RESUMO
The EU Chemicals Strategy for Sustainability is a first step to achieve the Green Deal ambition for a toxic-free environment, and ensure that chemicals are produced and used in a way that maximises their contribution to society while avoiding harm to our planet and to future generations. Advanced materials are predicted to play a pivotal role in achieving this ambition and the underlying sustainability goals, and considerable efforts are invested in designing new classes of materials. Examples of such materials are metamaterials, artificially architectured materials designed to have material properties beyond those of the individual ingredient materials, or active materials at the boundary between materials and devices (e.g., new biomedical soft materials). Such innovative advanced materials raise concern about possible future safety and sustainability issues and would benefit from appropriate risk governance that promotes innovation, while pushing for safety and sustainability. To balance these aspects, a methodology is proposed for the early-stage identification of emerging safety and sustainability issues of advanced materials. As exemplified by two case studies, the methodology aims to be of use for innovators, risk assessors, and regulators. Extension of the methodology is highlighted, as well as implementation in broader initiatives like the EU's industrial policy approach.
Assuntos
Indústrias , Políticas , Previsões , Medição de RiscoRESUMO
ATSDR and RIVM organized an Expert Panel Workshop on the Differences Between Children and Adults and Their Relevance to Risk Assessment. The workshop was held in June 2003, in Brussels, Belgium. The purpose of the workshop was to identify data gaps in current scientific knowledge related to children's health and to recognize areas of mutual interest that would serve as the basis for upcoming ATSDR/RIVM cooperative projects. The aim for both agencies is a better understanding of the issues related to children's health, and the improvement of scientifically based (chemical) risk assessment in children. Topics discussed included clinical trials/toxicity studies, testing in juvenile animals, PBPK modeling in children, and children's risk assessment.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Exposição Ambiental/efeitos adversos , Medição de Risco/métodos , Animais , Criança , Pré-Escolar , Educação , Exposição Ambiental/análise , Humanos , Preparações Farmacêuticas/análiseRESUMO
Whether children incur different risks from xenobiotics than adults will depend on the exposure, biokinetics, and dynamics of compound. In this paper, current knowledge on developmental physiology and possible effects on biokinetics are evaluated and the role of biokinetics in risk assessment both for drugs and chemicals is discussed. It is concluded that most dramatic age-related physiological changes that may affect biokinetics occur in the first 6-12 months of age. The difference in internal exposure between children and adults can generally be predicted from already known developmental physiological differences. However, for risk assessment it will also be necessary to determine whether internal exposure is within the drug's therapeutic window or if it will exceed the NOAEL of a chemical. Furthermore, the effects of internal exposure of potentially harmful compounds on developing organ systems is of utmost importance. However, knowledge on this aspect is very limited. Risk assessment in children could be improved by: (1) application of pediatric PBPK-models in order to gain insight into internal exposure in children, (2) studies in juvenile animals for studying effects on developing systems, and (3) extrapolation of knowledge on the relationship between internal exposure and dynamics for drugs to other chemicals.
Assuntos
Desenvolvimento Infantil/fisiologia , Modelos Biológicos , Preparações Farmacêuticas , Farmacocinética , Medição de Risco , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Fenômenos Fisiológicos do Sistema Digestório , Substâncias Perigosas/farmacocinética , Humanos , Lactente , Recém-Nascido , Fígado/enzimologia , Fígado/metabolismo , Metabolismo , Nível de Efeito Adverso não Observado , Fenômenos Fisiológicos Respiratórios , Absorção Cutânea , Distribuição TecidualRESUMO
Soil ingestion is an important pathway of exposure for many nonvolatile contaminants for man and in particular for children. A fraction of the ingested contaminant may not dissociate from the soil particles during digestion in the gastrointestinal tract, and is thus not available for transport across the intestinal epithelium. In order to estimate the contaminant fraction that is mobilized from soil, i.e., the bioaccessible fraction, several in vitro digestion models have been developed. The currently existing digestion models display many differences. One aspect that may affect bioaccessibility and may induce differences between digestion models is the bile that is used. Often freeze-dried bile of animal origin is preferred to purified bile salts. However, also the animal origin of bile may give rise to differences in bioaccessibility because bile composition appears to be species dependent. In the present study, we compared the bioaccessibility of benzo[a]pyrene, arsenic, cadmium, and lead of four different soils after digestion with ox bile from two different suppliers, pig bile, and chicken bile. Bioaccessibility appeared to vary amongst the different soils and contaminants. Only chicken bile increased the bioaccessibility of lead and cadmium significantly and relevantly for one of four soils. For chicken bile, the bioaccessibility of lead was 3-5.5 times greater than for the other bile types and the bioaccessibility of cadmium was 1.5 times greater. In all other cases, the bioaccessibility differences were less than 10%, which is considered irrelevant for risk assessment purposes.
