RESUMO
Exposure assessment is a fundamental part of the risk assessment paradigm, but can often present a number of challenges and uncertainties. This is especially the case for process contaminants formed during the processing, e.g. heating of food, since they are in part highly reactive and/or volatile, thus making exposure assessment by analysing contents in food unreliable. New approaches are therefore required to accurately assess consumer exposure and thus better inform the risk assessment. Such novel approaches may include the use of biomarkers, physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry, and/or duplicate diet studies. This review focuses on the state of the art with respect to the use of biomarkers of exposure for the process contaminants acrylamide, 3-MCPD esters, glycidyl esters, furan and acrolein. From the overview presented, it becomes clear that the field of assessing human exposure to process-related contaminants in food by biomarker monitoring is promising and strongly developing. The current state of the art as well as the existing data gaps and challenges for the future were defined. They include (1) using PBK modelling and duplicate diet studies to establish, preferably in humans, correlations between external exposure and biomarkers; (2) elucidation of the possible endogenous formation of the process-related contaminants and the resulting biomarker levels; (3) the influence of inter-individual variations and how to include that in the biomarker-based exposure predictions; (4) the correction for confounding factors; (5) the value of the different biomarkers in relation to exposure scenario's and risk assessment, and (6) the possibilities of novel methodologies. In spite of these challenges it can be concluded that biomarker-based exposure assessment provides a unique opportunity to more accurately assess consumer exposure to process-related contaminants in food and thus to better inform risk assessment.
Assuntos
Biomarcadores/análise , Exposição Dietética/análise , Contaminação de Alimentos/análise , Manipulação de Alimentos , Acroleína/sangue , Acroleína/química , Acroleína/urina , Acrilamida/sangue , Acrilamida/química , Acrilamida/urina , Animais , Furanos/sangue , Furanos/química , Furanos/urina , Humanos , Modelos Biológicos , Medição de Risco/métodos , alfa-Cloridrina/química , alfa-Cloridrina/urinaRESUMO
BACKGROUND: Several cancer therapies can prolong cardiac repolarization. This study assessed the potential of eribulin to affect cardiac repolarization in patients with advanced solid tumors. METHODS: In this Phase I, open-label, single-arm study, patients received eribulin mesylate (1.4 mg/m(2); Days 1 and 8 of a 21-day cycle). The primary objective was to assess the effect of eribulin on the QTcF pre- and post-infusion; QTcF and QTcNi were compared for ability to remove heart-rate dependence of the QT interval. Relationship between concentration of eribulin and ΔQTc was explored using linear mixed-effects analysis. Secondary objectives explored pharmacokinetics, safety, and tolerability. RESULTS: Twenty-six patients were enrolled. QTcNi was more effective than QTcF in correcting for heart-rate dependency of the QT interval. On Day 1, mean ΔQTcNi were ~0 at all timepoints. An apparent time-dependent increase in ΔQTc was observed: on Day 8, changes from baseline were larger and more variable, without clear relation to plasma levels of eribulin. Day 8 predose ΔQTcNi was 5 ms, post-infusion mean values ranged from 2 to 9 ms (largest mean ΔQTcNi at 6 h). No new or unexpected toxicities were reported. CONCLUSION: Eribulin demonstrated an acceptable safety profile and a minor prolongation of QTc not expected to be of clinical concern in oncology patients.
