dose-response relationship has yet to be established, leading some to doubt an association between occupational OP exposure and behavioral deficits. Pesticide application teams in Egypt who are primarily exposed to one OP, chlorpyrifos (CPF), were recruited into a field assessment. Trail Making A and the more challenging Trail Making B tests were administered to 54 engineers (who supervise the pesticide application process, usually from the side of the field), 59 technicians (who guide the pesticide applicators in the field), 31 applicators (who mix and apply pesticides using knapsack sprayers), and 150 controls (who did not work in the fields) at two different times during the OP application season as well as immediately after applications had ended and 1.5 months later. All participants were males since only males work on pesticide application teams in Egypt. Urinary levels of 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of CPF, confirmed the pattern of lower to higher CPF exposures from engineers to technicians to applicators, and these were all greater than urinary metabolite levels in controls. A consistent relationship between job title and performance speed on the behavioral task was observed: Controls had the best (fastest) performance on Trail Making A and B tests throughout the application season, and applicators had significantly slower performance than engineers on Trail Making A (p = 0.015) and B (p = 0.003). However, individual urinary TCPy, blood acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) levels did not predict individual performance. This study identifies a dose-related effect based on job title, which serves as a surrogate for chronic exposure in that differing job titles exhibit varying group exposure levels. The results establish that chronic occupational exposure to chlorpyrifos is neurotoxic and suggest that the classic biomarkers of recent CPF exposure are not predictive of chronic exposure effects

Metabolism of profenofos to 4-bromo-2-chlorophenol, a specific and sensitive exposure biomarker.

Profenofos is a direct acting phosphorothioate organophosphorus (OP) pesticide capable of inhibiting β-esterases such as acetylcholinesterase, butyrylcholinesterase, and carboxylesterase. Profenofos is known to be detoxified to the biologically inactive metabolite, 4-bromo-2-chlorophenol (BCP); however, limited data are available regarding the use of urinary BCP as an exposure biomarker in humans. A pilot study conducted in Egyptian agriculture workers, demonstrated that urinary BCP levels prior to application (3.3-30.0 μg/g creatinine) were elevated to 34.5-3,566 μg/g creatinine during the time workers were applying profenofos to cotton fields. Subsequently, the in vitro enzymatic formation of BCP was examined using pooled human liver microsomes and recombinant human cytochrome P-450s (CYPs) incubated with profenofos. Of the nine human CYPs studied, only CYPs 3A4, 2B6, and 2C19 were able to metabolize profenofos to BCP. Kinetic studies indicated that CYP 2C19 has the lowest Km, 0.516 μM followed by 2B6 (Km=1.02 μM) and 3A4 (Km=18.9μM). The Vmax for BCP formation was 47.9, 25.1, and 19.2 nmol/min/nmol CYP for CYP2B6, 2C19, and 3A4, respectively. Intrinsic clearance (Vmax/Km) values of 48.8, 46.9, and 1.02 ml/min/nmol CYP 2C19, 2B6, and 3A4, respectively, indicate that CYP2C19 and CYP2B6 are primarily responsible for the detoxification of profenofos. These findings support the use of urinary BCP as a biomarker of exposure to profenofos in humans and suggest polymorphisms in CYP 2C19 and CYP 2B6 as potential biomarkers of susceptibility

Primary healthcare policy implementation in the Eastern Mediterranean region: Experiences of six countries

Background: Primary healthcare (PHC) is essential for equitable access and cost-effective healthcare. This makes PHC a key factor in the global strategy for universal health coverage (UHC). Implementing PHC requires an understanding of the health system under prevailing circumstances, but for most countries, no data are available. Objectives: This paper describes and analyses the health systems of Bahrain, Egypt, Lebanon, Qatar, Sudan and the United Arab Emirates, in relation to PHC. Methods: Data were collected during a workshop at the WONCA East Mediterranean Regional Conference in 2017. Academic family physicians (FP) presented their country, using the WONCA framework of 11 PowerPoint slides with queries of the country demographics, main health challenges, and the position of PHC in the health system. Results: All six countries have improved the health of their populations, but currently face challenges of non-communicable diseases, aging populations and increasing costs. Main concerns were a lack of trained FPs in community settings, underuse of prevention and of equitable access to care. Countries differed in the extent to which this had resulted in coherent policy. Conclusion: Priorities were (i) advocacy for community-based PHC to policymakers, including the importance of coordination of healthcare at the community level, and UHC to respond to the needs of populations; (ii) collaboration with universities to include PHC as a core component of every medical curriculum; (iii) collaboration with communities to improve public understanding of PHC; (iv) engagement with the private sector to focus on PHC and UHC

Characterization of α-cypermethrin exposure in Egyptian agricultural workers.

