Canned Fish Consumption and Upper Digestive Tract Cancers.

Canned fish is a widely consumed and affordable food whose effect on cancer risk has been little investigated. We studied its effect on risk of upper digestive tract cancers using data from a network of hospital-based case-control studies from Northern Italy providing information about canned fish consumption as a separate item and including a total of 946 patients with oral cavity and pharynx cancer, 304 patients with esophageal cancer, 230 patients with gastric cancer and 3273 controls. Twenty-three percent of patients with cancer of the oral cavity or pharynx and 26% of those with cancer of the stomach consumed ≥1 serving per week of canned fish, compared to 40% and 49% of the respective control group. Among cases of esophageal cancer and controls 22% consumed ≥1 serving per week of canned fish. Odds ratios for ≥1 vs <1 portion per week were 0.79 (95% Confidence Interval, CI: 0.64-0.97) for cancer of the oral cavity and pharynx, and 0.59 (95% CI: 0.41-0.86) for stomach cancer, whereas there was no inverse association with esophageal cancer. These findings suggest a favorable role of canned fish for selected upper digestive tract cancers.

Toxicology of 3-monochloropropane-1,2-diol and its esters: a narrative review.

3-Monochloropropane-1,2-diol (3-MCPD) is a chiral molecule naturally existing as a racemic mixture of (R)- and (S)-enantiomers. It was thoroughly investigated during the 1970s as a male antifertility drug until research was abandoned because of the side effects observed in toxicity studies. More than 20 years later, 3-MCPD, both in the free form and esterified to the fatty acids, was detected in vegetable oil and discovered to be a widespread contaminant in different processed foods. This review summarises the main toxicological studies on 3-MCPD and its esters. Current knowledge shows that the kidney and reproductive system are the primary targets of 3-MCPD toxicity, followed by neurological and immune systems. Despite uncertainties, in vivo studies suggest that renal and reproductive toxicity is mediated by toxic metabolites, leading to inhibition of glycolysis and energy depletion. Few acute, short-term, and subchronic toxicity studies have investigated the 3-MCPD esters. The pattern of toxicity was similar to that of free 3-MCPD. Some evidence suggests that the toxicity of 3-MCPD diesters may be milder than 3-MCPD, likely because of an incomplete enzymatic hydrolysis in the equivalent free form in the gastrointestinal tract. Further research to clarify absorption, metabolism, and long-term toxicity of 3-MCPD esters would be pivotal to improve the risk assessment of these compounds via food.

Identification of Sulfonated and Hydroxy-Sulfonated Polychlorinated Biphenyl (PCB) Metabolites in Soil: New Classes of Intermediate Products of PCB Degradation?

In this paper we describe the identification of two classes of contaminants: sulfonated-PCBs and hydroxy-sulfonated-PCBs. This is the first published report of the detection of these chemicals in soil. They were found, along with hydroxy-PCBs, in soil samples coming from a site historically contaminated by the industrial production of PCBs and in background soils. Sulfonated-PCB levels were approximately 0.4-0.8% of the native PCB levels in soils and about twice the levels of hydroxy-sulfonated-PCBs and hydroxy-PCBs. The identification of sulfonated-PCBs was confirmed by the chemical synthesis of reference standards, obtained through the sulfonation of an industrial mixture of PCBs. We then reviewed the literature to investigate for the potential agents responsible for the sulfonation. Furthermore, we predicted their physicochemical properties and indicate that, given the low pKa of sulfonated- and hydroxy-sulfonated-PCBs, they possess negligible volatility, supporting the case for in situ formation from PCBs. This study shows the need of understanding their origin, their role in the degradation path of PCBs, and their fate, as well as their (still unknown) toxicological and ecotoxicological properties.

Dietary fats and cardiovascular health: a summary of the scientific evidence and current debate.

This narrative review summarises the main studies of the role of the different fatty acids in coronary heart disease (CHD) and cardiovascular disease (CVD) risk and the current scientific debate on dietary recommendations. Reduction and substitution of the saturated fatty acids (SFAs) with the polyunsaturated fatty acids (PUFAs) are still the main dietary recommendation to prevent CHD and CVD. In the last few years, however, the strength of the scientific evidence underlying this dietary advice has been questioned. Recent investigations reappraise the previously declared deleterious role of the SFAs and reduce the positive role of PUFAs, mainly the omega-6, whereas the role of monounsaturated fatty acids (MUFAs) remains unclear. In contrast, the negative effects of trans fatty acids (TFAs) seem stronger than previously thought. Finally, criticisms have emerged from a dietary recommendation approach focussed on individual components rather than on wide food items and eating habits.

Wastewater-based epidemiological evaluation of the effect of air pollution on short-acting beta-agonist consumption for acute asthma treatment.