Assuntos
Eletrocardiografia , Furanos/uso terapêutico , Cetonas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Algoritmos , Intervalos de Confiança , Demografia , Feminino , Furanos/efeitos adversos , Furanos/sangue , Furanos/farmacocinética , Frequência Cardíaca , Humanos , Cetonas/efeitos adversos , Cetonas/sangue , Cetonas/farmacocinética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/sangue , Neoplasias/fisiopatologia , UltrassonografiaRESUMO
This paper evaluates the results of contamination of residents and residential homes located in close proximity to a Wood Treatment Plant. The plant has produced treated wood products continuously since 1904. The principle chemicals used to treat the wood, which is primarily used for railroad ties (oblong objects laid perpendicular to the rails to act as a base for the tracks), are creosote and pentachlorophenol. For a number of years, the plant burned treated waste wood products containing creosote and pentachlorophenol. First the plant pressure impregnates the wood with creosote and pentachlorophenol, and then the wood is stacked on open ground to allow it to air dry. Chemicals from recently treated wood ties are allowed to evaporate into the air or drip onto the ground surrounding the stacked wood. Small drainage ditches carry the liquid wastes into larger water channels where eventually the waste streams are discharged into a river adjacent to the plant. The river serves as a source of drinking water for the nearby community. Prevailing wind patterns favor a drift of air emissions from the plant's boiler stack over the nearby community and its residents. Over the past few years, the town's residents have become increasingly concerned about their health status and have voiced concerns regarding multiple health problems (including cancer), possibly associated with plant discharges. The intention of this study is to examine a representative sample of the potentially affected residents and to evaluate their residential environment for the presence of dioxin and/or its congeners. Data obtained from EPA's Toxic Release Information (TRI) database revealed the plant routinely discharged creosote, pentachlorophenol, dioxin and dioxin-like compounds into the ambient air via fugitive air emissions and surface waste waters. Sampling of household dust and water sediment within and outside of residences within a 2-mile radius of the plant revealed the presence of significantly elevated levels of dioxins, principally octachlorodibenzo-p-dioxin (OCDD) and 1,2,3,4,6,7,8-hepta-CDD. Biomonitoring of 29 subjects identified the presence of significantly elevated chlorinated dioxins and furan levels (OCDD=1049 ppt for exposed and 374 ppt for controls and 1,2,3,4,6,7,8-hepta CDD=132 ppt for exposed and 45.1 ppt for controls). These levels are consistent with exposures to pentachlorophenol in this group of subjects. And they confirm the presence of unsafe levels of chlorinated dioxins in these persons.
Assuntos
Creosoto/sangue , Dioxinas/sangue , Exposição Ambiental , Poluentes Ambientais , Furanos/sangue , Pentaclorofenol/sangue , Madeira , Indústria Química , Creosoto/toxicidade , Dioxinas/toxicidade , Poeira/análise , Poluentes Ambientais/análise , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Contaminação de Alimentos , Furanos/toxicidade , Habitação , Humanos , Resíduos Industriais , Pentaclorofenol/toxicidade , Medição de Risco , Rios , Fatores de Tempo , Abastecimento de ÁguaRESUMO
A systematic program of sampling and analysis of blood serum for dioxins, furans, and dioxinlike polychlorinated biphenyls (PCBs) has been initiated in the United States through the National Health and Nutrition Examination Survey (NHANES) program. While such data could potentially be used to estimate population-level changes in human milk lipid concentrations of chemicals, such estimates would depend on understanding the relationship between human blood lipid and milk lipid concentrations of the compounds of interest. For dioxins and furans, extremely limited data in humans currently exist for paired blood/milk samples. These data reviewed in this article, support the hypothesis that, over a population and across time, human milk lipid levels of these compounds generally reflect blood lipid levels. However, these data also suggest that significant variations in these ratios are possible among individuals and at various times.
Assuntos
Dioxinas/análise , Furanos/análise , Leite Humano/química , Resíduos de Praguicidas/análise , Bifenilos Policlorados/análise , Dioxinas/sangue , Feminino , Furanos/sangue , Humanos , Lactente , Recém-Nascido , Inquéritos Nutricionais , Bifenilos Policlorados/sangue , Estados UnidosRESUMO
During 1990 and 1991, milk samples were collected from farms in Derbyshire, a county in the UK, as part of a study designed to establish background concentrations of polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) in cows' milk produced in the area. The concentrations found in two samples, both taken from farms near the town of Bolsover, were significantly elevated (40.0-42.0 ng TEQ kg(-1) fat) when compared with the normal range for these compounds in milk from the surrounding area (1.1-7.1 ng TEQ kg(-1) fat). An immediate intensive programme commenced in April 1991 to test milk from a further 27 dairy farms close to those where the original 'high' samples were obtained. A maximum tolerable concentration (MTC) was calculated to be 17.5 ng/TEQ kg(-1) fat. This was derived by using the tolerable daily intake (TDI) for 2,3,7,8-TCDD of 0.01 ng kg(-1) body weight day(-1) set by the World Health Organization in 1990 and accepted by the UK government (this figure has since been revised to 1-4 pg kg(-1) body weight day(-1)). MTC is defined as the amount of PCDD/Fs that could be present and still ensure that high-level (97.5 pecentile) consumers of milk would not exceed the TDI. Milk originating from dairies supplied by these farms and others contained PCDD/F in the range 1.8-3.1 ng TEQ kg(-1) fat, which indicated there was no risk to health for consumers purchasing milk in the normal manner. Milk from the two dairy farms was removed from the food supply until concentrations of PCDD/Fs were consistently below the MTC. The UK Department of Health monitored the blood concentrations of PCDD/Fs in individuals who had consumed milk produced on the affected farms and the Department of the Environment initiated a programme of work to identify and reduce the source of pollution.