RESUMEN
Addressing human anatomical and physiological variability is a crucial component of human health risk assessment of chemicals. Experts have recommended probabilistic chemical risk assessment paradigms in which distributional adjustment factors are used to account for various sources of uncertainty and variability, including variability in the pharmacokinetic behavior of a given substance in different humans. In practice, convenient assumptions about the distribution forms of adjustment factors and human equivalent doses (HEDs) are often used. Parameters such as tissue volumes and blood flows are likewise often assumed to be lognormally or normally distributed without evaluating empirical data for consistency with these forms. In this work, we performed dosimetric extrapolations using physiologically based pharmacokinetic (PBPK) models for dichloromethane (DCM) and chloroform that incorporate uncertainty and variability to determine if the HEDs associated with such extrapolations are approximately lognormal and how they depend on the underlying distribution shapes chosen to represent model parameters. We accounted for uncertainty and variability in PBPK model parameters by randomly drawing their values from a variety of distribution types. We then performed reverse dosimetry to calculate HEDs based on animal points of departure for each set of sampled parameters. Corresponding samples of HEDs were tested to determine the impact of input parameter distributions on their central tendencies, extreme percentiles, and degree of conformance to lognormality. This work demonstrates that the measurable attributes of human variability should be considered more carefully and that generalized assumptions about parameter distribution shapes may lead to inaccurate estimates of extreme percentiles of HEDs.
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Modelos Biológicos , Humanos , Animales , Medición de Riesgo , Cloroformo/farmacocinética , Incertidumbre , Distribución Tisular , Relación Dosis-Respuesta a DrogaRESUMEN
Objective: To quantify metabolism, a physiologically based pharmacokinetic (PBPK) model for a volatile compound can be calibrated with the closed chamber (i.e. vapor uptake) inhalation data. Here, we introduce global optimization as a novel component of the predictive process and use it to illustrate a procedure for metabolic parameter estimation.Materials and methods: Male F344 rats were exposed in vapor uptake chambers to initial concentrations of 100, 500, 1000, and 3000 ppm chloroform. Chamber time-course data from these experiments, in combination with optimization using a chemical-specific PBPK model, were used to estimate Michaelis-Menten metabolic constants. Matlab® simulation software was used to integrate the mass balance equations and to perform the global optimizations using MEIGO (MEtaheuristics for systems biology and bIoinformatics Global Optimization - Version 64 bit, R2016A), a toolbox written for Matlab®. The cost function used the chamber time-course data and least squares to minimize the difference between data and simulation values.Results and discussion: The final values estimated for Vmax (maximum metabolic rate) and Km (affinity constant) were 1.2 mg/h and a range between 0.0005 and 0.6 mg/L, respectively. Also, cost function plots were used to analyze the dose-dependent capacity to estimate Vmax and Km within the experimental range used. Sensitivity analysis was used to assess identifiability for both parameters and show these kinetic data may not be sufficient to identify Km.Conclusion: In summary, this work should help toxicologists interested in optimization techniques understand the overall process employed when calibrating metabolic parameters in a PBPK model with inhalation data.
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Cloroformo/administración & dosificación , Cloroformo/farmacocinética , Modelos Biológicos , Tejido Adiposo/metabolismo , Administración por Inhalación , Animales , Simulación por Computador , Riñón/metabolismo , Hígado/metabolismo , Masculino , Músculos/metabolismo , Ratas Endogámicas F344RESUMEN
CONTEXT: Poisoning due to chloroform ingestion is rare. The classic features of acute chloroform toxicity include central nervous system (CNS) and respiratory depression, and delayed hepatotoxicity. CASE DETAILS: A 30-year-old female ingested 20-30 mL of 99% chloroform solution, which caused rapid loss of consciousness, transient hypotension and severe respiratory depression requiring endotracheal intubation and ventilation. She was alert by 12 h and extubated 16 h post-overdose. At 38-h post-ingestion, her liver function tests started to rise and she was commenced on intravenous acetylcysteine. Her alanine transaminase (1283 U/L), aspartate transaminase (734 U/L) and international normalized ratio (2.3) peaked 67- to 72-h post-ingestion. She also developed severe abdominal pain, vomiting and diarrhoea. An abdominal CT scan was consistent with severe enterocolitis, and an upper gastrointestinal endoscopy showed erosive oesophagitis, severe erosive gastritis and ulceration. She was treated with opioid analgesia, proton pump inhibitors, sucralfate and total parenteral nutrition. Secretions caused a contact dermatitis of her face and back. Nine days post-ingestion she was able to tolerate food. Her liver function tests normalized and the dermatitis resolved. Chloroform was measured using headspace gas chromatograph mass spectrometry, with a peak concentration of 2.00 µg/mL, 4 h 20 min post-ingestion. The concentration-time data fitted a 1-compartment model with elimination half-life 6.5 h. DISCUSSION: In addition to early CNS depression and delayed hepatotoxicity, we report severe gastrointestinal injury and dermatitis with chloroform ingestion. Recovery occurred with good supportive care, acetylcysteine and management of gastrointestinal complications.