Assuntos
Bile/metabolismo , Fenômenos Fisiológicos do Sistema Digestório , Poluentes do Solo/farmacocinética , Animais , Arsênio/análise , Arsênio/farmacocinética , Benzo(a)pireno/análise , Benzo(a)pireno/farmacocinética , Disponibilidade Biológica , Cádmio/análise , Cádmio/farmacocinética , Galinhas/fisiologia , Técnicas In Vitro , Chumbo/análise , Chumbo/farmacocinética , Modelos Biológicos , Medição de Risco , Poluentes do Solo/análiseRESUMO
Soil ingestion can be a major route of human exposure to many immobile soil contaminants. The present risk assessment is based on toxicity studies in which contaminants are typically ingested in liquid or food matrices. The difference in bioavailability of contaminants ingested in a soil matrix is not taken into account. To become bioavailable, contaminants first need to become bioaccessible, i.e., they must be mobilized from the soil during digestion. Soil contaminants may be less bioaccessible than contaminants from liquid or food, so that the risks can be overestimated. This article describes the development of an in vitro human digestion model that is physiologically based. It can be used as a tool to assess bioaccessibility. We explain the rationale behind the experimental design of the model. We address the aspects of the simulated compartments of the gastrointestinal tract, temperature, soil-to-fluid ratio, ratio of digestive juices, transit times, centrifugation, pH values, mixing, constituents and their concentrations, and bile. The optimized in vitro digestion model was applied in a case study. The bioaccessibility of lead in pottery flakes with glazing was determined and compared to the bioaccessibility of lead in the soil from which the pottery flakes were removed. The data indicate that pottery flake lead is considerably less bioaccessible (0.3 +/- 0.2%) than lead in soil without pottery flakes (42-66% at the same site, and 28-73% at other sites in the same town). Furthermore, bioaccessibility values of lead in soil appear to be less than calculated bioaccessibility values for dietary lead (which are based on the criterion used by the Dutch risk assessment and on literature absorption data). This indicates that accounting for the matrix of ingestion can affect the exposure assessment for lead. The in vitro digestion model is a promising tool for studying the effect of the ingestion matrix on bioaccessibility.
Assuntos
Fenômenos Fisiológicos do Sistema Digestório , Modelos Biológicos , Poluentes do Solo/farmacocinética , Disponibilidade Biológica , Humanos , Chumbo/farmacocinética , Medição de RiscoRESUMO
For children, soil ingestion via hand-to-mouth behavior can be a main route of exposure to contaminants such as lead. The ingested lead can be mobilized from the soil and form new species during the digestion process. Speciation is known to affect the availability of metals for transport across biological membranes. In the present study, in vitro digestions were performed with (artificially contaminated) standard soil. Lead speciation was investigated in the artificial human intestinal fluid, i.e., chyme, to gain insight into the lead species and lead fractions that may be available for transport across the intestinal epithelium. To that end, both a lead ion selective electrode (Pb-ISE) and a voltammetric technique (differential pulse anodic stripping voltammetry, DPASV) were used. The results indicate that in chyme only a negligible lead fraction is present as free Pb(2+), whereas lead phosphate and lead bile complexes are important fractions. The lead phosphate complexes appear to be voltammetrically labile, i.e., in dynamic equilibrium with Pb(2+). Labile complexes can dissociate and the produced metal ions can subsequently be transported across the intestinal epithelium. Lead bile complexes may behave in a similar manner, or this organometal complex may be able to traverse the intestinal membrane. Therefore, substantially more than only the free metal ion should be considered available for transport across the intestinal epithelium.
