Management options to reduce exposure to methyl mercury through the consumption of fish and fishery products by the French population

This paper presents an updated assessment of exposure in France to methyl mercury through the consumption of fish and fishery products, and proposes several management scenarios which could reduce this exposure through changes to fish contamination levels or fish consumption patterns. The exposure model was applied in line with previous methodological results [Tressou, J., Crépet, A., Bertail, P., Feinberg, M.H., Leblanc J.Ch., 2004a. Probabilistic exposure assessment to food chemicals based on extreme value theory: application to heavy metals from fish and sea products. Food Chem. Toxicol. 42, 1349-1358; Tressou, J., Leblanc, J.Ch., Feinberg, M., Bertail, P., 2004b. Statistical methodology to evaluate food exposure to a contaminant and influence of sanitary limits: application to ochratoxin A. Regul. Toxicol. Pharmacol. 40, 252-263] so as to obtain a realistic estimate of probability and confidence intervals (95% CI) concerning French consumers exposed to levels exceeding the revised fixed provisional tolerable weekly intake (PTWI) for methyl mercury of 1.6 microg/week/kg of body weight, established by the Joint FAO/WHO Expert Committee on Food Additives in 2003. The results showed that young children aged between 3 and 6 years old or 7 and 10 years old, and women of childbearing age were at the risk groups. With respect to these groups and according to the fish consumers patterns (consumers of predatory fish only or consumers of predatory and nonpredatory fish), the results suggested that strategies to diminish MeHg exposure by reducing the amount of predatory fish consumed would be more efficient in significantly decreasing the probability of exceeding the PTWI than the implementation of international standards.     

Dietary exposure of 18-month-old Guadeloupian toddlers to chlordecone

Chlordecone is an organochlorine insecticide used in the French West Indies until 1993. Toddlers are expected to be differently exposed than older children and adults. The dietary exposure to chlordecone of 18-month-old Guadeloupian toddlers was assessed through different scenarios depending on whether the subjects live on a soil-contaminated place or not and on their supply habits. Food contamination data came from the RESO study performed in 2005–2006. Consumption data derived from a dietary survey conducted in 2005–2008. Results were compared to those of other age groups. Chronic dietary exposures to chlordecone were estimated in a range of 0.018–0.051 μg/kg bw/day (P95: 0.044–0.096) for toddlers living in a non contaminated area and between 0.045–0.078 μg/kg bw/day (P95: 0.110–0.144) for toddlers living in a contaminated area. The probability of exceeding the chronic health-based value of 0.5 μg/kg bw/day was null. These results suggest that 18-month-old toddlers are less exposed than groups aged over 3 years old. This can be explained by their consumption pattern mostly based on milk and fruits, which are not highly contaminated by chlordecone. The acute health-based value of 10 μg/kg bw/day could be exceeded when consuming of highly contaminated taros, showing the importance of regulatory maximum limit.     

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.     

Variability and uncertainty assessment of patulin exposure for preschool children in Flanders.

The objective of the present study was to evaluate the patulin exposure of children consuming organic, handcrafted or conventional apple juice through a probabilistic approach and to evaluate the effectiveness of several risk management options aiming to reduce the risk for children due to patulin exposure. However, a large part of the data on patulin contamination of apple juice fell under the limit of detection (LOD). Different methods were tested to deal with these so-called left censored data and a uniform distribution with uncertain bounds was selected to handle this censorship. Variability and uncertainty assessment of patulin exposure showed that 0.9% [90% confidence interval (CI): 0.3-1.8%] of the children consuming only organic apple juice exceed the tolerable daily intake (TDI). For consumers of conventional and handcrafted apple juice this was respectively 0.1% [90% CI: 0-0.3%] and 0% [90% CI: 0-0.2%]. Reduction of the patulin contamination in apple juice to concentrations below 25 microg/kg reduced the percentage of the children exceeding the TDI to 0% [90%CI: 0-0.2%] for organic apple juice. Reduction of the apple juice consumption was less effective than a reduction of the patulin concentration in apple juice and is only useful when the patulin concentration of apple juice is below 25 microg/kg.     