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Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Cloroformo/envenenamiento , Erupciones por Medicamentos/etiología , Enfermedades Gastrointestinales/inducido químicamente , Dolor Abdominal/inducido químicamente , Acetilcisteína/uso terapéutico , Adulto , Antídotos/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Cloroformo/farmacocinética , Erupciones por Medicamentos/patología , Erupciones por Medicamentos/terapia , Sobredosis de Droga , Femenino , Enfermedades Gastrointestinales/fisiopatología , Enfermedades Gastrointestinales/terapia , Semivida , Humanos , Pruebas de Función Hepática , Modelos Biológicos , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/terapiaRESUMEN
The MetaMap(®)-Tox database contains plasma-metabolome and toxicity data of rats obtained from oral administration of 550 reference compounds following a standardized adapted OECD 407 protocol. Here, metabolic profiles for aniline (A), chloroform (CL), ethylbenzene (EB), 2-methoxyethanol (ME), N,N-dimethylformamide (DMF) and tetrahydrofurane (THF), dosed inhalatively for six hours/day, five days a week for 4 weeks were compared to oral dosing performed daily for 4 weeks. To investigate if the oral and inhalative metabolome would be comparable statistical analyses were performed. Best correlations for metabolome changes via both routes of exposure were observed for toxicants that induced profound metabolome changes. e.g. CL and ME. Liver and testes were correctly identified as target organs. In contrast, route of exposure dependent differences in metabolic profiles were noted for low profile strength e.g. female rats dosed inhalatively with A or THF. Taken together, the current investigations demonstrate that plasma metabolome changes are generally comparable for systemic effects after oral and inhalation exposure. Differences may result from kinetics and first pass effects. For compounds inducing only weak changes, the differences between both routes of exposure are visible in the metabolome.
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Compuestos de Anilina/toxicidad , Derivados del Benceno/toxicidad , Cloroformo/toxicidad , Dimetilformamida/toxicidad , Glicoles de Etileno/toxicidad , Furanos/toxicidad , Metaboloma , Metabolómica , Pruebas de Toxicidad , Administración por Inhalación , Administración Oral , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/farmacocinética , Animales , Derivados del Benceno/administración & dosificación , Derivados del Benceno/farmacocinética , Cloroformo/administración & dosificación , Cloroformo/farmacocinética , Bases de Datos Factuales , Dimetilformamida/administración & dosificación , Dimetilformamida/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Glicoles de Etileno/administración & dosificación , Glicoles de Etileno/farmacocinética , Femenino , Furanos/administración & dosificación , Furanos/farmacocinética , Exposición por Inhalación , Masculino , Análisis de Componente Principal , Ratas Wistar , Medición de RiesgoRESUMEN
CONTEXT: Urinary biomarkers are widely used among biomonitoring studies because of their ease of collection and nonintrusiveness. Chloroform and TEX (i.e., toluene, ethylbenzene, and m-xylene) are chemicals that are often found together because of common use. Although interactions occurring among TEX are well-known, no information exists on possible kinetic interactions between these chemicals and chloroform at the level of parent compound or urinary biomarkers. OBJECTIVE: The objective of this study was therefore to study the possible interactions between these compounds in human volunteers with special emphasis on the potential impact on urinary biomarkers. MATERIALS AND METHODS: Five male volunteers were exposed by inhalation for 6 h to single, binary, and quaternary mixtures that included chloroform. Exhaled air and blood samples were collected and analyzed for parent compound concentrations. Urinary biomarkers (o-cresol, mandelic, and m-methylhippuric acids) were quantified in urine samples. Published PBPK model for chloroform was used, and a Vmax of 3.4 mg/h/kg was optimized to provide a better fit with blood data. Adapted PBPK models from our previous study were used for parent compounds and urinary biomarkers for TEX. RESULTS: Binary exposures with chloroform resulted in no significant interactions. Experimental data for quaternary mixture exposures were well predicted by PBPK models using published description of competitive inhibition among TEX components. However, no significant interactions were observed at levels used in this study. CONCLUSION: PBPK models for urinary biomarkers proved to be a good tool in quantifying exposure to VOC.
