Dietary exposure to trace elements and health risk assessment in the 2nd French Total Diet Study

Dietary exposure of the French population to trace elements has been assessed in the second national Total Diet Study (TDS). Food samples (n = 1319) were collected between 2007 and 2009 to be representative of the whole diet of the population, prepared as consumed, and analyzed. Occurrence data were combined with national individual consumption data to estimate dietary exposure for adults and children mean and high consumers. Compared to the 1st French TDS performed in 2000–2004, exposure is higher for cadmium, aluminium, antimony, nickel, cobalt and lower for lead, mercury and arsenic. For aluminium, methylmercury, cadmium, lead and inorganic arsenic risk cannot be ruled out for certain consumer groups. It still appears necessary to continue undertaking efforts to reduce exposure to these elements. Due to the lack of robust toxicological data and/or speciation analysis in food on chromium, tin, silver and vanadium to perform a risk assessment, data on occurrence and dietary exposure are provided as Supplementary material. In order to minimize nutritional and chemical risks, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) reiterates its recommendation for a diversified diet (food items and origins).     

Dietary acrylamide exposure of the French population: results of the second French Total Diet Study

Acrylamide is a heat-induced carcinogen compound that is found in some foods consequently to cooking or other thermal processes. In the second French Total Diet Study (TDS), acrylamide was analysed in 192 food samples collected in mainland France to be representative of the population diet and prepared "as consumed". Highest mean concentrations were found in potato chips/crisps (954 μg/kg), French fries and other fried potatoes (724 μg/kg), and salted biscuits other than potato chips (697 μg/kg). Exposure of general adult and child populations was assessed by combining analytical results with national consumption data. Mean acrylamide exposure was assessed to be 0.43±0.33 μg/kg of body weight (bw) per day for adults and 0.69±0.58 μg/kg bw/day for children. Although the exposure assessed is lower than in previous evaluations, the calculated margins of exposure, based on benchmark dose limits defined for carcinogenic effects, remain very low especially for young children (below 100 at the 95th percentile of exposure), indicating a health concern. It is therefore advisable to continue efforts in order to reduce dietary exposure to acrylamide.     

Handling of contamination variability in exposure assessment: a case study with ochratoxin A.

The contamination of foods dedicated to human consumption varies over space and time. In exposure assessment, this is usually addressed through probabilistic modelling. The present work explores how the variability and uncertainty of exposures estimated at the population level are affected by: (a) the (non-)parametric nature of input contamination distributions; (b) the time-window used to sample contamination values within those distributions. Focusing on exposure of the French population to food mycotoxin ochratoxin A, we implement a range of second-order Monte-Carlo simulations that allow distinguishing variability of exposures from uncertainty of distributional parameters estimates. A simulation runs 10,000 iterations. Overall estimates of parameters are given by the median across iterations and 95%CI by 2.5th and 97.5th percentiles. Our results show that: (a) parametric (log-normal) input distributions may lead to over-estimation of variability and greater uncertainty as compared to non-parametric ones (P97.5 [95%CI] of 7.1 [6.6;7.7] for Parametric-Occasion, 4.6 [4.3;5.0] for Non-Parametric-Occasion), and that (b) the 'Occasion' time-window combines better estimate of variability and lower uncertainty when exposure modelling is applied to populations living in developed countries with complex agri-food systems (P97.5 [95%CI]: 7.3 [6.2;8.9] for Non-Parametric-Week, 4.6 [4.3;5.0] for Non-Parametric-Occasion). A deterministic approach is nevertheless preferred to probabilistic modelling every time input data quality is questionable.     

A profile of methylphenidate exposures

INTRODUCTION: Methylphenidate is prescribed commonly for children with attention deficit hyperactivity disorder. An estimated 2.8% of US youths aged 5 to 18 years use it for the management of this disorder. Despite the widespread use of methylphenidate, the demographics and outcome of intentional and unintentional exposures to methylphenidate have not been described. METHODS: To profile human exposures to methylphenidate, a retrospective review of all reports to a certified regional poison information center during 1998 was conducted. Data analysis included patient demographics, reason for the exposure, dose ingested, clinical effects, and patient outcome. RESULTS: There were 113 methylphenidate human exposures. The following table summarizes the values for selected parameters that were investigated: [table in text] CONCLUSIONS: The majority of exposures in children < or = 12 years of age involved unintentional ingestion of a sibling's medication, self-administration of an excessive therapeutic dose, or the administration of an inadvertent dose given by a caregiver. Methylphenidate abuse was common among adolescents and adults. Regardless of the reason for the exposure, the amount ingested, or treatment, all exposures had a favorable outcome. Pediatric doses of less than 1 mg/kg were not associated with adverse events.     