Acrylamide exposure from foods of the Dutch population and an assessment of the consequent risks.

At the end of April 2002, the Swedish Food Administration reported the presence of acrylamide in heat treated food products. Acrylamide has been shown to be toxic and carcinogenic in animals, and has been classified by the WHO/IARC among others as 'probably carcinogenic for humans'. The purposes of this study were firstly to analyse acrylamide contents of the most important foods contributing to such exposure, secondly, to estimate the acrylamide exposure in a representative sample of the Dutch population, and thirdly to estimate the public health risks of this consumption. We analysed the acrylamide content of foods with an LC-MS-MS method. The results were then used to estimate the acrylamide exposure of consumers who participated in the National Food Consumption Survey (NFCS) in 1998 (n=6250). The exposure was estimated using the probabilistic approach for the total Dutch population and several age groups. For 344 food products, acrylamide amounts ranged from <30 to 3100 microg/kg. Foods with the highest mean acrylamide amounts were potato crisps (1249 microg/kg), chips (deep-fried) (351 microg/kg), cocktail snacks (1060 microg/kg), and gingerbread (890 microg/kg). The mean acrylamide exposure of the NFCS participants was 0.48 microg/kg bw/day. Risk of neurotoxicity is negligible. From exposure estimations it appears that the additional cancer risk might not be negligible.     

A comparison of plethysmography, spirometry and oscillometry for assessing the pulmonary effects of inhaled ipratropium bromide in healthy subjects and patients with asthma

AIMS: We have compared the ability of plethysmography (sGaw), impulse oscillometry (IOS) and spirometry (FEV(1), MMEF) to detect bronchodilation in response to an anticholinergic. METHODS: IOS (R5, R20, X5, RF), sGaw and spirometry were measured in 12 healthy subjects and 12 asthmatics. Variability was assessed by performing two measurements, 30 min apart and the effect of increasing the number of readings for each sGaw measurement was also studied. Ipratropium bromide (IB) 10, 20, 100 and 200 microg was administered and the sensitivity of the methods compared by determining the lowest dose that caused changes greater than variability. RESULTS: In healthy subjects significant changes (P < or = 0.05) occurred at 10 microg for FEV(1) (mean [95% CI]; 1.3%[0.3-2.3]), R5 (mean [95% CI]; -7.9%, [-13.2-2.6]) and R20 (mean [95% CI], -6.4%, [-11.4-1.4]). No significant change was detected when the mean of 3 sGaw readings was used, but with 10 readings significant change was observed at 20 microg; (mean increase [95% CI] 15.2%[8.3-22.1]). In asthmatics significant changes (P < or = 0.05) occurred with IB 10 microg for sGaw (mean [95% CI] 25.6%[11.1-40.1]), R5 (mean [95% CI]-11.3%, [-15.5-7.2]), RF (mean [95% CI] 11.7%[6.1-16.3]), FEV(1) (mean [95% CI] 5.1%[2.6-7.7]) and MMEF (mean [95% CI] 12.3%[2.3-22.2]). CONCLUSION: IOS and spirometry are more sensitive than sGaw in healthy subjects, but the sensitivity of sGaw improved when the number of readings was increased. The most sensitive method for assessing bronchodilation in asthmatics was sGaw.     

Metabolic coronary-flow regulation and exogenous nitric oxide in human coronary artery disease: assessment by intravenous administration of nitroglycerin