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Cloroformo/farmacocinética , Cloroformo/orina , Monitoreo del Ambiente/métodos , Modelos Biológicos , Compuestos Orgánicos Volátiles/farmacocinética , Compuestos Orgánicos Volátiles/orina , Adolescente , Adulto , Derivados del Benceno/farmacocinética , Derivados del Benceno/orina , Biomarcadores/sangre , Biomarcadores/orina , Cloroformo/administración & dosificación , Simulación por Computador , Cresoles/orina , Hipuratos/orina , Humanos , Exposición por Inhalación , Masculino , Ácidos Mandélicos/orina , Valor Predictivo de las Pruebas , Tolueno/farmacocinética , Tolueno/orina , Urinálisis , Compuestos Orgánicos Volátiles/administración & dosificación , Compuestos Orgánicos Volátiles/sangre , Xilenos/farmacocinética , Xilenos/orina , Adulto JovenRESUMEN
Background. Fusarium moniliforme is a phytopathogenic facultative fungus with a cosmopolitan distribution in all types of climates, and has a wide host range, including, among others, bean, rice, wheat and sorghum crops. There is a current lack of knowledge regarding the potential of these fungi, so it is considered to be of great importance to obtain information related to the biological activity of extracts and secondary metabolites. Aims. An evaluation of the role of methanol:chloroform extract of F. moniliforme in the production of inflammatory cytokines and their cytotoxic activity. Methods. The production of nitric oxide was analyzed by the Griess method, the production of cytokines using ELISA, and the effects of the extract on cell cycle and induction of apoptosis by flow cytometry. Results. The extract of F. moniliforme was seen to be able to stimulate nitric oxide (NO) production in J774A.1 cells, as well as to produce cytokines such as, IL-1β, IL-6, and TNF-α. It was also observed that the extract of F. moniliforme produces activity on cell cycle modulation and apoptosis when tested in carcinogenic cell lines. Conclusions. The results obtained from this study open the possibility of obtaining and identifying metabolites of the extract of F. moniliforme that can be evaluated for possible use in cancer therapy (AU)
Antecedentes. Fusarium moniliforme es un hongo fitopatógeno facultativo con distribución cosmopolita en todos los tipos de climas y con una gran variedad de huéspedes, como el frijol, el arroz, el trigo y el sorgo. Actualmente existe una falta de conocimiento sobre el potencial de este hongo, por lo que es de gran importancia obtener información relacionada con la actividad biológica de los extractos y sus metabolitos secundarios. Objetivos. En este trabajo se evaluó el papel del extracto metanol:cloroformo de F. moniliforme sobre la producción de citocinas y su actividad citotóxica sobre líneas celulares. Métodos. Se analizó la producción de óxido nítrico por el método de Griess, la producción de citocinas se evalúo por el método de ELISA y los efectos del extracto sobre el ciclo celular e inducción de apoptosis se analizó por citometría de flujo. Resultados. El extracto de F. moniliforme fue capaz de inducir la producción de óxido nítrico (ON) en células J774A.1, así como la producción de citocinas IL-1β, IL-6 y TNF-α. También se observó que el extracto de F. moniliforme posee actividad en la modulación del ciclo celular y en la inducción de apoptosis observada en líneas células cancerígenas. Conclusiones. Los resultados de este trabajo abren la posibilidad de obtener e identificar los metabolitos del extracto de F. moniliforme para que puedan ser evaluados en una posible terapia para el cáncer (AU)
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Mediadores de Inflamación/análisis , Inflamación/fisiopatología , Citotoxicidad Inmunológica/inmunología , Fusarium/inmunología , Citocinas , Metanol/farmacocinética , Óxido Nítrico/análisis , Antineoplásicos/farmacocinética , Cloroformo/farmacocinéticaRESUMEN
The present study investigated the time-course changes of concentration of chloroform (CHCl3) in the blood during and after exposure of male rats to CHCl3 by inhalation. Increasing the dose of CHCl3 in the inhalation exposed groups caused a commensurate increase in the concentration of CHCl3 in the blood and the area under the blood concentration-time curve (AUC). There was good correlation (r = 0.988) between the inhalation dose and the AUC/kg body weight. Based on the AUC/kg body weight-inhalation dose curve and the AUC/kg body weight after oral administration, inhalation equivalent doses of orally administered CHCl3 were calculated. Calculation of inhalation equivalent doses allows the body burden due to CHCl3 by inhalation exposure and oral exposure to be directly compared. This type of comparison facilitates risk assessment in humans exposed to CHCl3 by different routes. Our results indicate that when calculating inhalation equivalent doses of CHCl3, it is critical to include the AUC from the exposure period in addition to the AUC after the end of the exposure period. Thus, studies which measure the concentration of volatile organic compounds in the blood during the inhalation exposure period are crucial. The data reported here makes an important contribution to the physiologically based pharmacokinetic (PBPK) database of CHCl3 in rodents.