Pyrethroids are neurotoxic insecticides that exert their effects by prolonging the open time of sodium channels, which increases the duration of neuronal excitation. α-cypermethrin (αCM) is derived from the 8-stereoisomers that together make up the pyrethroid cypermethrin, which is one of the most common pyrethroids being used in agriculture throughout the world. The objective of this study was to characterize the occupational exposure to αCM in a cohort of Egyptian agriculture workers (n=37) before, during and after 6-10 consecutive days of application of αCM to cotton fields. Daily spot urine specimens were collected and analyzed by GC-MS NCI for the αCM metabolites 3-phenoxybenzoic acid (3-PBA) and cis-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DCCA). Prior to αCM application, median urinary levels of 3-PBA (4.59nmol/g creatinine) were greater than cis-DCCA (0.33nmole/g creatinine) demonstrating low background exposures to pyrethroids. During the application period for αCM, median urinary levels of both biomarkers increased (13.44nmol 3-PBA/g creatinine and 7.76nmol cis-DCCA/g creatinine) and ranged from 2.3-93.96nmol 3-PBA/g creatinine and 0.09-90.94nmol cis-DCCA/g creatinine, demonstrating that workers had a wide range of exposures to αCM. The data also demonstrate that pesticide applicators had greater exposures to αCM than workers who play a supporting role in the seasonal application of pesticides on the cotton crop. Urinary cis-DCCA and 3-PBA concentrations were elevated at 7-11 days after the cessation of αCM application, compared to baseline levels. This study is the first to use these biomarkers to quantify occupational exposures specifically to αCM. This urinary biomarker data will be useful for estimating daily internal dose, comparing exposures across job categories within the Egyptian pesticide application teams, and for modeling human exposures to αCM

Magnitude of behavioral deficits varies with job-related chlorpyrifos exposure levels among Egyptian pesticide workers.

Chronic occupational exposure to organophosphorus pesticides (OPs) is consistently associated with deficits on behavioral tests when compared to unexposed comparison groups. However, a dose-response relationship has yet to be established, leading some to doubt an association between occupational OP exposure and behavioral deficits. Pesticide application teams in Egypt who are primarily exposed to one OP, chlorpyrifos (CPF), were recruited into a field assessment. Trail Making A and the more challenging Trail Making B tests were administered to 54 engineers (who supervise the pesticide application process, usually from the side of the field), 59 technicians (who guide the pesticide applicators in the field), 31 applicators (who mix and apply pesticides using knapsack sprayers), and 150 controls (who did not work in the fields) at two different times during the OP application season as well as immediately after applications had ended and 1.5 months later. All participants were males since only males work on pesticide application teams in Egypt. Urinary levels of 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of CPF, confirmed the pattern of lower to higher CPF exposures from engineers to technicians to applicators, and these were all greater than urinary metabolite levels in controls. A consistent relationship between job title and performance speed on the behavioral task was observed: Controls had the best (fastest) performance on Trail Making A and B tests throughout the application season, and applicators had significantly slower performance than engineers on Trail Making A (p = 0.015) and B (p = 0.003). However, individual urinary TCPy, blood acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) levels did not predict individual performance. This study identifies a dose-related effect based on job title, which serves as a surrogate for chronic exposure in that differing job titles exhibit varying group exposure levels. The results establish that chronic occupational exposure to chlorpyrifos is neurotoxic and suggest that the classic biomarkers of recent CPF exposure are not predictive of chronic exposure effects

Metabolism of profenofos to 4-bromo-2-chlorophenol, a specific and sensitive exposure biomarker.