Asthma, one of the most common chronic diseases in the world and a leading cause of hospitalization among children, has been associated with outdoor air pollution. We applied the wastewater-based epidemiology (WBE) approach to study the association between the use of salbutamol, a short-acting beta-agonist used to treat acute bronchospasm, and air pollution in the population of Milan, Italy. Composite 24-h samples of untreated wastewater were collected daily and analyzed for human metabolic residues of salbutamol by liquid chromatography tandem mass spectrometry. Corresponding daily outdoor concentrations of particular matter up to 10µm (PM10) and 2.5µm (PM2.5) in aerodynamic diameter, nitrogen dioxide, ozone, sulfur dioxide, and benzene were collected from the public air monitoring network. Associations at different lag times (0-10 days) were assessed by a log-linear Poisson regression model. We found significant direct associations between defined daily doses (DDD) of salbutamol and mean daily concentrations of PM10 and PM2.5 up to nine days of lag time. The highest rate ratio, and 95% confidence interval (CI), of DDD of salbutamol was 1.06 (95% CI: 1.02-1.10) and 1.07 (95% CI: 1.02-1.12) at seven days of lag time and for an increase of 10 µg/m(3) of PM10 and PM2.5, respectively. Reducing the mean daily PM10 concentration in Milan from 50 to 30µg/m(3) means that 852 (95% CI: 483-1504) daily doses of salbutamol per day would not be used. These results confirm the association between asthma and outdoor PM10 and PM2.5 and prove the potential of the WBE approach to quantitatively estimate the relation between environmental exposures and diseases.

Protein profiling reveals energy metabolism and cytoskeletal protein alterations in LMNA mutation carriers.

Nuclear envelope-related muscular dystrophies, in particular those referred to as laminopathies, are relatively novel and unclear diseases, also considering the increasing number of mutations identified so far in genes of the nuclear envelope. As regard LMNA gene, only tentative relations between phenotype, type and localization of the mutations have been established in striated muscle diseases, while laminopathies affecting adipose tissue, peripheral nerves or progerioid syndromes could be linked to specific genetic variants. This study describes the biochemical phenotype of neuromuscular laminopathies in samples derived from LMNA mutant patients. Since it has been reported that nuclear alterations, due to LMNA defects, are present also in fibroblasts from Emery-Dreifuss muscular dystrophy and familial partial lipodystrophy patients, we analyzed 2D-maps of skin fibroblasts of patients carrying 12 different LMNA mutations spread along the entire gene. To recognize distinctive proteins underlying affected biochemical pathways, we compared them with fibroblasts from healthy controls and, more importantly, fibroblasts from patients with non-lamin related neuromuscular disorders. We found less abundance of cytoskeletal/structural proteins, confirming a dominant role for Lamin A/C in structural support of nuclear architecture. Interestingly, we also established significant changes in the expression of proteins involved in cellular energy production and oxidative stress response. To our knowledge, this is the first report where proteomics was applied to characterize ex-vivo cells from LMNA patients, suggesting that this may represent a new approach to better understand the molecular mechanisms of these rare diseases and facilitate the development of novel therapeutic treatments.

Establishment of the cumulative margin of exposure for a group of polychlorinated biphenyl (PCB) congeners using an improved approach that accounts for both variability and uncertainty.

In this study, the cumulative margin of exposure (MOE) was estimated for a group of polychlorinated biphenyls (PCBs) based on reduction of hepatic retinoids as a mode-of-action relevant toxicological endpoint. The MOE was defined as the ratio between a reference dose, derived using the benchmark dose (BMD) approach, and the estimated human dietary PCB exposure. A distribution for the cumulative MOE was established, taking into account inter- and intra-individual variability as well as uncertainty in data measurements. The cumulative MOE reflected mainly the MOE for PCB 126; other PCB congeners had little contribution to the cumulative exposure and MOE. The median of the 0.1st percentile for the cumulative MOE was about 20 for women; depending on the percentile, cumulative MOE was 2-4 times higher for men compared to women. Furthermore, a relative potency factor (RPF) based approach was compared to an RPF-free approach for estimating the cumulative MOE. The RPF-free approach more completely accounts for variability and uncertainty but is more data intensive than the RPF-based approach, which can be more easily implemented in practice and allows for a use of historical data on RPFs. Consideration of the discussed approaches may contribute to improving cumulative health risk assessments.

Palm oil and palmitic acid: a review on cardiovascular effects and carcinogenicity.

We reviewed the scientific literature on the evidence of the relationship between palm oil and adverse effects on human health. Few studies have investigated the effects of palm oil per se, and the main reason why it has been associated with negative health effects is the relatively high content of saturated fatty acids (SFAs), particularly palmitic acid, which in turn have been associated with increased risk of coronary heart disease and some tumours. However, more recent investigations on the topic seem to have reconsidered the negative role of the dietary SFAs as a risk factor for cardiovascular diseases and show that not only the type of fat, but also that the triglyceride structure plays a role in cholesterolaemia. As regards to a role in cancer, specific studies on dietary palmitic acid or palm oil and the risk of cancer development are scanty, and the evidence is not convincing.