Assuntos
Sistema Digestório/química , Chumbo/química , Chumbo/farmacocinética , Poluentes do Solo/farmacocinética , Administração Oral , Criança , Eletrofisiologia , Humanos , Mucosa Intestinal/fisiologia , ÍonsRESUMO
Children might be exposed substantially to contaminants such as lead via soil ingestion. In risk assessment of soil contaminants there is a need for information on oral bioavailability of soilborne lead. Oral bioavailability can be seen as the result of four steps: (1) soil ingestion; (2) mobilization from soil during digestion, i.e., bioaccessibility; (3) transport across the intestinal epithelium; and (4) first-pass effect. Lead bioaccessibility and speciation in artificial human small intestinal fluid, i.e., chyme, have been investigated in previous studies. In the present study, transport of bioaccessible lead across the intestinal epithelium was investigated using the Caco-2 cell line. Cell monolayers were exposed to (diluted) artificial chyme. In 24 h, approximately 27% of the lead were associated to the cells and 3% were transported across the cell monolayer, without signs of approaching equilibrium. Lead associated to the cells showed a linear relationship with the total amount of lead in the system. Bile levels did not affect the fraction of lead associated to Caco-2 cells. Extrapolation of the lead flux across the Caco-2 monolayer to the in vivo situation indicates that only a fraction of the bioaccessible lead is transported across the intestinal epithelium. Furthermore, the results indicate that as the free Pb(2+) concentration in chyme was negligible, lead species other than the free metal ion must have contributed to the lead flux toward the cells. On the basis of lead speciation in chyme, this can be attributed to dissociation of labile lead species, such as lead phosphate and lead bile complexes, and subsequent transport of the released free metal ions toward the intestinal membrane.
Assuntos
Chumbo/farmacocinética , Poluentes do Solo/farmacocinética , Administração Oral , Disponibilidade Biológica , Células CACO-2 , Sistema Digestório/química , Humanos , Mucosa Intestinal/química , Mucosa Intestinal/fisiologia , ÍonsRESUMO
Children may ingest contaminated soil from hand to mouth. To assess this exposure route, we need to know the oral bioavailability of the contaminants. Two determining steps in bioavailability of soil-borne contaminants are mobilization from soil during digestion, which is followed by intestinal absorption. The first step has been investigated in previous studies that showed that a substantial fraction of PCBs and lindane is mobilized from soil during artificial digestion. Furthermore, almost all contaminants are sorbed to constituents of artificial human small intestinal fluid (i.e., chyme), whereas only a small fraction is freely dissolved. In this study, we examine the second step using intestinal epithelial Caco-2 cells. The composition of the apical exposure medium was varied by addition of artificial chyme, bile, or oleic acid at similar or increasing total contaminant concentrations. The uptake curves were described by rate constants. The uptake flux seemed to be dose-dependent. Furthermore, different exposure media with similar total contaminant concentrations resulted in various uptake rates. This can be attributed to different freely dissolved concentrations and carrier effects. In addition, the large fractions of contaminants in the cells indicate that PCBs and lindane sorbed to bile, oleic acid, and digestive proteins contributed to the uptake flux toward the cells. These results can be extrapolated qualitatively to in vivo conditions. Because the sorbed contaminants should be considered available for absorption, the first step of mobilization from soil is the most important step for oral bioavailability of the presently investigated soil-borne contaminants.