To which chemical mixtures is the French population exposed? Mixture identification from the second French Total Diet Study

Through their diet, humans are exposed to a wide range of substances with possible adverse effects. Total diet studies (TDS) assess exposure and risk for many single substances or mixtures from the same chemical family.This research aims to identify from 440 substances in the second French TDS, the major mixtures to which the French population is exposed and their associated diet. Firstly, substances with a contamination value over the detection limit were selected. Secondly, consumption systems comprising major consumed foods were identified using non-negative matrix factorisation and combined with concentration levels to form the main mixture. Thirdly, individuals were clustered to identify “diet clusters” with similar consumption patterns and co-exposure profiles.Six main consumption systems and their associated mixtures were identified. For example, a mixture of ten pesticides, six trace elements and bisphenol A was identified. Exposure to this mixture is related to fruit and vegetables consumed by a diet cluster comprising 62% of women with a mean age of 51 years. Six other clusters are described with their associated diets and mixtures. Cluster co-exposures were compared to the whole population.This work helps prioritise mixtures for which it is crucial to investigate possible toxicological effects.     

Dietary exposure of the Italian population to inorganic arsenic: The 2012–2014 Total Diet Study

Dietary exposure of the Italian population to inorganic arsenic has been assessed in the national Total Diet Study (TDS) carried out in 2012-2014. Within the TDS, food samples (>3000) were collected to be representative of the whole diet of the population, prepared as consumed, and pooled into 51 food groups, thus modelling the Italian diet. Inorganic arsenic was determined by HPLC-ICP-MS after chemical extraction and quantified in all samples. Occurrence data were combined with national individual consumption data to estimate mean and high level dietary exposure of the general population and of population subgroups according to age and gender, both at the national level and for each of the four main geographical areas of Italy. The intakes assessed are in the lower range of iAs exposure estimates in other European countries carried out without the support of the TDS approach. However, taking the lower limit of the BMDL₀₁ range established by the EFSA as reference point, the margins of exposure are <2 for the mean intake in infants and toddlers and <1 for the 95th percentile intakes in all younger age groups. Our results indicate the goal to check and further reduce the dietary exposure to inorganic arsenic.     

全胃切除术后两种消化道重建术的效果比较

目的 比较改良袢式空肠代胃术与P型空肠代胃术的优缺点及临床应用价值.方法 56例胃癌患者依据胃切除术后消化道重建方式分为两组,观察组35例采取改良袢式空肠代胃术；对照组21例采取P型空肠代胃术,比较两组临床效果.结果 两组手术时间和术中出血量差异无统计学意义(P＞0.05).观察组排空时间[(61±23)min]较对照组[(37±19)min]长(t=3.03,P＜0.05),每次饮食量[(308±44) ml]较对照组[(262±34) ml]高(t=2.55,P＜0.05),每天饮食次数[(4.2±1.2)次]较对照组[(5.7±2.3)次]少(t=2.46,P＜0.05).观察组术后并发症发生率(14.3％)显著低于对照组(42.9％)(x2=5.71,P＜0.05).结论 全胃切除术后,采用改良袢式空肠代胃术重建消化道,相对于P型空肠代胃术,能有效提高患者术后生活质量,降低并发症发生率,但并未使手术过程复杂化.     

Dietary exposure to inorganic arsenic of the Hong Kong population: Results of the first Hong Kong Total Diet Study

Inorganic arsenic, a human carcinogen, can be found in the environment and food. In the first Hong Kong Total Diet Study, the dietary exposure of the Hong Kong people, including various age-gender subgroups, to inorganic arsenic was estimated for assessing the associated health risk. Food samples, which represented the Hong Kong people’s diet, were collected and prepared “as consumed” for analysis. Concentrations of inorganic arsenic, as sum of arsenite (As(III)) and arsenate (As(V)) were determined in 600 composite samples by using inductively coupled plasma mass spectrometry. The dietary exposures were estimated by combining the analytical results with the local food consumption data of the adult population. The mean and 95th percentile of inorganic arsenic exposures of the Hong Kong people were 0.22 and 0.38 μg/kg body weight (bw)/day, respectively. Among the 12 age-gender subgroups, the respective exposures ranged from 0.19 to 0.26 μg/kg bw/day and from 0.33 to 0.46 μg/kg bw/day. The main food category that contributed inorganic arsenic was “cereals and their products” (53.5% of the total exposure), particularly rice. Having considered the carcinogenic risk of inorganic arsenic to humans, it is suggested that efforts should be made to reduce the inorganic arsenic exposure of the Hong Kong population.     