We sought to evaluate the effect of intravenous administration of the nitric oxide--donor substance nitroglycerin (NTG) on metabolic coronary-flow regulation in patients with coronary artery disease (CAD). In 12 patients with stable CAD, we measured coronary sinus blood flow and myocardial oxygen supply and consumption (MVO2) at sinus rhythm and during atrial pacing (30 beats/min above sinus rate), both at control and during infusion of NTG, 1 microg/kg/min, and NTG, 2 microg/kg/min. To study metabolic coronary vasodilation, changes in myocardial oxygen supply were related to pacing-induced changes in MVO2, by using standard regression analysis. The myocardial oxygen supply/consumption ratio (i.e., the slope of the regression line at control, characterizing physiological metabolic coronary flow regulation) was compared with the ratios obtained during infusion of NTG. Compared with control measurements, NTG, 1 microg/kg/min, and NTG, 2 microg/kg/min, attenuated pacing-induced increases in MVO2 by 29 and 60%, respectively, whereas coronary blood flow during pacing remained unchanged. At control, normal metabolic coronary-flow regulation resulted in a myocardial oxygen supply/demand ratio of 1.39 (95% CI, 1.29-1.49). This ratio did not change during NTG, 1 microg/kg/min: 1.44 (95% CI, 1.33-1.56). However, during NTG, 2 microg/kg/min, this ratio significantly increased to 1.84 (95% CI, 1.63-2.05; p<0.01). Intravenous administration of high-dose NTG, a donor of exogenous NO, blunts pacing-induced increases in MVO2 and may increase metabolic coronary vasodilation in patients with CAD.     

Chlorpromazine as a discriminative stimulus in rats: Generalization to typical and atypical antipsychotics

The discriminative stimulus properties of the typical antipsychotic chlorpromazine were examined in a two‐lever drug discrimination procedure for food reward. Six of nine rats readily acquired the discrimination between 1.0 mg/kg chlorpromazine (i.p.) and vehicle in a mean of 29.7 training sessions. The chlorpromazine generalization curve was dose‐dependent and yielded an ED₅₀ of 0.305 mg/kg (95% confidence interval (CI) = 0.201–0.463 mg/kg). The chlorpromazine cue generalized to the atypical antipsychotics clozapine (ED₅₀ for the clozapine curve was 0.258 mg/kg [95% CI = 0.047–1.420 mg/kg]) and olanzapine (ED₅₀ for the olanzapine curve was 0.199 mg/kg [95% CI = 0.076–0.522 mg/kg]) and to the typical antipsychotic thioridazine (ED₅₀ for the thioridazine curve was 3.103 mg/kg [95% CI = 1.993–4.832 mg/kg]). Haloperidol (a typical antipsychotic) and raclopride (an atypical antipsychotic) did not substitute for chlorpromazine. It is clear from the present results that the discriminative stimulus properties of chlorpromazine share similarities both with the atypical antipsychotics clozapine and olanzapine and with the typical antipsychotic thioridazine. The extent to which the discriminative stimulus properties of antipsychotic drugs reflect or are predictive of their therapeutic effects in schizophrenic patients remains unclear. Drug Dev. Res. 48:38–44, 1999. © 1999 Wiley‐Liss, Inc.     

Exploration of different methods to assess dietary acrylamide exposure in pregnant women participating in the Norwegian Mother and Child Cohort Study (MoBa)

We assessed dietary exposure to acrylamide in 119 pregnant Norwegian women. The aim of the study was to explore three different methods for estimation of long-term intake of acrylamide and whether it is possible by a food frequency questionnaire (FFQ) to identify pregnant women with high exposure to acrylamide. Acrylamide excreted as mercapturic acid metabolites in 24-h urine was used as an evaluation tool. Food consumption was assessed by an FFQ and by a 4-day weighed food diary (FD). Acrylamide intake was also estimated by a probabilistic approach based on 2 days from the FD. Primarily, acrylamide concentrations reported from analyses of Norwegian foods were used. The dietary exposure to acrylamide estimated as mug/kg bw/day (median and 95 percentile) was 0.48 (0.92) by the FFQ, 0.41 (0.82) by the FD and 0.42 (0.70) by the probabilistic approach. The amount of acrylamide excreted as urinary metabolites (median and 95 percentile) was 0.16 microg/kg bw/24-h (0.50) in non-smokers, corresponding to a dietary exposure of approximately 0.30 microg/kg bw/day (0.91). Linear regression of acrylamide excreted as urinary metabolites identified crisp bread and potato crisps as significant independent predictors, along with cooking oil and onion/garlic. Dietary exposure to acrylamide calculated by FFQ, FD and probabilistic modelling were comparable. The comparison of FFQ acrylamide estimates with levels of urinary acrylamide metabolites showed that the MoBa FFQ was able to identify participants with high dietary acrylamide exposure. Our findings facilitate future studies on acrylamide exposure and health outcomes in the MoBa study.     

