RESUMEN
The tobacco-specific nitrosamine (TSNA) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is classified by the International Agency for Research on Cancer as a Group 1 carcinogen. Cancer risk assessment in humans exposed to TSNAs largely relies on potency values estimated from animal studies, but available cancer potency values for NNK derived from such studies are conflicting. In this analysis, oral cancer slope factors (CSFo) for NNK were derived according to U.S. Environmental Protection Agency guidelines. An animal study in which rats were exposed to NNK in drinking water was selected as the key study. The multistage-cancer model was fit to the tumor incidence data to determine a point of departure for low dose linear extrapolation, using a benchmark response of 10%. CSFo distributions were then computed using Bayesian methods and Monte Carlo simulation. The resultant CSFo point estimate (BMR/BMDL(10)) was 19.2 (mg/kg day)(-1) based on lung tumor data and 12.2 (mg/kg day)(-1) based on pancreatic tumors. The 95th percentiles of the CSFo distributions were 27.3 and 19.3 (mg/kg day)(-1) based on lung and pancreatic tumors, respectively. The approach using Bayesian methods better accounts for the uncertainty inherent in the values generated using input assumptions and provides for a more robust probabilistic dose-response assessment.
Asunto(s)
Carcinógenos/toxicidad , Exposición a Riesgos Ambientales/normas , Modelos Biológicos , Neoplasias de la Boca/inducido químicamente , Nitrosaminas/toxicidad , Animales , Teorema de Bayes , Pruebas de Carcinogenicidad , Carcinógenos/normas , Técnicas de Apoyo para la Decisión , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Neoplasias Pulmonares/inducido químicamente , Masculino , Ratones , Método de Montecarlo , Neoplasias Experimentales/inducido químicamente , Nitrosaminas/normas , Neoplasias Pancreáticas/inducido químicamente , Ratas , Medición de Riesgo/métodos , Estados Unidos , United States Environmental Protection AgencyRESUMEN
The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6-12 mg m(-2)) and docetaxel (50-75 mg m(-2)). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m(-2) with docetaxel 60 mg m(-2). Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (>or=18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/administración & dosificación , Cinesinas/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Quinazolinas/administración & dosificación , Taxoides/administración & dosificación , Adulto , Anciano , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Docetaxel , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Taxoides/efectos adversos , Taxoides/farmacocinéticaRESUMEN
The goal of the present analysis is to fit a Bayesian population pharmacokinetic pharmacodynomic (PK-PD) model to characterize the relationship between the concentration of ispinesib and changes in absolute neutrophil counts (ANC). Ispinesib, a kinesin spindle protein (KSP) inhibitor, blocks assembly of a functional mitotic spindle, leading to G2/M arrest. A first time in human, phase I open-label, non-randomized, dose-escalating study evaluated ispinesib at doses ranging from 1 to 21 mg/m(2). PK-PD data were collected from 45 patients with solid tumors. The pharmacokinetics of ispinesib were well characterized by a two-compartment model. A semimechanistic model was fit to the ANC. The PK and PD data were successfully modelled simultaneously. This is the first presentation of simultaneously fitting a PK-PD model to ANC using Bayesian methods. Bayesian methods allow for the use of prior information for some system-related parameters. The model may be used to examine different schedules, doses, and infusion times.
Asunto(s)
Antineoplásicos/farmacología , Teorema de Bayes , Benzamidas/farmacología , Neutropenia/inducido químicamente , Quinazolinas/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Recuento de Leucocitos , Masculino , Cadenas de Markov , Persona de Mediana Edad , Modelos Biológicos , Método de Montecarlo , Neutropenia/sangre , Quinazolinas/efectos adversos , Quinazolinas/farmacocinéticaRESUMEN
Blood serum concentrations of polychlorinated biphenyls (PCBs) were measured in members of a residential community who lived near a chemical plant that formerly manufactured PCBs. Elevated blood serum PCB concentrations were detected in some of the older adults who were long-term residents of the community. Congener-specific analyses indicated that PCB congeners 153, 138/158, 180, 118, and 187 contributed 60-67% of the total PCBs detected in blood from adults and children. Blood PCB concentrations correlated strongly with age and length of residency in the neighborhood. However, blood PCB concentrations did not correlate with PCB concentrations in soil or house dust samples from the homes. Past exposures to PCBs may be a significant contributor to the elevated PCB concentrations detected in some adult members of the community.
Asunto(s)
Exposición a Riesgos Ambientales , Contaminantes Ambientales/sangre , Bifenilos Policlorados/sangre , Adolescente , Adulto , Factores de Edad , Industria Química , Niño , Preescolar , Contaminantes Ambientales/análisis , Femenino , Humanos , Masculino , Bifenilos Policlorados/análisisRESUMEN
The Agency for Toxic Substances and Disease Registry (ATSDR) conducted biological testing to assess dioxin exposure in residents of a community who lived in an area with heavy chemical industry. Dioxin concentrations were measured in blood serum samples from 28 adult residents of the community. Fourteen of those tested had blood dioxin concentrations that exceeded the 95th percentile prediction level of an age-matched comparison population. Specific congener analyses indicated that the elevated dioxin concentrations were primarily due to high concentrations of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8 pentachlorodibenzo-p-dioxin (PeCDD), and hexachlorodibenzo-p-dioxins (HxCDs). Principal components analysis (PCA) indicated that the profiles of dioxin congeners were different in people with elevated blood dioxin concentrations compared to those with background concentrations. Elevated blood dioxin concentrations were detected only in older members of the population, which suggests that dioxin exposures were higher in the past. The sources of the dioxin exposure have not been identified.
Asunto(s)
Dioxinas/sangre , Contaminantes Ambientales/sangre , Sistema de Registros , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Industria Química , Exposición a Riesgos Ambientales , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Our first objective was to determine the effects of explosive amount and distance of the explosive to the meat surface in the Hydrodyne process on broiler breast tenderness. Early deboned (EB) breasts were removed immediately after initial chill (45 min postmortem), stored for 24 h (4 C), and subjected to one of four Hydrodyne treatments (200 g at 20 cm, 350 g at 23 cm, 275 g at 20 cm, or 350 g at 20 cm). Breasts were water-cooked (78 C internal). Hydrodyne treatment (HYD) of 350 g at 20 cm produced the greatest reduction (28.3%) in Warner-Bratzler shear (WBS, 1.9-cm wide strips). This combination was the only treatment to improve tenderness (peak force 4.3 kg) to a level equivalent (P > 0.05) to aged controls (CA; peak force 3.1 kg). The second objective was to determine the quality and sensory characteristics of Hydrodyne-treated (350 g explosive at 20 cm) broiler breasts as compared with CA and EB. The WBS values (1.0-cm wide and thick strips) for CA (1.56 kg) were different from both HYD (3.7 kg) and EB breasts (4.7 kg). The CA resulted in more tender, flavorful, and juicer breasts than EB and HYD. The EB was higher in initial moisture release than HYD. The EB breasts with tenderness problems can be tenderized by the Hydrodyne process based on WBS results. However, higher levels of explosive may be required to optimize the tenderness improvement of EB breasts that vary significantly in initial tenderness.