儿童与成人使用拉莫三嗪发生不良事件之比较——英国运用处方事件监测开展儿童上市后药物警戒之介绍

目的以拉莫三嗪为例,介绍英国运用处方事件监测对上市后儿童药物警戒,以期为我国的药品不良反应监测与评价提供参考。方法对拉莫三嗪处方事件监测(PEM)研究(观察性的队列研究)的数据进行年龄分层,汇总统计药品不良反应(ADR)、停止治疗的原因、死亡及随访信息。将儿童(0～17岁)及成人(18岁以上)第1个治疗月的不良事件(AE)发生密度与第2～6治疗月的发生密度进行比较,以检验在这两个时段中不良事件发生密度是否有差异;同时,还比较了儿童与成人两个年龄组中的AE发生率。结果队列研究包括2 457例儿童及7 379例成人。观察了儿童和成人组中AE的发生情况。儿童中皮疹(PRR=1.2)和Stevens-Johnson综合征(PRR=4.5)更普遍,成人中更常见精神紊乱(PRR=6.3)。儿童中有33%的ADR报告至监管部门,而成人中则有44%报告至监管部门。儿童中由于疗效缺乏停止治疗的比例更高(儿童45%,成人38%),无归因于拉莫三嗪的死亡病例。结论该研究显示,信号挖掘方法能够用于检测儿童及成人使用新药发生AE情况的定量和定性差异。     

Dietary intake of non-dioxin-like PCBs (NDL-PCBs) in France, impact of maximum levels in some foodstuffs

NDL-PCBs dietary intake was recently estimated in France by combining results of food products contamination by NDL-PCBs (1665 samples collected through 2002–2006 national monitoring programs) with food consumption data of the French “INCA” survey (individual and national survey of dietary intake, performed in 1998–1999). The mean dietary intake of NDL-PCBs estimated from the sum of 6 congeners (PCB 28, 52, 101, 138, 153, 180) is 7.6, 7.7 and 12.9 ng/kg bw/d for women of childbearing age (19–44 years), adults (15 years and over) and children (3–14 years), respectively. Impact of draft maximal levels (MLs) for NDL-PCBs in some foodstuffs was evaluated. The exposure scenario indicates that use of European draft MLs would have a very limited impact on the French population dietary exposure compared with the existing situation (no MLs). Simulations show that lowered MLs required for reducing significantly the French exposure would result to reject more than 20% of the targeted products from the French market compared with 1.3% according to the European draft MLs.     

The effects of copper and benzo[a]pyrene on retinoids and reproduction in zebrafish

This study examines whether a link exists between toxicant exposure, retinoids and reproduction in fish. Zebrafish were fed a control diet (8.1 microg Cu/g diet, 0 microg benzo[a]pyrene/g diet) or diets containing elevated copper (100 microg, 500 microg and 1000 microg Cu/g diet) or benzo[a]pyrene (B[a]P; 30 and 150 microg B[a]P/g diet) for 260 days. Toxicant-supplemented diets did not affect growth or mortality rates. While whole body retinoid levels in control zebrafish decreased during the experiment, females exposed to Cu or B[a]P for 200 days or more experienced additional losses of retinyl esters (45-100% depleted) and retinal (45% depleted in B[a]P-fed fish). Despite the reduced retinoids, Cu and B[a]P did not effect reproduction with respect to the number of eggs spawned, fertilization rates or egg retinal content (retinal was instead increased 55-65% in eggs from B[a]P-fed fish). There were no apparent deformities observed in 36 h post fertilization embryos from any treatment. It appears that although internal retinoid stores were depleted in adults, dietary retinoids were sufficient to meet the daily requirement for retinal deposition in the eggs and retinoic acid synthesis. This study has shown that retinoid levels in female zebrafish are sensitive to Cu and B[a]P, and are a good indicator of long-term exposure. It also brings to light the resiliency of the retinoid system in fish and the importance of the diet on the toxicological response. Specifically that dietary retinoids appear to support normal reproduction in the absence of internal retinoid stores.     