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Cloroformo/administración & dosificación , Cloroformo/farmacocinética , Administración por Inhalación , Administración Oral , Animales , Área Bajo la Curva , Cloroformo/sangre , Relación Dosis-Respuesta a Droga , Exposición por Inhalación , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Drinking water quality standard (DWQS) criteria for chemicals for which there is a threshold for toxicity are derived by allocating a fraction of tolerable daily intake (TDI) to exposure from drinking water. We conducted physiologically based pharmacokinetic model simulations for chloroform and have proposed an equation for total oral-equivalent potential intake via three routes (oral ingestion, inhalation, and dermal exposures), the biologically effective doses of which were converted to oral-equivalent potential intakes. The probability distributions of total oral-equivalent potential intake in Japanese people were estimated by Monte Carlo simulations. Even when the chloroform concentration in drinking water equaled the current DWQS criterion, there was sufficient margin between the intake and the TDI: the probability that the intake exceeded TDI was below 0.1%. If a criterion that the 95th percentile estimate equals the TDI is regarded as both providing protection to highly exposed persons and leaving a reasonable margin of exposure relative to the TDI, then the chloroform drinking water criterion could be a concentration of 0.11mg/L. This implies a daily intake equal to 34% of the TDI allocated to the oral intake (2L/d) of drinking water for typical adults. For the highly exposed persons, inhalation exposure via evaporation from water contributed 53% of the total intake, whereas dermal absorption contributed only 3%.
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Cloroformo/administración & dosificación , Exposición a Riesgos Ambientales/análisis , Contaminantes Químicos del Agua/administración & dosificación , Abastecimiento de Agua/normas , Cloroformo/farmacocinética , Cloroformo/toxicidad , Ingestión de Líquidos , Exposición a Riesgos Ambientales/efectos adversos , Monitoreo del Ambiente/métodos , Humanos , Modelos Biológicos , Método de Montecarlo , Nivel sin Efectos Adversos Observados , Contaminantes Químicos del Agua/farmacocinética , Contaminantes Químicos del Agua/toxicidad , Calidad del AguaRESUMEN
The kidney is a primary target for numerous toxic compounds. Cytochrome P450 enzymes (P450) are responsible for the metabolic activation of various chemical compounds, and in the kidney are predominantly expressed in proximal tubules. The aim of this study was to test the hypothesis that renal proximal tubular P450s are critical for nephrotoxicity caused by chemicals such as chloroform. We developed two new mouse models, one having proximal tubule-specific deletion of the cytochrome P450 reductase (Cpr) gene (the enzyme required for all microsomal P450 activities), designated proximal tubule-Cpr-null (PTCN), and the other having proximal tubule-specific rescue of CPR activity with the global suppression of CPR activity in all extra-proximal tubular tissues, designated extra-proximal tubule-Cpr-low (XPT-CL). The PTCN, XPT-CL, Cpr-low (CL), and wild-type (WT) mice were treated with a single oral dose of chloroform at 200mg/kg. Blood, liver and kidney samples were obtained at 24h after the treatment. Renal toxicity was assessed by measuring BUN and creatinine levels, and by pathological examination. The blood and tissue levels of chloroform were determined. The severity of toxicity was less in PTCN and CL mice, compared with that of WT and XPT-CL mice. There were no significant differences in chloroform levels in the blood, liver, or kidney, between PTCN and WT mice, or between XPT-CL and CL mice. These findings indicate that local P450-dependent activities play an important role in the nephrotoxicity induced by chloroform. Our results also demonstrate the usefulness of these novel mouse models for studies of chemical-induced kidney toxicity.
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Cloroformo/toxicidad , Sistema Enzimático del Citocromo P-450/metabolismo , Enfermedades Renales/inducido químicamente , Enfermedades Renales/enzimología , Túbulos Renales Proximales/enzimología , NADPH-Ferrihemoproteína Reductasa/genética , Animales , Nitrógeno de la Urea Sanguínea , Western Blotting , Línea Celular , Cloroformo/sangre , Cloroformo/farmacocinética , Creatinina/sangre , Inmunohistoquímica , Isoenzimas/biosíntesis , Isoenzimas/genética , Riñón/patología , Ratones , Ratones Noqueados , NADPH-Ferrihemoproteína Reductasa/fisiología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Distribución TisularRESUMEN
Physiologically based pharmacokinetic (PBPK) models are tools for interpreting toxicological data and extrapolating observations across species and route of exposure. Chloroform (CHCl(3)) is a chemical for which there are PBPK models available in different species and multiple sites of toxicity. Because chloroform induces toxic effects in the liver and kidneys via production of reactive metabolites, proper characterization of metabolism in these tissues is essential for risk assessment. Although hepatic metabolism of chloroform is adequately described by these models, there is higher uncertainty for renal metabolism due to a lack of species-specific data and direct measurements of renal metabolism. Furthermore, models typically fail to account for regional differences in metabolic capacity within the kidney. Mischaracterization of renal metabolism may have a negligible effect on systemic chloroform levels, but it is anticipated to have a significant impact on the estimated site-specific production of reactive metabolites. In this article, rate parameters for chloroform metabolism in the kidney are revised for rats, mice, and humans. New in vitro data were collected in mice and humans for this purpose and are presented here. The revised PBPK model is used to interpret data of chloroform-induced kidney toxicity in rats and mice exposed via inhalation and drinking water. Benchmark dose (BMD) modeling is used to characterize the dose-response relationship of kidney toxicity markers as a function of PBPK-derived internal kidney dose. Applying the PBPK model, it was also possible to characterize the dose response for a recent data set of rats exposed via multiple routes simultaneously. Consistent BMD modeling results were observed regardless of species or route of exposure.
