RESUMO
Sunscreen products are composed of ultraviolet (UV) filters and formulated to reduce exposure to sunlight thereby lessening skin damage. Concerns have been raised regarding the toxicity and potential endocrine disrupting (ED) effects of UV filters. The ToxCast/Tox21 program, that is, CompTox, is a high-throughput in vitro screening database of chemicals that identify adverse outcome pathways, key events, and ED potential of chemicals. Using the ToxCast/Tox21 database, octisalate, homosalate, octocrylene, oxybenzone, octinoxate, and avobenzone, 6 commonly used organic UV filters, were found to have been evaluated. These UV filters showed low potency in these bioassays with most activity detected above the range of the cytotoxic burst. The pathways that were most affected were the cell cycle and the nuclear receptor pathways. Most activity was observed in liver and kidney-based bioassays. These organic filters and their metabolites showed relatively weak ED activity when tested in bioassays measuring estrogen receptor (ER), androgen receptor (AR), thyroid receptor, and steroidogenesis activity. Except for oxybenzone, all activity in the endocrine assays occurred at concentrations greater than the cytotoxic burst. Moreover, except for oxybenzone, plasma concentrations (Cmax) measured in humans were at least 100× lower than bioactive (AC50/ACC) concentrations that produced a response in ToxCast/Tox21 assays. These data are consistent with in vivo animal/human studies showing weak or negligible endocrine activity. In sum, when considered as part of a weight-of-evidence assessment and compared with measured plasma concentrations, the results show these organic UV filters have low intrinsic biological activity and risk of toxicity including endocrine disruption in humans.
Assuntos
Benzofenonas , Protetores Solares , Animais , Humanos , Protetores Solares/toxicidade , Benzofenonas/toxicidade , Receptores de EstrogênioRESUMO
Fatty esters of 2-ethylhexanoic acid (EHA) and 2-ethylhexanol (EH) are commonly used in cosmetics. Human liver and skin S9 and human plasma were used to determine the in vitro rates of clearance (CLint) of a series of compounds, with a range of 2-11 carbons on the acid or alcohol moiety and branching at the C2 position. The impact of carbon chain length on in vitro CLint was most prominent for the liver metabolism of esters of EH, while for in vitro skin metabolism it was greater for esters of EHA. The position of the branching also impacted the liver hydrolysis rates, especially for the C3, C4, and C5 esters with lower CLint in vitro rates for esters of EHA relative to those of EH. When the in vitro intrinsic clearance rates were scaled to in vivo rates of hepatic clearance, all compounds approximated the rate for hepatic blood flow, mitigating this dependence of metabolism on structure. This work shows how structural changes to the molecule can affect in vitro metabolism and, furthermore, allows for an estimation of the in vivo metabolism.
Assuntos
Ésteres , Fígado , Humanos , Hidrólise , Taxa de Depuração Metabólica , Fígado/metabolismoRESUMO
We present a case study that provides a practical step-by-step example of how the internal Threshold of Toxicological Concern (iTTC) can be used as a tool to refine a TTC-based assessment for dermal exposures to consumer products. The case study uses a theoretical scenario where there are no systemic toxicity data for the case study chemicals (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, octinoxate, and ecamsule). Human dermal pharmacokinetic data following single and repeat dermal exposure to products containing the case study chemicals were obtained from data published by the US FDA. The clinical studies utilized an application procedure that followed maximal use conditions (product applied as 2 mg/cm2 to 75% of the body surface area, 4 times a day). The case study chemicals were first reviewed to determine if they were in the applicability domain of the iTTC, and then, the human plasma concentrations were compared to an iTTC limit of 1 µM. When assessed under maximum usage, the external exposure of all chemicals exceeded the external dose TTC limits. By contrast, the internal exposure to all chemicals, except oxybenzone, was an order of magnitude lower than the 1 µM interim iTTC threshold. This work highlights the importance of understanding internal exposure relative to external dose and how the iTTC can be a valuable tool for assessing low-level internal exposures; additionally, the work demonstrates how to use an iTTC, and highlights considerations and refinement opportunities for the approach.