Health effect levels for risk assessment of childhood exposure to arsenic

Health risks to children from chemicals in soil and consumer products have become a regulatory focus in the U.S. This study reviews short-term health effect levels for arsenic exposure in young children (i.e., 0-6 years old). Acute health effects are described mostly in adults in case reports of arsenic poisoning from water or food and in studies of medicinal arsenic treatment. Several epidemiological studies report health effects from subchronic arsenic exposure in children primarily from drinking water in developing countries. Acute health effects typically include gastrointestinal, neurological, and skin effects, and in a few cases facial edema and cardiac arrhythmia. Dermatoses are most consistently reported in both adults and children with subchronic exposure. With low exposure, the prevalence and severity of disease generally increases with age (i.e., length of exposure) and arsenic dose. The available data collectively indicate a lowest-observed-adverse-effect level around 0.05mg/kg-day for both acute and subchronic exposure. At low doses, children do not appear to be more sensitive than adults on a dose-per-body-weight basis, although data for acute exposures are limited and uncertainties exist for quantifying potential neurological or vascular effects at low-level subchronic exposures. Based on these data, possible reference levels for acute and subchronic exposure in young children are 0.015 and 0.005mg/kg-day, respectively.     

托吡酯与A型肉毒抗毒素治疗儿童型偏侧面肌痉挛的临床对比研究

目的：探讨托吡酯（TP）治疗儿童型偏侧面肌痉挛（HFS）的临床疗效及安全性，并与A型肉毒抗毒素（BAT）的临床疗效进行比较。方法：TP组和BAT组各20例，两组治疗前和治疗5周后根据改良痉挛性斜颈量表（TWSTRS-II）评分进行疗效评定，同时观察平均起效时间、不良反应发生率、不良反应持续时间、显效率及总有效率。结果：治疗后TP组和BAT组的平均起效时间分别为（13．8±3．9）d和（2．4±1．1）d（P〈0．05），不良反应发生率分别为35．0％和40．0％（P〉0．05），不良反应持续时间分别为（5．0±1．5）d和（18．7±6．4）d（P〈0．05）。治疗前TWSTRS-Ⅱ评分分别为21．26±3．48和22．57±3．89（P〉0．05）；治疗5周后分别为9．32±2．75和7．87±1．74，与同组治疗前比较以及两组间比较均有显著性差异（P〈0．05）。但两组的显效率（分别为70．0％和85．0％）和总有效率（分别为85．0％和100％）比较，并无明显差异（P〉0．05）。结论：口服TP和局部注射BAT均可显著改善儿童型HFS患者的临床症状，前者不良反应轻且持续时间短，后者临床起效快，总体上两种治疗方法安全性均较好，显效率和总有效率均较高，均适于儿童型HFS的治疗。     

Exposure assessment within a Total Diet Study: A comparison of the use of the pan-European classification system FoodEx-1 with national food classification systems

A Total Diet Study (TDS) consists of selecting, collecting and preparing commonly consumed foods purchased at retail level and analysing them for harmful and/or beneficial chemical substances. A food classification system is needed to link food consumption data with the contaminant concentration data obtained in the TDS for the exposure assessment. In this study a comparison was made between the use of a national food classification systems and the use of FoodEx-1, developed and recommended by the European Food Safety Authority (EFSA). The work was performed using data of six European countries: Belgium, Czech Republic, France, The Netherlands, Spain and the UK. For each population, exposure to contaminant A (organic compounds) and/or contaminant B (inorganic compound) was assessed by the Monte Carlo Risk Assessment (MCRA) software using the national classification system and FoodEx-1 for food consumption data and for TDS laboratory results. Minimal differences between both approaches were observed. This observation applied for both contaminant A and contaminant B. In general risk assessment will be similar for both approaches; however, this is not guaranteed. FoodEx-1 proved to be a valuable hierarchic classification system in order to harmonise exposure assessment based on existing TDS results throughout Europe.     