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Cloroformo/toxicidad , Citocromo P-450 CYP2E1/metabolismo , Corteza Renal/efectos de los fármacos , Modelos Biológicos , Animales , Cloroformo/farmacocinética , Relación Dosis-Respuesta a Droga , Corteza Renal/enzimología , Corteza Renal/metabolismo , Ratones , RatasRESUMEN
The objective of this study was to assess the impact of the exposure route on the human kinetic adjustment factor (HKAF), for which a default value of 3.16 is used in non-cancer risk assessment. A multi-route PBPK model was modified from the literature and used for computing the internal dose metrics in adults, neonates, children, elderly and pregnant women following three route-specific scenarios to chloroform, bromoform, tri- or per-chloroethylene (TCE or PERC). These include 24-h inhalation exposure, body-weight adjusted oral exposure and 30 min dermal exposure to contaminated drinking water. Distributions for body weight (BW), height (BH) and hepatic cytochrome P450 2E1 (CYP2E1) content were obtained from the literature, whereas model parameters (flows, volumes) were calculated from BW and BH. Monte Carlo simulations were performed and the HKAF was calculated as the ratio of the 95th percentile value of internal dose metrics in subpopulation to the 50th percentile value in adults. On the basis of the area under the parent compound's arterial blood concentration vs time curve (AUC(pc)), highest HKAFs were obtained in neonates for every scenario considered, and were the highest for bromoform (range: 3.6-7.4). Exceedance of the default value based on AUC(PC) was also observed for an oral exposure to chloroform in neonates (4.9). In all other cases, HKAFs remained below the default value. Overall, this study has pointed out the dependency of the HKAF on the exposure route, dose metrics and subpopulation considered, as well as characteristics of the chemicals investigated.
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Modelos Biológicos , Farmacocinética , Contaminantes Químicos del Agua/farmacocinética , Contaminantes Químicos del Agua/toxicidad , Adaptación Psicológica , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Peso Corporal , Niño , Preescolar , Cloroformo/administración & dosificación , Cloroformo/farmacocinética , Cloroformo/toxicidad , Simulación por Computador , Citocromo P-450 CYP2E1/metabolismo , Femenino , Humanos , Lactante , Recién Nacido , Exposición por Inhalación , Persona de Mediana Edad , Embarazo , Medición de Riesgo/métodos , Trihalometanos/administración & dosificación , Trihalometanos/farmacocinética , Trihalometanos/toxicidad , Cloruro de Vinilo/administración & dosificación , Cloruro de Vinilo/farmacocinética , Cloruro de Vinilo/toxicidad , Contaminantes Químicos del Agua/administración & dosificaciónRESUMEN
The present investigation was undertaken to determine the distribution and accumulation of chloroform in the blood, liver, kidney and abdominal fat of rats after simultaneous exposure by two routes, inhalation and oral. To distinguish the contribution of each route, unmodified chloroform (CHCl3) was administered by inhalation and deuterated chloroform (CDCl3) was administered orally. Exposure by inhalation and oral administration resulted in CHCl3 and CDCl3 concentrations in the tissues which were significantly higher than when exposure was by either inhalation or oral administration alone. This is the first study to follow the contribution of each of two routes of chloroform exposure on chloroform distribution and accumulation in target tissues. Our results indicate that when assessing the toxicity and carcinogenicity of chloroform, exposure routes, especially the effects of exposure by multiple routes, must be taken into consideration.