Assuntos
Benzofenonas , Humanos , Medição de RiscoRESUMO
A standard protocol was used to determine partition (K) and diffusion (D) coefficients in dermatomed human skin and isolated human skin layers for 50 compounds relevant to cosmetics ingredients. K values were measured in dermatomed skin, isolated dermis, whole epidermis, intact stratum corneum (SC), delipidized SC and SC lipids by direct measurements of the radioactivity in the tissue layers/lipid component vs. buffer samples. D determinations were made in dermatomed skin, isolated dermis, whole epidermis and intact SC using a non-linear regression of the cumulative receptor fluid content of radiolabeled compound, fit to the solution of Fick's 2nd Law. Correlation analysis was completed between K, D, and physicochemical properties. The amount of interindividual (donor) and intraindividual (replicate) variability in the K and D data was characterized for each skin layer and chemical. These data can be further used to help inform the factors that influence skin bioavailability and to help improve in silico models of dermal penetration.
Assuntos
Cosméticos/química , Cosméticos/metabolismo , Medição de Risco/métodos , Absorção Cutânea , Pele/metabolismo , Adulto , Idoso , Difusão , Feminino , Humanos , Técnicas In Vitro , Lipídeos/química , Pessoa de Meia-Idade , Permeabilidade , Soroalbumina BovinaRESUMO
This work provides case studies for the pharmacokinetic (PK) analog approach, where a physiologically based pharmacokinetic (PBPK) model for a target chemical (has no PK data) is evaluated using PK data from a source chemical (has existing PK data). A bottom up PBPK modeling approach (using in vitro and in silico inputs) is used to develop human oral PBPK models for caffeine and diphenhydramine. Models are evaluated using in vivo data from structural and functional PK analogs. At the end of the case studies, in vivo PK data for caffeine and diphenhydramine is introduced and both models were able to simulate plasma concentrations which agreed with the in vivo PK data. To further demonstrate that structural analogs can serve as PK analogs, in vitro metabolism and plasma protein binding was compared for a subset of structurally similar ToxCast chemicals and shown to be similar. Next steps for the PK analog approach should focus on evaluating this concept for a broader set of compounds. Using PK analogs for evaluating and establishing confidence in a PBPK model will ensure that PBPK modeling remains a viable option in animal alternative safety assessments.
Assuntos
Cafeína/farmacocinética , Difenidramina/farmacocinética , Modelos Biológicos , Alternativas aos Testes com Animais , Animais , Cafeína/química , Difenidramina/química , Humanos , Estrutura MolecularRESUMO
The Threshold of Toxicological Concern (TTC) is a risk assessment tool for evaluating low-level exposure to chemicals with limited toxicological data. A next step in the ongoing development of TTC is to extend this concept further so that it can be applied to internal exposures. This refinement of TTC based on plasma concentrations, referred to as internal TTC (iTTC), attempts to convert the chemical-specific external NOAELs (in mg/kg/day) in the TTC database to an estimated internal exposure. A multi-stakeholder collaboration formed, with the aim of establishing an iTTC suitable for human safety risk assessment. Here, we discuss the advances and future directions for the iTTC project, including: (1) results from the systematic literature search for metabolism and pharmacokinetic data for the 1,251 chemicals in the iTTC database; (2) selection of ~350 chemicals that will be included in the final iTTC; (3) an overview of the in vitro caco-2 and in vitro hepatic metabolism studies currently being generated for the iTTC chemicals; (4) demonstrate how PBPK modeling is being utilized to convert a chemical-specific external NOAEL to an internal exposure; (5) perspective on the next steps in the iTTC project.
RESUMO
The Threshold of Toxicological Concern (TTC) is an important risk assessment tool which establishes acceptable low-level exposure values to be applied to chemicals with limited toxicological data. One of the logical next steps in the continued evolution of TTC is to develop this concept further so that it is representative of internal exposures (TTC based on plasma concentration). An internal TTC (iTTC) would provide threshold values that could be utilized in exposure-based safety assessments. As part of a Cosmetics Europe (CosEu) research program, CosEu has initiated a project that is working towards the development of iTTCs that can be used for the human safety assessment. Knowing that the development of an iTTC is an ambitious and broad-spanning topic, CosEu organized a Working Group comprised a balance of multiple stakeholders (cosmetics and chemical industries, the EPA and JRC and academia) with relevant experience and expertise and workshop to critically evaluate the requirements to establish an iTTC. Outcomes from the workshop included an evaluation on the current state of the science for iTTC, the overall iTTC strategy, selection of chemical databases, capture and curation of chemical information, ADME and repeat dose data, expected challenges, as well as next steps and ongoing work.