Assuntos
Poluentes Ambientais/farmacocinética , Hexaclorocicloexano/farmacocinética , Inseticidas/farmacocinética , Bifenilos Policlorados/farmacocinética , Poluentes do Solo/farmacocinética , Administração Oral , Disponibilidade Biológica , Células CACO-2/efeitos dos fármacos , Células CACO-2/fisiologia , Exposição Ambiental , Ácidos Graxos/metabolismo , Humanos , Absorção Intestinal , Cinética , SolubilidadeRESUMO
The applicability of stable strontium as a marker for measuring intestinal calcium absorption is mainly dependent on the validity of the assumption that calcium and strontium are absorbed with a constant ratio. Up to now, it is not clear whether this ratio is affected by intervention therapy. Therefore, preclinical screening of this ratio before and after treatment is indispensable for a clinical calcium absorption test based on the use of stable strontium as a marker. We studied the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D(3)], a potent enhancer of active intestinal calcium absorption, on the pharmacokinetics of both calcium-45 and strontium in adult male rats, in a short-term dose-finding study [0-50 ng 1,25(OH)2D(3)/100 g body weight] and also in a placebo-controlled study in which 12.5 ng 1,25(OH)2D(3)/100 g body weight were applied to assess the long-term pharmacokinetics. The mean bioavailability (true absorption) was 33% for calcium and 19% for strontium (ratio 1.7:1), whereas, after 1,25(OH)2D(3) pretreatment, it was 73 and 43% (ratio 1.7:1), respectively. These findings demonstrate that intestinal strontium absorption has, like intestinal calcium absorption, an active component. Moreover, they underscore the applicability of stable strontium as a tool for investigating calcium absorption under various conditions.
Assuntos
Calcitriol/farmacologia , Cálcio/metabolismo , Absorção Intestinal/efeitos dos fármacos , Estrôncio , Animais , Biomarcadores , Cálcio/farmacocinética , Masculino , Fosfatos/sangue , Ratos , Ratos Wistar , Estrôncio/farmacocinéticaRESUMO
1. The absorption kinetics of orally administered strontium chloride and its reproducibility were investigated in healthy volunteers after administering strontium either under fasting conditions (study I, n = 8) or in combination with a standardized meal (study II, n = 8). Each subject received strontium orally at day 0, 14, and 28 and intravenously at day 42. The study was performed as part of a project in which a simple clinical test for measuring intestinal calcium absorption is being developed, based on the use of stable strontium as a marker. 2. Plasma strontium concentration-time curves were analysed by noncompartment analysis and a four compartment disposition model. Within a volunteer each oral curve was fitted simultaneously with the intravenous curve, by which means a two segment model for absorption was revealed. 3. Mean absolute bioavailability of strontium was 25% without a meal and 19% with a meal, whereas the intraindividual variation was 24% and 20%, respectively. 4. Various limited sampling absorption parameters were determined in order to select a potential test parameter for measuring intestinal calcium absorption using strontium as a marker. Fractional absorption at 4 h (Fc240), obtained after co-ingestion of strontium with a meal, appeared to be the best test parameter, because it represented bioavailability well (r = 0.90).
Assuntos
Absorção Intestinal , Estrôncio/farmacocinética , Administração Oral , Adulto , Disponibilidade Biológica , Biomarcadores/sangue , Jejum , Alimentos , Humanos , Injeções Intravenosas , Masculino , Reprodutibilidade dos Testes , Estrôncio/administração & dosagem , Estrôncio/sangueRESUMO
Calcium absorption tests have rarely been validated for being representative for absolute bioavailability (true absorption) or for intraindividual variation. Therefore, we investigated the reproducibility of the absolute bioavailability of strontium chloride, a marker for intestinal calcium absorption, in healthy male volunteers (n = 8) by measuring the area under the plasma strontium concentration-time curve after oral and intravenous administration of strontium. Subsequently, we selected a simple test variable as being representative of absolute bioavailability. The mean absolute bioavailability (+/- SD) was 25% +/- 7%. The best test variable appeared to be the fractional absorption at 240 min (Fc240) after oral intake, which demonstrated the highest correlation with absolute bioavailability (r = 0.66). The intraindividual variations of the data for this variable and for the absolute bioavailability are similar to those described for various absorption tests based on the use of calcium isotopes. Thus, the Fc240 of strontium offers the potential of a simple clinical test for use as a measure of intestinal calcium absorption and its modulation.