Minireview on the toxicity of dietary acrylamide.

Acrylamide is a commodity chemical with many industrial and laboratory uses. It is also formed from carbohydrate and amino acid containing food by heating (primarily in fried potato products, bread, coffee). Neurotoxicity was detected as the primary toxic effect after occupational exposure. In rats and mice AA is toxic for reproduction and development and to male germ cells, is genotoxic through a reactive metabolite, glycidamide, and carcinogenic to several organs. Epidemiological studies did not point to an association between either occupational or dietary exposure and an excess of cancer incidence. Health risks of the general population are based on an average exposure to 1 microg/kg bw/day increasing for high consumers to 4 microg/kg bw/day. For average consumers a margin of exposure of 200 for neurotoxicity can be regarded as sufficiently protective. However, a margin of 300 for carcinogenic risks appears not sufficient when applying a precautionary principle. This is also illustrated when the benchmark dose lower confidence limit for cancer is divided by an uncertainty factor of 300, which arrives at a tolerable daily intake of 1 microg/kg bw/day, and thus is in the range of average consumption. Further measures to minimize acrylamide formation in food should therefore be explored to reduce human exposure.     

Estimation of dietary exposure to acrylamide of Polish teenagers from an urban environment

The aim of this study was to evaluate the dietary exposure to acrylamide (AA) in a group of teenagers (n = 261) from an urban environment. The intake of AA from food was estimated based on a 7-day food record diary (consecutive days). The food rations obtained (n = 1827) were used to calculate the amounts of the consumed food products, which were the main sources of AA. In the case of girls, the estimated dietary intake of AA per kg body weight (BW) amounted to 0.09 µg/kg BW/day (50th percentile), 0.32 µg/kg BW/day (75th percentile) and 1.04 µg/kg BW/day (95th percentile), and among boys it was 0.13, 0.41, and 1.18 µg/kg BW/day, respectively. The main sources of AA exposure were French fries, potato crisps, corn flakes, bread and salty sticks. The lowest values for margin of exposure (MOE) were calculated for the P95th percentiles of exposure, and ranged from 152 to 173.     

Economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts.

The economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts is described. The pharmacodynamics of novel meropenem dosing regimens were compared with FDA-approved regimens by using Monte Carlo simulation with 5000 subjects. Using the meropenem NCCLS-susceptibility breakpoint of 4 micrograms/mL, the percentage of the dosing interval that drug concentration remained above the minimum inhibitory concentration (%t > MIC) was calculated for each regimen. Probability distributions for half-life and volume of distribution using previously published pharmacokinetic data from healthy volunteers were developed. Cost-minimization analysis was performed from the institution's perspective using both drug acquisition and supply costs. Daily costs for the lower dosage regimens were calculated using 2001 average wholesale prices. The mean %t > MIC for meropenem 500 mg administered every six hours (43.91% [95% confidence interval (CI), 36.77-51.46%]) was similar to that of 1000 mg every eight hours (45.77% [95% CI, 40.06-50.69%]). The mean %t > MIC for meropenem 1000 mg administered every six hours (61.02% [95% CI, 54.71-67.43%]) was similar to the regimen of 2000 mg every eight hours (57.77% [95% CI, 51.84-63.76%]). The 500-mg regimen reduced drug costs by $38.64 per day compared with the standard regimen of 1000 mg administered every eight hours. A pharmacodynamically influenced dosage strategy for meropenem resulted in %t > MIC exposure similar to standard regimens and required a lesser amount of the drug, thereby reducing costs without compromising efficacy.     

Does gender, food or grapefruit juice alter the pharmacokinetics of primaquine in healthy subjects?