Assuntos
Cosméticos/toxicidade , Animais , Cosméticos/efeitos adversos , Cosméticos/metabolismo , Europa (Continente) , Humanos , Medição de RiscoRESUMO
Physiologically based pharmacokinetic (PBPK) models enable simulations of absorption, distribution, metabolism, and elimination of chemicals from the body. Model evaluation is a key step in the PBPK model development processes whereby model predictions are compared to pharmacokinetic (PK) data. A prerequisite for PBPK model evaluation has always been the availability of PK data for the modeled compound, a requirement which has limited the use and acceptance of PBPK models since PK data is often limited or not available. The current work tests the hypothesis that an adequately developed PBPK model for a target chemical (chemical with no PK data) can be evaluated using PK data from a source chemical (chemical with existing PK data). Two different approaches for identifying the source chemical, a structural PK analog and functional PK analog technique, are used to evaluate a series of oral human PBPK models. Results show that both analog approaches can identify PK analogs which display similar PK as the target chemical and can be used as alternative ways for evaluating PBPK models. As animal free safety assessment strategies continue to develop, it's important to develop alternative approaches for PBPK model evaluation which does not rely on generating new PK data.
Assuntos
Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Animais , Humanos , Modelos Biológicos , Farmacocinética , Medição de Risco , Relação Estrutura-AtividadeRESUMO
Profenofos is a direct acting phosphorothioate organophosphorus (OP) pesticide capable of inhibiting ß-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.
Assuntos
Clorofenóis/farmacocinética , Inseticidas/farmacocinética , Organotiofosfatos/farmacocinética , Agricultura , Biomarcadores/urina , Clorofenóis/urina , Sistema Enzimático do Citocromo P-450/metabolismo , Egito , Humanos , Inativação Metabólica , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Exposição Ocupacional/análise , Projetos PilotoRESUMO
Animal studies have shown that paraoxonase 1 (PON1) genotype can influence susceptibility to the organophosphorus pesticide chlorpyrifos (CPF). However, Monte Carlo analysis suggests that PON1 genotype may not affect CPF-related toxicity at low exposure conditions in humans. The current study sought to determine the influence of PON1 genotype on the activity of blood cholinesterase as well as the effect of CPF exposure on serum PON1 in workers occupationally exposed to CPF. Saliva, blood and urine were collected from agricultural workers (n=120) from Egypt's Menoufia Governorate to determine PON1 genotype, blood cholinesterase activity, serum PON1 activity towards chlorpyrifos-oxon (CPOase) and paraoxon (POase), and urinary levels of the CPF metabolite 3,5,6-trichloro-2-pyridinol (TCPy). The PON1 55 (P≤0.05) but not the PON1 192 genotype had a significant effect on CPOase activity. However, both the PON1 55 (P≤0.05) and PON1 192 (P≤0.001) genotypes had a significant effect on POase activity. Workers had significantly inhibited AChE and BuChE after CPF application; however, neither CPOase activity nor POase activity was associated with ChE depression when adjusted for CPF exposure (as determined by urinary TCPy levels) and stratified by PON1 genotype. CPOase and POase activity were also generally unaffected by CPF exposure although there were alterations in activity within specific genotype groups. Together, these results suggest that workers retained the capacity to detoxify chlorpyrifos-oxon under the exposure conditions experienced by this study population regardless of PON1 genotype and activity and that effects of CPF exposure on PON1 activity are minimal.