纸片法和国标法对食品霉菌检验效果比较

目的：比较纸片法和国标法对食品霉菌的检验效果。方法采样标本来自安徽省望江县疾病预防控制中心质管科送检的糕点、饮料等共416份,其中糕点317份,饮料99份。所有样本均同时采用纸片法和国标法进行霉菌检验,比较2种方法的检验效果。结果国标法检测糕点、饮料的合格率[75.7%（240/317）、63.6%（63/99）]与纸片法检测糕点、饮料的合格率[78.9%（250/317）、65.7%（65/99）]比较,差异均无统计学意义（χ^2=0.899、0.088,P＞0.05）。结论2种方法均可准确检验食品中的霉菌,但相对国标法而言,纸片法更快速、简便、有效、实用,可替代国标法。     

Analytical approach to determination of safety of milk ingredients from hyperimmunized cows

Bovine milk-derived ingredients from cows hyperimmunized with a variety of antigens have been available experimentally or commercially for several decades. Although the safety of milk is rarely questioned, an assessment of ingredients derived from the milk of cows hyperimmunized with a proprietary bacterin (S100) was made to determine that these ingredients share the human food safety profile traditionally ascribed to regular milk. The critical elements in this determination are: (1) quantitative determination of the difference between S100 and regular dairy ingredients, (2) comparison of exposures resulting from proposed uses to background exposures already in the American diet, and (3) corroborative results of controlled clinical trials comparing safety outcomes from consumption of S100 with those of conventional dairy ingredients. Comparative analytical data reveal that the only difference between S100 and conventional dairy ingredients is significantly higher active (undenatured) immunoglobulin G (IgG) (61-79% vs. control Grade A fluid and powdered skim, respectively, p<0.005) with slightly altered specific antibody activity. Estimated daily intake projections show that use of S100 ingredients at maximum proposed levels results in exposures to active (undenatured) IgG below background in the present American diet in infants but above background in children and adults, whose intake of conventional dairy products is markedly lower. Safety of this consumption level is corroborated by clinical results showing no difference in safety outcomes between S100 ingredients, consumed at exaggerated levels, and conventional dairy products, in a variety of adult populations. There is no evidence that demonstrates a hazard to the public when S100 ingredients are used at levels that might reasonably be expected from the proposed applications.     

Practical Considerations for Dose Selection in Pediatric Patients to Ensure Target Exposure Requirements

Pediatric dosing recommendations are often not based on allometry, despite recognition that metabolic processes in mammals scale to the ¾ power. This report reviews the allometric size model for clearance and its implications for defining doses for children while considering practical limitations. Fondaparinux exposures in children were predicted using allometric and mg/kg dosing. Additional simulations further refined the dose based on the predicted Cmax, target exposure range, complexity of the dosing regimen, and previous exposure/response data. The percent reduction of the adult dose of an oral lozenge fixed-dose formulation which would predict similar exposures in children and adults was recommended based on simulations. Allometric dosing predicted a consistent fondaparinux exposure across the weight range. Size-optimized mg/kg dosing, which partially approximates the allometric relationship, allows for consistent fondaparinux exposures (i.e., 0.12 mg/kg ≤35 kg or 0.1 mg/kg >35 kg). Simulations of the oral lozenge formulation demonstrated rapidly changing clearance in children less than 6 years prohibiting practical dosing recommendations for satisfying all conventional exposure metrics (Cmax and AUC) in this age group. In children between 13 and 18 or 6 and 13 years, a 8.6% and 54% reduction in dose would maintain target exposures but dose reductions of 12.5% or 62.5% were ultimately recommended as deemed manufacturable. Dose selection in children should consider the known and/or predicted covariate relationships which affect exposure. Presented examples applied the allometric model in dose selection with the goal of PK bridging and considered practical limitations in dose selection.     

Impact of subsistence production on the management options to reduce the food exposure of the Martinican population to Chlordecone