AIMS: To evaluate the effects of gender, food and grapefruit juice on the pharmacokinetics of primaquine in healthy subjects. METHODS: In a randomized, two-phase cross-over study, 10 male and 10 female healthy Vietnamese subjects were administered 30 mg primaquine in the fasting state or with food, followed by administration of primaquine with grapefruit juice. RESULTS: The pharmacokinetics of primaquine were comparable between male and female subjects, with geometric mean ratios of Cmax = 0.89 [95% confidence interval (CI) 0.65, 1.22] and AUC = 0.80 (95% CI 0.56, 1.15). The mean CL/F of primaquine was slightly higher in males than in females [0.52 l h(-1) kg(-1)vs. 0.43 l h(-1) kg(-1), mean difference of 0.09 (95% CI -0.10, 0.28), P = 0.32]. When compared with fasting state values, food increased the geometric mean Cmax of primaquine by 26% (95% CI 12, 40) and the AUC by 14% (95% CI 3, 27). Similarly, grapefruit juice increased the geometric mean Cmax by 23% (95% CI 4, 45) and the AUC by 19% (95% CI 4, 37). CONCLUSIONS: The disposition of primaquine was comparable between genders, suggesting no need to modify the dose of primaquine for malaria treatment or prophylaxis. Food increased the oral bioavailability of primaquine, which may lead to higher antimalarial efficacy. Grapefruit juice increased the bioavailability of primaquine, with marked interindividual differences suggesting that people should not take primaquine with grapefruit juice.     

Analysis of multivariate extreme intakes of food chemicals.

A recently published multivariate Extreme Value Theory (EVT) model is applied to the estimation of population risks associated with dietary intake of pesticides. The objective is to quantify the acute risk of pesticide intake above a threshold and relate it to the consumption of specific primary food products. As an example daily intakes of a pesticide from three foods are considered. The method models and extrapolates simultaneous intakes of pesticide, and estimates probability of exceeding unobserved large intakes. Multivariate analysis was helpful in identifying whether the avoidance of certain food combinations would reduce the likelihood of exceeding a threshold. We argue that the presented method can be an important contribution to exposure assessment studies.     

Age dependent systemic exposure to inhaled salbutamol

AIMS: To determine the effect of age on systemic exposure to inhaled salbutamol in children. METHODS: Fifty-eight asthmatic children, aged 3-16 years, inhaled 400 microg of salbutamol from a pressurized metered dose inhaler with spacer. The 20 min serum profile was analyzed. RESULTS: Prescribing a dose on a microg kg(-1) basis caused reduced systemic exposure in young children (Y) compared with older children (O) (C(max-microg kg(-1)-adjusted) Y : O ratio (95%CI) = 0.55 (0.47, 0.65)) whereas a fixed nominal dose irrespective of age caused increased exposure in young children (C(max) Y : O ratio (95%CI) = 1.7 (1.3, 2.2)). CONCLUSIONS: For similar systemic exposure, dosing should be adjusted to age or size but not on a fixed microg kg(-1) basis, which may lead to unnecessary suboptimal dosing.     

An integrative risk assessment approach for persistent chemicals: A case study on dioxins,furans and dioxin-like PCBs in France

For persistent chemicals slowly eliminated from the body, the accumulated concentration (body burden), rather than the daily exposure, is considered the proper starting point for the risk assessment. This work introduces an integrative approach for persistent chemical risk assessment by means of a dynamic body burden approach. To reach this goal a Kinetic Dietary Exposure Model (KDEM) was extended with the long term time trend in the exposure (historic exposure) and the comparison of bioaccumulation with body burden references for toxicity. The usefulness of the model was illustrated on the dietary exposure to PolyChlorinatedDibenzo-p-Dioxins (PCDDs), PolyChlorinatedDibenzoFurans (PCDFs) and PolyChlorinated Biphenyls (PCBs) in France. Firstly the dietary exposure to these compounds was determined in 2009 and combined with its long term time trend. In order to take differences between the kinetics of PCDD/F and dl-PCBs into account, three groups of congeners were considered i.e. PCDD/Fs, PCB 126 and remaining dl-PCBs. The body burden was compared with reference body burdens corresponding to reproductive, hepatic and thyroid toxicity. In the case of thyroid toxicity this comparison indicated that in 2009 the probability of the body burden to exceed its reference ranged from 2.8% (95% CI: 1.5–4.9%) up to 3.9% (95% CI: 2.7–7.1%) (18–29 vs. 60–79 year olds). Notwithstanding the decreasing long-term time trend of the dietary dioxin exposure in France, this probability still is expected to be 1.5% (95% CI: 0.3–2.5%) in 2030 in 60–79 olds. In the case of reproductive toxicity the probability of the 2009 body burden to exceed its reference ranged from 3.1% (95% CI: 1.4–5.0%) (18–29 year olds) to 3.5% (95% CI: 2.2–5.2%) (30–44 year olds). In 2030 this probability is negligible in 18–29 year olds, however small though significant in 30–44 year olds (0.7%, 95% CI: 0–1.6%). In the case of hepatic toxicity the probability in 2009 even in 60–79 year olds already was negligible. In conclusion this approach indicates that in France dioxin levels in food form a declining, though still present, future health risk with respect to thyroid and reproductive toxicity.     