Assuntos
Acetilcolinesterase/metabolismo , Doenças dos Trabalhadores Agrícolas/induzido quimicamente , Arildialquilfosfatase/metabolismo , Butirilcolinesterase/metabolismo , Clorpirifos , Inibidores da Colinesterase/intoxicação , Intoxicação por Organofosfatos/metabolismo , Acetilcolinesterase/sangue , Doenças dos Trabalhadores Agrícolas/enzimologia , Doenças dos Trabalhadores Agrícolas/genética , Doenças dos Trabalhadores Agrícolas/metabolismo , Agricultura , Arildialquilfosfatase/genética , Butirilcolinesterase/sangue , DNA/química , DNA/genética , Egito , Genótipo , Humanos , Modelos Lineares , Desequilíbrio de Ligação , Intoxicação por Organofosfatos/enzimologia , Intoxicação por Organofosfatos/etiologia , Intoxicação por Organofosfatos/genética , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Piridonas/metabolismo , Piridonas/urinaRESUMO
Genetic variability in cytochrome P-450 (CYP) has the potential to modify pharmacological and toxicological responses to many chemicals. Both CYP2B6 and CYP2C19 are pharmacologically and toxicologically relevant due to their ability to metabolize multiple drugs and environmental contaminants, including the organophosphorus (OP) pesticide chlorpyrifos. The aim of this study was to determine the prevalence of CYP2B6 and CYP2C19 variants in an indigenous Egyptian population (n = 120) that was shown to be occupationally exposed to chlorpyrifos. Further, the genotyping data was compared for Egyptians with previously studied populations to determine between population differences. Allelic frequencies were CYP2B6 1459C > T (3.8%), CYP2B6 785A > G (30.4%), CYP2B6 516G > T (28.8%), CYP2C19 681G > A (3.8%), and CYP2C19 431G > A (0%). The most prevalent CYP2B6 genotype combinations were CYP2B6 *1/*1 (44%), *1/*6 (38%), *6/*6 (8%), and *1/*5 (6%). The frequency of the CYP2C19 genotype combinations were CYP2C19 *1/*1 (93%), *1/*2 (6%), and *2/*2 (1%). The frequency of the CYP2B6 516G > T and CYP2B6 785A > G polymorphisms in this Egyptian cohort is similar to that found North American and European populations but significantly different from that reported for West African populations, while that of CYP2B6 1459C > T is similar to that found in Africans and African Americans. The observed frequency of CYP2C19 681G > A in Egyptians is similar to that of African pygmies but significantly different from other world populations, while CYP2C19 431 G > A was significantly different from that of African pygmies but similar to other world populations.
Assuntos
Agricultura , Hidrocarboneto de Aril Hidroxilases/genética , Frequência do Gene , Oxirredutases N-Desmetilantes/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Clorpirifos , Estudos de Coortes , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP2C19 , Egito , Marcadores Genéticos , Genótipo , Humanos , Inseticidas , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Exposição Ocupacional , Saliva/química , Adulto JovemRESUMO
Organophosphorus pesticides (OPs) are a public health concern due to their worldwide use and documented human exposures. Phosphorothioate OPs are metabolized by cytochrome P450s (P450s) through either a dearylation reaction to form an inactive metabolite, or through a desulfuration reaction to form an active oxon metabolite, which is a potent cholinesterase inhibitor. This study investigated the rate of desulfuration (activation) and dearylation (detoxification) of methyl parathion and diazinon in human liver microsomes. In addition, recombinant human P450s were used to determine the P450-specific kinetic parameters (K(m) and V(max)) for each compound for future use in refining human physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models of OP exposure. The primary enzymes involved in bioactivation of methyl parathion were CYP2B6 (K(m) = 1.25 µM; V(max) = 9.78 nmol · min(-1) · nmol P450(-1)), CYP2C19 (K(m) = 1.03 µM; V(max) = 4.67 nmol · min(-1) · nmol P450(-1)), and CYP1A2 (K(m) = 1.96 µM; V(max) = 5.14 nmol · min(-1) · nmol P450(-1)), and the bioactivation of diazinon was mediated primarily by CYP1A1 (K(m) = 3.05 µM; V(max) = 2.35 nmol · min(-1) · nmol P450(-1)), CYP2C19 (K(m) = 7.74 µM; V(max) = 4.14 nmol · min(-1) · nmol P450(-1)), and CYP2B6 (K(m) = 14.83 µM; V(max) = 5.44 nmol · min(-1) · nmol P450(-1)). P450-mediated detoxification of methyl parathion only occurred to a limited extent with CYP1A2 (K(m) = 16.8 µM; V(max) = 1.38 nmol · min(-1) · nmol P450(-1)) and 3A4 (K(m) = 104 µM; V(max) = 5.15 nmol · min(-1) · nmol P450(-1)), whereas the major enzyme involved in diazinon detoxification was CYP2C19 (K(m) = 5.04 µM; V(max) = 5.58 nmol · min(-1) · nmol P450(-1)). The OP- and P450-specific kinetic values will be helpful for future use in refining human PBPK/PD models of OP exposure.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Diazinon/metabolismo , Metil Paration/metabolismo , Microssomos Hepáticos/metabolismo , Praguicidas/metabolismo , Ativação Enzimática/fisiologia , Humanos , Microssomos Hepáticos/enzimologia , Compostos Organofosforados/metabolismoRESUMO