Assuntos
Cálcio/metabolismo , Absorção Intestinal , Estrôncio/farmacocinética , Adulto , Disponibilidade Biológica , Biomarcadores , Humanos , Masculino , Valores de Referência , Estrôncio/metabolismoRESUMO
For long-term pharmacokinetic studies in humans as well as in experimental animals, an analysis of strontium (Sr) with a low detection limit and high sensitivity is necessary. The data presented here describe the optimization of the furnace program and sample handling for measuring Sr in plasma by using graphite furnace atomic absorption spectrophotometry. The method was validated and applied to studies on the pharmacokinetics of SrCl2 in humans and rats. Calibration curves were linear up to 57.1 nmol/L. The limit of detection and lower limit of quantification were 0.21 and 0.57 nmol/L, respectively. Reciprocal sensitivity was 0.53 nmol/L Sr at A = 0.0044. The intraassay precision was 2.2%, 1.5%, and 1.1% (n = 6) at 4.57, 22.7, and 49.2 nmol/L Sr, respectively. At these concentrations, the interassay precision and recovery were 0.7%, 1.5%, and 1.8% and 100.4%, 99.1%, and 100.6% (n = 12), respectively. The endogenous Sr concentration in human plasma samples was 0.27 +/- 0.07 mumol/L (n = 18). Pharmacokinetic studies in a human volunteer and in rats demonstrated that this procedure was suited for measuring low Sr concentrations and was applicable to small sample volumes.
Assuntos
Espectrofotometria Atômica/métodos , Estrôncio/sangue , Adulto , Animais , Calibragem , Grafite , Humanos , Cinética , Masculino , Ratos , Ratos Wistar , Sensibilidade e Especificidade , Espectrofotometria Atômica/estatística & dados numéricos , Estrôncio/farmacocinéticaRESUMO
BACKGROUND: Topical calcitriol, a potent inhibitor of cell proliferation and inducer of terminal cell differentiation, can clear psoriasis. However, possible side effects on calcium and bone metabolism from transdermal absorption have not been evaluated. OBJECTIVE: The calciotropic effects of low-dose calcitriol (3 micrograms/gm) ointment, applied twice daily for 6 weeks, were investigated. METHODS: A double-blind study was carried out in 18 patients with chronic stable plaque-type psoriasis, of whom nine were treated with calcitriol (3 micrograms/gm) and nine with betamethasone dipropionate (500 micrograms/gm). The main end points were calcitriol plasma concentrations, intestinal calcium absorption, and bone turnover. RESULTS: Serum alkaline phosphatase concentrations increased slightly (p < 0.02) and intestinal calcium absorption decreased slightly (p < 0.01) in the calcitriol-treated group. However, the alterations were too small to have any clinical relevance. CONCLUSION: Low-dose calcitriol, topically applied for 6 weeks on a maximal body surface area of 30%, can be considered as safe regarding calcium and bone metabolism.
Assuntos
Anti-Inflamatórios/uso terapêutico , Osso e Ossos/efeitos dos fármacos , Calcitriol/uso terapêutico , Cálcio/metabolismo , Dexametasona/análogos & derivados , Psoríase/tratamento farmacológico , Administração Cutânea , Adulto , Fosfatase Alcalina/sangue , Anti-Inflamatórios/administração & dosagem , Osso e Ossos/metabolismo , Calcitriol/administração & dosagem , Calcitriol/sangue , Cálcio/sangue , Cálcio/urina , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Pomadas , Estudos ProspectivosRESUMO
Intestinal absorption of calcium is a relevant marker in a broad spectrum of diseases; however, its determination in clinical practice is difficult. Our aim was to design a simple test for this based on stable strontium (88Sr). The correlation between the intestinal absorption of simultaneously administered 45Ca and 88Sr was investigated in patients with various disorders of the bone and calcium metabolism. The area under the curve for the period 0-60 min after dosing (AUC0-60 in mmol.L-1.min), being a representative measure of intestinal absorption, showed a close correlation between both elements (r = 0.90, P < 0.001). Moreover, the measure of agreement in classifying the patients as low, intermediate, or high absorbers was high (kappa = 0.80). We conclude that a test based on measuring AUC0-60 of strontium is a fast and inexpensive way to obtain reliable information about the level of intestinal calcium absorption.