Dietary intake of acrylamide in Sweden.

High levels of acrylamide have been found in foods heated at high temperatures, especially in carbohydrate rich foods. Several kinds of foods (industrially produced) representing different food/product groups available on the Swedish market have been analysed for acrylamide. A considerable variation in levels of acrylamide between single foodstuffs (different brands) within food categories were found, which also applies for levels in different food categories. Using recent Swedish food consumption data the dietary intake of acrylamide for the Swedish adult population was assessed based on foodstuffs with low to high levels of acrylamide (<30-2300 microg/kg), such as processed potato products, bread, breakfast cereals, biscuits, cookies, snacks and coffee. The estimated dietary intake of acrylamide per person (total population) given as the 5th, 50th and 95th percentile were 9.1, 27 and 62 microg/day respectively, from those food/product groups (mean 31 microg/day). No acrylamide was found in many other foodstuffs analysed and those were therefore not included in the dietary intake assessment of acrylamide. However, an additional minor contribution of a few microg/day of acrylamide from foods/products like poultry, meat, fish, cocoa powder and chocolates cannot be excluded. An average daily intake of 35 microg corresponds to 0.5 microg per kg body weight and day (body weight 70 kg). Risk assessments of acrylamide, made by US EPA and WHO, imply that this dietary intake of acrylamide could be associated with potential health risks.     

Current use of nonsteroidal antiinflammatory drugs and the risk of acute myocardial infarction

STUDY OBJECTIVE: To evaluate the risk of acute myocardial infarction during current exposure to nonsteroidal antiinflammatory drugs (NSAIDs). DESIGN: Retrospective case-control analysis. SETTING: General practice offices. SUBJECTS: A total of 8688 case patients, aged 89 years or younger, with a first-time acute myocardial infarction and 33,923 control subjects matched on age, sex, calendar time, and general practice attended. INTERVENTION: The United Kingdom General Practice Research Database was searched for potential cases of first-time acute myocardial infarction between January 1995 and April 2001. Control subjects without acute myocardial infarction were identified at random. MEASUREMENTS AND MAIN RESULTS: Exposure to NSAIDs was assessed, and 650 case patients and 2339 control subjects were found to be currently taking NSAIDs. After adjusting for various risk factors for acute myocardial infarction (e.g., hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, body mass index, smoking), the relative risk (expressed as odds ratio [OR]) of acute myocardial infarction was 1.07 (95% confidence interval [CI] 0.96-1.19) for subjects with current NSAID exposure compared with those not taking NSAIDs. The adjusted OR for current diclofenac use was 1.23 (95% CI 1.00-1.51), for current ibuprofen use 1.16 (95% CI 0.92-1.46), and for current naproxen use 0.96 (95% CI 0.66-1.38) compared with those not taking NSAIDs. Current aspirin use combined with current NSAID use was associated with a statistically significant risk reduction (adjusted OR 0.74, 95% CI 0.57-0.97), compared with nonuse of NSAIDs and aspirin. Current use of aspirin together with current use of ibuprofen yielded an adjusted OR of 0.69 (95% CI 0.42-1.15). CONCLUSIONS: Our results provide additional evidence that the risk of first-time acute myocardial infarction during current use of NSAIDs is not materially altered. We found no evidence for a reduced cardioprotective effect of aspirin with concomitant NSAID use.