Chlorpyrifos (CPF) is a commonly used organophosphorus pesticide. Several pharmacokinetic and pharmacodynamic studies have been conducted in rats in which CPF was administered as a single bolus dose. However, there is limited data regarding the pharmacokinetics and pharmacodynamics following daily exposure. Since occupational exposures often consist of repeated, daily exposures, there is a need to evaluate the pharmacokinetics and pharmacodynamics of CPF under exposure conditions which more accurately reflect real world human exposures. In this study, the pharmacokinetics and pharmacodynamics of CPF were assessed in male Long-Evans rats exposed daily to CPF (0, 3 or 10mg/kg/day, s.c. in peanut oil) over a 10 day study period. Throughout the study, multiple pharmacokinetic (urinary TCPy levels and tissue CPF and metabolite levels) and pharmacodynamic (blood and brain AChE activity) determinants were measured. Average blood AChE activity on day 10 was 54% and 33% of baseline among animals in the 3 and 10mg/kg/day CPF treatment groups, respectively, while average brain AChE activity was 67% and 28% of baseline. Comparable dose-response relationships between brain AChE inhibition and blood AChE inhibition, suggests that blood AChE activity is a valid biomarker of brain AChE activity. The pharmacokinetic and pharmacodynamic measures collected in this study were also used to optimize a rat physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model for multiple s.c. exposures to CPF based on a previously published rat PBPK/PD model for CPF following a single bolus injection. This optimized model will be useful for determining pharmacokinetic and pharmacodynamic responses over a wide range of doses and durations of exposure, which will improve extrapolation of results between rats and humans.
Assuntos
Clorpirifos/farmacocinética , Inseticidas/farmacocinética , Acetilcolinesterase/metabolismo , Animais , Encéfalo/enzimologia , Clorpirifos/administração & dosagem , Clorpirifos/farmacologia , Injeções Subcutâneas , Fígado/metabolismo , Masculino , Modelos Biológicos , Ratos , Ratos Long-EvansRESUMO
Organophosphorus pesticides (OPs) remain a potential concern to human health because of their continuing use worldwide. Phosphororthioate OPs like chlorpyrifos and parathion are directly activated and detoxified by various cytochrome P450s (CYPs), with the primary CYPs involved being CYP2B6 and CYP2C19. The goal of the current study was to convert a previously reported human pharmacokinetic and pharmacodynamic (PBPK/PD) model for chlorpyrifos, that used chlorpyrifos metabolism parameters from rat liver, into a human CYP based/age-specific model using recombinant human CYP kinetic parameters (V(max), K(m)), hepatic CYP content and plasma binding measurements to estimate new values for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition and to use the model as a template for the development of a comparable parathion PBPK/PD model. The human CYP based/age-specific PBPK/PD models were used to simulate single oral exposures of adults (19 year old) and infants (1 year) to chlorpyrifos (10,000, 1000 and 100 µg/kg) or parathion (100, 25 and 5 µg/kg). Model simulations showed that there is an age dependency in the amount of blood cholinesterase inhibition observed, however additional age-dependent data are needed to further optimize age-specific human PBPK/PD modeling for these OP compounds. PBPK/PD model simulations estimated that a 4-fold increase or decrease in relative CYP2B6 and CYP2C19 content would produce a 9-22% inhibition in blood AChE activity following exposure of an adult to chlorpyrifos (1000 µg/kg). Similar model simulation produced an 18-22% inhibition in blood AChE activity following exposure of an adult to parathion (25 µg/kg). Individuals with greater CYP2B6 content and lower CYP2C19 content were predicted to be most sensitive to both OPs. Changes in hepatic CYP2B6 and CYP2C19 content had more of an influence on cholinesterase inhibition for exposures to chlorpyrifos than parathion, which agrees with previously reported literature that these CYPs are more reaction biased for desulfurization (activation) and dearylation (detoxification) of chlorpyrifos compared to parathion. The data presented here illustrate how PBPK/PD models with human enzyme-specific parameters can assist ongoing risk assessment efforts and aid in the identification of sensitive individuals and populations.