Profenofos is a direct acting phosphorothioate organophosphorus (OP) pesticide capable of inhibiting β-esterases such as acetylcholinesterase, butyrylcholinesterase, and carboxylesterase. Profenofos is known to be detoxified to the biologically inactive metabolite, 4-bromo-2-chlorophenol (BCP); however, limited data are available regarding the use of urinary BCP as an exposure biomarker in humans. A pilot study conducted in Egyptian agriculture workers, demonstrated that urinary BCP levels prior to application (3.3-30.0 μg/g creatinine) were elevated to 34.5-3,566 μg/g creatinine during the time workers were applying profenofos to cotton fields. Subsequently, the in vitro enzymatic formation of BCP was examined using pooled human liver microsomes and recombinant human cytochrome P-450s (CYPs) incubated with profenofos. Of the nine human CYPs studied, only CYPs 3A4, 2B6, and 2C19 were able to metabolize profenofos to BCP. Kinetic studies indicated that CYP 2C19 has the lowest Km, 0.516 μM followed by 2B6 (Km=1.02 μM) and 3A4 (Km=18.9μM). The Vmax for BCP formation was 47.9, 25.1, and 19.2 nmol/min/nmol CYP for CYP2B6, 2C19, and 3A4, respectively. Intrinsic clearance (Vmax/Km) values of 48.8, 46.9, and 1.02 ml/min/nmol CYP 2C19, 2B6, and 3A4, respectively, indicate that CYP2C19 and CYP2B6 are primarily responsible for the detoxification of profenofos. These findings support the use of urinary BCP as a biomarker of exposure to profenofos in humans and suggest polymorphisms in CYP 2C19 and CYP 2B6 as potential biomarkers of susceptibility

Experimental strategy for translational studies of organophosphorus pesticide neurotoxicity based on real-world occupational exposures to chlorpyrifos.

Translational research is needed to understand and predict the neurotoxic consequences associated with repeated occupational exposures to organophosphorus pesticides (OPs). In this report, we describe a research strategy for identifying biomarkers of OP neurotoxicity, and we characterize pesticide application workers in Egypt's Menoufia Governorate who serve as our anchor human population for developing a parallel animal model with similar exposures and behavioral deficits and for examining the influence of human polymorphisms in cytochrome P450 (CYP) and paraoxonase 1 (PON1) enzymes on OP metabolism and toxicity. This population has previously been shown to have high occupational exposures and to exhibit a broad range of neurobehavioral deficits. In addition to observational studies of work practices in the field, questionnaires on demographics, lifestyle and work practices were administered to 146 Egyptian pesticide application workers applying pesticides to the cotton crop. Survey results indicated that the application workforce uses standard operating procedures and standardized equipment provided by Egypt's Ministry of Agriculture, which provides a workforce with a stable work history. We also found that few workers report using personal protective equipment (PPE), which likely contributes to the relatively high exposures reported in these application workers. In summary, this population provides a unique opportunity for identifying biomarkers of OP-induced neurotoxicity associated with occupational exposure

Longitudinal assessment of occupational exposures to the organophosphorous insecticides chlorpyrifos and profenofos in Egyptian cotton field workers.

Chlorpyrifos (CPF) and profenofos (PFF) are organophosphorus (OP) insecticides that are applied seasonally in Egypt to cotton fields. Urinary trichloro-2-pyridinol (TCPy), a specific CPF metabolite, and 4-bromo-2-chlorophenol (BCP), a specific PFF metabolite, are biomarkers of exposure, while inhibition of blood butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) activities are effect biomarkers that may be associated with neurotoxicity. Urinary TCPy and BCP and blood BChE and AChE activities were measured in 37 adult Egyptian Ministry of Agriculture workers during and after 9-17 consecutive days of CPF application followed by an application of PFF (9-11 days), and a second CPF application (5 days) in 2008. During the OP applications, urinary TCPy and BCP levels were significantly higher than baseline levels, remained elevated following the application periods, and were associated with an exposure related inhibition of blood BChE and AChE. Analysis of blood AChE levels before and after the PFF application period suggests that individual workers with peak BCP levels greater than 1000 μg/g creatinine exhibited further inhibition of blood AChE with PFF application, demonstrating that PFF exposure had a negative impact on AChE activity in this highly exposed worker population. While large interindividual differences in exposure were observed throughout this longitudinal study (peak urinary BCP and peak TCPy levels for individuals ranging from 13.4 to 8052 and 16.4 to 30,107 μg/g creatinine, respectively), these urinary biomarkers were highly correlated within workers (r=0.75, p<0.001). This suggests that the relative exposures to CPF and PFF were highly correlated for a given worker. The variable exposures between job classification and work site suggest that job title and work location should not be used as the sole basis for categorizing OP exposures when assessing neurobehavioral and other health outcomes in Egyptian cotton field workers. Together, these findings will be important in educating the Egyptian insecticide application workers in order to encourage the development and implementation of work practices and personal protective equipment to reduce their exposure to CPF and PFF