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Cloroformo/administración & dosificación , Cloroformo/farmacocinética , Administración por Inhalación , Administración Oral , Animales , Masculino , RatasRESUMEN
Biologically based dose-response (BBDR) modeling of environmental pollutants can be utilized to inform the mode of action (MOA) by which compounds elicit adverse health effects. Chemicals that produce tumors are typically labeled as either genotoxic or nongenotoxic. Though both the genotoxic and the nongenotoxic MOA may be operative as a function of dose, it is important to note that the label informs but does not define a MOA. One commonly proposed MOA for nongenotoxic carcinogens is characterized by the key events cytotoxicity and regenerative proliferation. The increased division rate associated with such proliferation can cause an increase in the probability of mutations, which may result in tumor formation. We included these steps in a generalized computational pharmacodynamic (PD) model incorporating cytotoxicity as a MOA for three carcinogens (chloroform, CHCl(3); carbon tetrachloride, CCL(4); and N,N-dimethylformamide, DMF). For each compound, the BBDR model is composed of a chemical-specific physiologically based pharmacokinetic model linked to a PD model of cytotoxicity and cellular proliferation. The rate of proliferation is then linked to a clonal growth model to predict tumor incidences. Comparisons of the BBDR simulations and parameterizations across chemicals suggested that significant variation among the models for the three chemicals arises in a few parameters expected to be chemical specific (such as metabolism and cellular injury rate constants). Optimization of model parameters to tumor data for CCL(4) and DMF resulted in similar estimates for all parameters related to cytotoxicity and tumor incidences. However, optimization of the CHCl(3) data resulted in a higher estimate for one parameter (BD) related to death of initiated cells. This implies that additional steps beyond cytotoxicity leading to induced cellular proliferation can be quantitatively different among chemicals that share cytotoxicity as a hypothesized carcinogenic MOA.
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Tetracloruro de Carbono/toxicidad , Carcinógenos/toxicidad , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/patología , Cloroformo/toxicidad , Dimetilformamida/toxicidad , Neoplasias Hepáticas/patología , Animales , Tetracloruro de Carbono/farmacocinética , Carcinógenos/farmacocinética , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Cloroformo/farmacocinética , Biología Computacional , Computadores , Dimetilformamida/farmacocinética , Femenino , Humanos , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Modelos Biológicos , Regeneración/efectos de los fármacos , Medición de RiesgoRESUMEN
Chemical carcinogenesis is a complex, multi-stage process and the relationship between dose and tumour formation is an important consideration in the risk assessment of chemicals. Extrapolation from empirical dose-response relationships obtained in experimental studies has been criticized, as it fails to take into account information on mode of action. Strategies for incorporating mode of action information into the risk assessment of chemical carcinogens are described, with a focus on hepatic cancer. Either toxicokinetic or toxicodynamic processes can be addressed. Whilst the former have been the focus of more attention to date, for example by using physiologically based modelling, there is increasing interest in the development of mode of action-based toxicodynamic models. These have the advantage that they do not require extreme assumptions, and may be amenable to paramaterization using human data. This is rarely if ever possible when using conventional dose-tumour response relationships. The approaches discussed are illustrated using chloroform as a case study. This compound is converted to a cytotoxic metabolite, phosgene, by CYP2E1 in liver and/or kidney. Cytotoxicity results in proliferative regeneration, with increased probability of tumour formation. Both physiologically based toxicokinetic and toxicodynamic models have been developed, and it is possible to use probabilistic approaches incorporating, for example, data on the distribution of hepatic CYP2E1 levels. Mode of action can provide an invaluable link between observable, experimental data, on both toxicokinetics and toxicodynamics, and chemical-specific risk assessment, based on physiological approaches.
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Cloroformo/toxicidad , Neoplasias Hepáticas Experimentales/inducido químicamente , Animales , Pruebas de Carcinogenicidad/métodos , Proliferación Celular/efectos de los fármacos , Cloroformo/farmacocinética , Relación Dosis-Respuesta a Droga , Humanos , Riñón/efectos de los fármacos , Riñón/enzimología , Riñón/patología , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/enzimología , Neoplasias Hepáticas Experimentales/patología , Modelos Biológicos , Medición de RiesgoRESUMEN
A Bayesian hierarchical model was developed to estimate the parameters in a physiologically based pharmacokinetic (PBPK) model for chloroform using prior information and biomarker data from different exposure pathways. In particular, the model provides a quantitative description of the changes in physiological parameters associated with hot-water bath and showering scenarios. Through Bayesian inference, uncertainties in the PBPK parameters were reduced from the prior distributions. Prediction of biomarker data with the calibrated PBPK model was improved by the calibration. The posterior results indicate that blood flow rates varied under two different exposure scenarios, with a two-fold increase of the skin's blood flow rate predicted in the hot-bath scenario. This result highlights the importance of considering scenario-specific parameters in PBPK modeling. To demonstrate the application of a probability approach in toxicological assessment, results from the posterior distributions from this calibrated model were used to predict target tissue dose based on the rate of chloroform metabolized in liver. This study demonstrates the use of the Bayesian approach to optimize PBPK model parameters for typical household exposure scenarios.