Assuntos
Clorpirifos/farmacocinética , Inibidores da Colinesterase/farmacocinética , Inseticidas/farmacocinética , Modelos Biológicos , Paration/farmacocinética , Fatores Etários , Animais , Hidrocarboneto de Aril Hidroxilases/metabolismo , Clorpirifos/administração & dosagem , Clorpirifos/toxicidade , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/toxicidade , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP2C19 , Relação Dose-Resposta a Droga , Humanos , Lactente , Inseticidas/administração & dosagem , Inseticidas/toxicidade , Fígado/enzimologia , Fígado/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Paration/administração & dosagem , Paration/toxicidade , Ratos , Especificidade da Espécie , Adulto JovemRESUMO
BACKGROUND: Chlorpyrifos (CPF), a widely used organophosphorus pesticide (OP), is metabolized to CPF-oxon, a potent cholinesterase (ChE) inhibitor, and trichloro-2-pyridinol (TCPy). Urinary TCPy is often used as a biomarker for CPF exposure, whereas blood ChE activity is considered an indicator of CPF toxicity. However, whether these biomarkers are dose related has not been studied extensively in populations with repeated daily OP exposures. OBJECTIVE: We sought to determine the relationship between blood ChE and urinary TCPy during repeated occupational exposures to CPF. METHODS: Daily urine samples and weekly blood samples were collected from pesticide workers (n=38) in Menoufia Governorate, Egypt, before, during, and after 9-17 consecutive days of CPF application to cotton fields. We compared blood butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) activities with the respective urinary TCPy concentrations in each worker. RESULTS: Average TCPy levels during the middle of a 1- to 2-week CPF application period were significantly higher in pesticide applicators (6,437 µg/g creatinine) than in technicians (184 µg/g) and engineers (157 µg/g), both of whom are involved in supervising the application process. We observed a statistically significant inverse correlation between urinary TCPy and blood BuChE and AChE activities. The no-effect level (or inflection point) of the exposure-effect relationships has an average urinary TCPy level of 114 µg/g creatinine for BuChE and 3,161 µg/g creatinine for AChE. CONCLUSIONS: Our findings demonstrate a dose-effect relationship between urinary TCPy and both plasma BuChE and red blood cell AChE in humans exposed occupationally to CPF. These findings will contribute to future risk assessment efforts for CPF exposure.
Assuntos
Agricultura , Biomarcadores/sangue , Biomarcadores/urina , Clorpirifos/toxicidade , Inseticidas/toxicidade , Exposição Ocupacional , Acetilcolinesterase/sangue , Adulto , Butirilcolinesterase/sangue , Clorpirifos/análogos & derivados , Clorpirifos/metabolismo , Relação Dose-Resposta a Droga , Egito , Gossypium , Humanos , Inseticidas/metabolismo , Piridonas/metabolismo , Piridonas/urina , Medição de Risco , Adulto JovemRESUMO
BACKGROUND: Two year cancer bioassays conducted by the National Toxicology Program have shown chronic exposure to dioxin-like compounds (DLCs) to lead to the development of both neoplastic and non-neoplastic lesions in the hepatic tissue of female Sprague Dawley rats. Most, if not all, of the hepatotoxic effects induced by DLC's are believed to involve the binding and activation of the transcription factor, the aryl hydrocarbon receptor (AhR). Toxicogenomics was implemented to identify genomic responses that may be contributing to the development of hepatotoxicity in rats. RESULTS: Through comparative analysis of time-course microarray data, unique hepatic gene expression signatures were identified for the DLCs, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (100 ng/kg/day) and 3,3',4,4',5-pentachlorobiphenyl (PCB126) (1000 ng/kg/day) and the non-DLC 2,2',4,4',5,5',-hexachlorobiphenyl (PCB153) (1000 µg/kg/day). A common time independent signature of 41 AhR genomic biomarkers was identified which exhibited at least a 2-fold change in expression following subchronic (13-wk) and chronic (52-wk) p.o. exposure to TCDD and PCB126, but not the non DLC, PCB153. Real time qPCR analysis validated that 30 of these genes also exhibited at least a 2-fold change in hepatic expression at 24 hr following a single exposure to TCDD (5 µg/kg, po). Phenotypic anchoring was conducted which identified forty-six genes that were differently expressed both following chronic p.o. exposure to DLCs and in previously reported studies of cholangiocarcinoma or hepatocellular adenoma. CONCLUSIONS: Together these analyses provide a comprehensive description of the genomic responses which occur in rat hepatic tissue with exposure to AhR ligands and will help to isolate those genomic responses which are contributing to the hepatotoxicity observed with exposure to DLCs. In addition, the time independent gene expression signature of the AhR ligands may assist in identifying other agents with the potential to elicit dioxin-like hepatotoxic responses.