Chlordecone is an organochlorine insecticide used until 1993 in the banana plantations of the French Antilles. Recent surveys revealed its wide presence in the environment. This current paper focuses on the impact of different management options on the Martinican population's food exposure, taking into account that an appreciable part of the food consumed in Martinique corresponds to subsistence production. Food exposure is assessed through deterministic models. Consumption data derive from the ESCAL Survey on 1814 subjects aged 3 and over. Residues data come from the Monitoring Programs 2002-2004. Different scenarios are studied depending on whether the subjects live on a soil-contaminated place or not and on their supply habits. The impact of various maximum limits is then analysed. The probability of exceeding the chronic health-based guidance value (CHGV) of 0.5 microg/kg bw/day is, respectively, 20.9% (CI(95th) [6.2; 34.4]) and 15.6% (CI(95th) [9.6; 20.8]) for children and adults living in a soil-contaminated area and null for the remaining population. MLs below 300 microg/kg fw would reduce significantly the exposure but the probability of exceeding the CHGV remains statistically different from zero when only commercialised products are taken into account. This study shows the supply habits may have significant impacts on food exposure to contaminants. It reveals that setting MLs, which can only be controlled on commercialised products, is not enough in such situations. Other management options like consumption recommendations for self-produced foodstuffs are necessary to protect the Martinican consumer.     

Maternal flaxseed diet during pregnancy or lactation increases female rat offspring's susceptibility to carcinogen-induced mammary tumorigenesis

Flaxseed contains several dietary components that have been linked to low breast cancer risk; i.e., n-3 polyunsaturated fatty acids (PUFAs), lignans and fiber, but it also contains detectable levels of cadmium, a heavy metal that activates the estrogen receptor (ER). Since estrogenic exposures early in life modify susceptibility to develop breast cancer, we wondered whether maternal dietary intake of 5% or 10% flaxseed during pregnancy or lactation (between postpartum days 5 and 25) might affect 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis in the rat offspring. Our data indicated that both in utero and postnatal 5% and 10% flaxseed exposures shortened mammary tumor latency, and 10% flaxseed exposure increased tumor multiplicity, compared to the controls. Further, when assessed in 8-week-old rats, in utero 10% flaxseed exposure increased lobular ER-alpha protein levels, and both in utero and postnatal flaxseed exposures dose-dependently reduced ER-beta protein levels in the terminal end buds (TEBs) lobules and ducts. Exposures to flaxseed did not alter the number of TEBs or affect cell proliferation within the epithelial structures. In a separate group of immature rats that were fed 5% defatted flaxseed diet (flaxseed source different than in the diets fed to pregnant or lactating rats) for 7 days, cadmium exposure through the diet was six-fold higher than allowed for humans by World Health Organization, and cadmium significantly accumulated in the liver and kidneys of the rats. It remains to be determined whether the increased mammary cancer in rats exposed to flaxseed through a maternal diet in utero or lactation was caused by cadmium present in flaxseed, and whether the reduced mammary ER-beta content was causally linked to increased mammary cancer risk among the offspring.     

The utility of mixed-effects covariate analysis in rapid selection of doses in pediatric subjects: a case study with fexofenadine hydrochloride

Fexofenadine hydrochloride is a non-sedating antihistamine that is used in the treatment of symptoms associated with seasonal allergic rhinitis and chronic idiopathic urticaria. A pooled analysis of pharmacokinetic data from children 6 months to 12 years of age and adults was conducted to identify the dose(s) in children that produce exposures comparable to those in adults for the treatment of seasonal allergic rhinitis. The pharmacokinetic parameter database included peak and overall exposure data from 269 treatment exposures from 136 adult subjects, and 90 treatment exposures from 77 pediatric allergic rhinitis patients. The data were pooled and analysed using NONMEM software, version 5.0. A covariate model based on body weight and age and a power function model based on body weight were identified as appropriate models to describe the variability in fexofenadine oral clearance and peak concentration, respectively. Individual oral clearance estimates were on average 44%, 36% and 61% lower in children 6 to 12 years (n=14), 2 to 5 years (n=21), and 6 months to 2 years (n=42), respectively, compared with adults. Trial simulations (n=100) were carried out based on the final pharmacostatistical models and parameter estimates to identify the appropriate dose(s) in children relative to the marketed dose of 60 mg fexofenadine hydrochloride in adults. The trials were designed as crossover studies in 18 subjects comprising various potential dosing regimens with and without weight stratification. Pharmacokinetic parameter variability was assumed to have a log-normal distribution. Individual weights and ages were simulated using mean (SD) estimates derived from the studies used in this analysis and proportional measurement/model mis-specification errors derived from the analysis were incorporated into the simulation. The results indicated that a 30 mg dose of fexofenadine hydrochloride administered to children 1 to 12 years of age and weighing >10.5 kg and a 15 mg dose administered to children 6 months and older and weighing 相似文献