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Baños , Teorema de Bayes , Cloroformo/farmacocinética , Exposición por Inhalación/análisis , Modelos Biológicos , Absorción Cutánea/fisiología , Adulto , Contaminantes Atmosféricos , Femenino , Calor , Humanos , Masculino , Medición de RiesgoRESUMEN
In order to obtain basic risk assessment data on human health exposure to volatile organic compound (VOC) vapor by inhalation, a whole-body inhalation exposure system which allows blood collection during the exposure period was designed. The system was tested using chloroform as a model VOC. Chloroform vapor, sampled from the supply-header, animal-chambers and exhaust-header, remained constant in this system with variations in its concentration being less than 2%; flow rate of the vapor through the system was also constant. Rats were exposed to chloroform vapor and blood collected from the tail during exposure to the chloroform vapor. The chloroform concentration in the blood increased during the initial 60 min of exposure, and afterwards its concentration remained at about 2 microg/ml from 60 to 360 min. In conclusion, our design allows blood to be collected from individual rats during exposure by inhalation to test VOCs and changes in the blood concentration of the VOC during exposure to be assessed.
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Recolección de Muestras de Sangre/instrumentación , Recolección de Muestras de Sangre/métodos , Vivienda para Animales , Exposición por Inhalación , Administración por Inhalación , Contaminantes Atmosféricos/farmacocinética , Contaminantes Atmosféricos/toxicidad , Animales , Cloroformo/administración & dosificación , Cloroformo/farmacocinética , Cloroformo/toxicidad , Diseño de Equipo , Masculino , Ratas , Ratas Sprague-Dawley , Solventes/administración & dosificación , Solventes/farmacocinética , Solventes/toxicidadRESUMEN
Multiple research teams have reported data from in vivo human trials in which breath was monitored during and after whole-body or partial immersion in aqueous solutions of volatile organic compounds. Estimation of total dermal absorption from exhaled breath measurements requires modeling, a task to which physiologically based pharmacokinetic (PBPK) models have often been applied. In the context of PBPK models, the exposed skin compartment can be modeled in many different ways. To demonstrate potential effects of alternative skin models on overall PBPK model performance, alternative models of skin have been incorporated in a PBPK model used to predict chloroform in breath during and after immersion in aqueous solution. The models investigated include treatment of skin as both a homogeneous phase and as a membrane in which concentration varies with depth. Model predictions are compared with in vivo human experimental results reported in the prior literature. In the example chosen, the common practice of modeling skin as a homogenous phase leads to prediction of more rapid initial uptake and lower cumulative uptake than does modeling skin as a membrane. Numerical estimates of the permeability coefficient are shown to be dependent upon skin model form and temperature of the aqueous solution.
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Cloroformo/farmacocinética , Modelos Biológicos , Absorción Cutánea , Administración Cutánea , Espiración , Humanos , Pulmón/metabolismo , Piel/metabolismo , TemperaturaRESUMEN
Chloroform causes hepatic and renal toxicity in a number of species. In vitro studies have indicated that chloroform can be metabolized by P450 enzymes in the kidney to nephrotoxic intermediate, although direct in vivo evidence for the role of renal P450 in the nephrotoxicity has not been reported. This study was to determine whether chloroform renal toxicity persists in a mouse model with a liver-specific deletion of the P450 reductase (Cpr) gene (liver-Cpr-null). Chloroform-induced renal toxicity and chloroform tissue levels were compared between the liver-Cpr-null and wild-type mice at 24 h following differing doses of chloroform. At a chloroform dose of 150 mg/kg, the levels of blood urea nitrogen (BUN) were five times higher in the exposed group than in the vehicle-treated one for the liver-Cpr-null mice, but they were only slightly higher in the exposed group than in the vehicle-treated group for the wild-type mice. Severe lesions were found in the kidney of the liver-Cpr-null mice, while only mild lesions were found in the wild-type mice. At a chloroform dose of 300 mg/kg, severe kidney lesions were observed in both strains, yet the BUN levels were still higher in the liver-Cpr-null than in the wild-type mice. Higher chloroform levels were found in the tissues of the liver-Cpr-null mice. These findings indicated that loss of hepatic P450-dependent chloroform metabolism does not protect against chloroform-induced renal toxicity, suggesting that renal P450 enzymes play an essential role in chloroform renal toxicity.
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Cloroformo/toxicidad , Sistema Enzimático del Citocromo P-450/metabolismo , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Animales , Disponibilidad Biológica , Cloroformo/farmacocinética , Sistema Enzimático del Citocromo P-450/genética , Inmunohistoquímica , Hígado/enzimología , Masculino , Ratones , Ratones NoqueadosRESUMEN
Chloroform is a carcinogen in rodents and its carcinogenicity is secondary to events associated with cytotoxicity and regenerative cell proliferation. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that links the processes of chloroform metabolism, reparable cell damage, cell death, and regenerative cellular proliferation was developed to support a new cancer dose-response assessment for chloroform. Model parameters were estimated using Markov Chain Monte Carlo (MCMC) analysis in a two-step approach: (1) metabolism parameters for male and female mice and rats were estimated against available closed chamber gas uptake data; and (2) PD parameters for each of the four rodent groups were estimated from hepatic and renal labeling index data following inhalation exposures. Subsequently, the resulting rodent PD parameters together with literature values for human age-dependent physiological and metabolism parameters were used to scale up the rodent model to a human model. The human model was used to predict exposure conditions under which chloroform-mediated cytolethality is expected to occur in liver and kidney of adults and children. Using the human model, inhalation Reference Concentrations (RfCs) and oral Reference Doses (RfDs) were derived using an uncertainty factor of 10. Based on liver and kidney dose metrics, the respective RfCs were 0.9 and 0.09 ppm; and the respective RfDs were 0.4 and 3 mg/kg/day.
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Carcinógenos/toxicidad , Cloroformo/farmacocinética , Cloroformo/toxicidad , Neoplasias Experimentales/inducido químicamente , Animales , Teorema de Bayes , Transporte Biológico Activo , Carcinógenos/farmacocinética , Carcinógenos/farmacología , Cloroformo/farmacología , Exposición a Riesgos Ambientales , Femenino , Humanos , Riñón/metabolismo , Hígado/metabolismo , Masculino , Cadenas de Markov , Ratones , Modelos Biológicos , Método de Montecarlo , Neoplasias/inducido químicamente , Neoplasias Experimentales/metabolismo , Ratas , Ratas Endogámicas F344 , Medición de RiesgoRESUMEN
The derivation of reference concentrations (RfCs) for systemically acting volatile organic chemicals (VOCs) uses a default factor of 10 to account for the interindividual variability in pharmacokinetics (PK) and pharmacodynamics (PD). The magnitude of the PK component of the interindividual variability factor (IVF; also referred to as human kinetic adjustment factor (HKAF)) has previously been estimated using Monte Carlo approaches and physiologically based pharmacokinetic (PBPK) models. Since the RfC derivation considers continuous lifetime human exposure to VOCs in the environment, algorithms to compute steady-state internal dose (SS-ID), such as steady-state arterial blood concentration (Ca) and the steady-state rate of amount metabolized (RAM), can be used to derive IVF-PKs. In this context, probability-bounds (P-bounds) approach is potentially useful for computing an interval of probability distribution of SS-ID from knowledge of population distribution of input parameters. The objective of this study was therefore to compute IVF-PK using the P-bounds approach along with an algorithm for SS-ID in an adult population exposed to VOCs. The existing steady-state algorithms, derived from PBPK models, were rewritten such that SS-ID could be related, without any interdependence, to the following input parameters: alveolar ventilation (Qp), hepatic blood flow (Ql), intrinsic clearance (CL(int)) and blood:air partition coefficient (Pb). The IVF-PK was calculated from the P-bounds of SS-ID corresponding to the 50th and 95th percentiles. Following either specification of probability distribution-free bounds (characterized by minimal, maximal, and mean values) or distribution-defined values (mean, standard deviation and shape of probability distribution where: Qp=lognormal, Ql=lognormal, CL(int)=lognormal and Pb=normal) in RAMAS Risk Calc software version 3.0 (Applied Biomathematics, Setauket, NY), the P-bound estimates of SS-ID for benzene, carbon tetrachloride, chloroform and methyl chloroform were obtained for low level exposures (1ppm). Using probability distribution-defined inputs, the IVF-PK for benzene, carbon tetrachloride, chloroform and methyl chloroform were, respectively, 1.18, 1.28, 1.24, and 1.18 (based on P-bounds for Ca), and 1.31, 1.58, 1.30, and 1.24 (based on P-bounds for RAM). A validation of the P-bounds computation was performed by comparing the results with those obtained using Monte Carlo simulation of the steady-state algorithms. In data-poor situations, when the statistical distributions for all input parameters were not known or available, the P-bounds approach allowed the estimation of IVF-PK. The use of P-bounds method along with steady-state algorithms, as done in this study for the first time, is a practical and scientifically sound way of computing IVF-PKs for systemically acting VOCs.