Inverse Association between Canned Fish Consumption and Colorectal Cancer Risk: Analysis of Two Large Case-Control Studies.

Fish is among the foods exerting favourable effects on colorectal cancer (CRC), but the possible role of canned fish has been insufficiently investigated. We aimed to investigate the relationship between canned fish consumption and CRC risk. We analysed data from two case−control studies conducted between 1992 and 2010 in several Italian areas, comprising a total of 2419 incident cases and 4723 hospital controls. Canned fish consumption was analysed according to the weekly frequency of consumption as <1 serving per week (s/w) (reference category), 1 < 2 s/w, and ≥2 s/w. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models, adjusting for several recognised confounding factors. Overall, canned fish consumption was lower among cases than among controls (23.8% vs. 28.6%). An inverse association was found between canned fish consumption and CRC risk with a significant trend in risk (OR = 0.81, 95% CI: 0.71−0.92 for intermediate consumption and OR = 0.66, 95% CI: 0.51−0.85 for the highest one), which was consistent across strata of several covariates. This study is the first to offer a basis of support for canned fish consumption as a component of a healthy diet, and it has relevant public health implications given the high ranking of CRC in incidence and mortality worldwide.

Human health risk in relation to air quality in two municipalities in an industrialized area of Northern Italy.

Air quality is one of the major environmental issues related to human health, and people and authorities are increasingly aware and concerned about it, asking to be involved in decisions whose fallout can have consequences on their health. The objectives of the present study were to provide quantitative data on the impact of air pollution on the health of people living in two small municipalities in a highly industrialized, densely populated area of Northern Italy. We applied the approach proposed by the World Health Organization (WHO) using the AirQ 2.2.3 software developed by the WHO European Centre for Environment and Health, Bilthoven Division. Daily concentrations of ozone, nitrogen dioxide, and particulate matter of aerodynamic diameter≤10 µm (PM10) and ≤2.5 µm (PM2.5) were used to assess human exposure and health effects in terms of attributable proportion of the health outcome, annual number of excess cases of mortality for all causes, and cardiovascular and respiratory diseases. Long-term effects were estimated for PM2.5 as years of life lost. Considering short-term effects, PM2.5 had the highest health impact on the 24,000 inhabitants of the two small towns, causing an excess of total mortality of 8 out of 177 in a year. Ozone and nitrogen dioxide each caused about three excess cases of total mortality. Results on long-term effects showed, respectively, 433, 180, and 72 years of life lost for mortality for all causes, cardiopulmonary diseases and lung cancer, in a year. These results are consistent with other reports of the impact of air quality on human health and the AirQ software seems an effective and easy tool, helpful in decision-making.

Effect of fructose instead of glucose or sucrose on cardiometabolic markers: a systematic review and meta-analysis of isoenergetic intervention trials.

CONTEXT: Free, or added, sugars are considered important determinants in the pandemics of obesity and associated chronic diseases, and fructose has emerged as the sugar of main concern. OBJECTIVE: The aim of this review was to assess the evidence of the effects of isoenergetic replacement of fructose or high-fructose corn syrup (HFCS) for glucose or sucrose on cardiometabolic markers in controlled dietary intervention trials. DATA SOURCES: The electronic databases PubMed/MEDLINE, the Cochrane Library, and Embase were searched from 1980 to May 5, 2020. STUDY SELECTION: Studies were eligible if they measured at least one of the following outcomes: total cholesterol, low- and high-density lipoprotein cholesterol, triacylglycerols, apolipoprotein A1, apolipoprotein B, systolic blood pressure, diastolic blood pressure, fasting glucose, and body weight. DATA EXTRACTION: For each outcome, the mean values and the corresponding measure of dispersion were extracted after the intervention or control diet. DATA ANALYSIS: Fixed-effects and random-effects models were used to pool study-specific estimates. Between-study heterogeneity was assessed by the χ2 test and the I2 statistic and publication bias by the Egger test and funnel plots. RESULTS: Twenty-five studies involving 1744 volunteers were identified. No significant effects were found when fructose or HFCS was substituted for glucose, except for a slight decrease in diastolic blood pressure when fructose was substituted for glucose. Similarly, no effects were found when fructose or HFCS was substituted for sucrose, except for a small increase, of uncertain clinical significance, of apolipoprotein B when HFCS was substituted for sucrose. CONCLUSIONS: Isoenergetic substitution of fructose or HFCS for glucose or sucrose has no significant effect on most of the cardiometabolic markers investigated; however, some results were affected by residual between-study heterogeneity and studies with high or unclear risk of bias. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42016042930.

Estimating temporal and spatial levels of PAHs in air using rain samples and SPME analysis: Feasibility evaluation in an urban scenario.

There is a growing interest in evaluating the role of concentration changes of contaminants in temporal and spatial gradients. This is often relevant for fast moving environmental phases such as air and water. In this paper, small volumes of rainwater were sampled as proxy for air concentrations of Polycyclic Aromatic Hydrocarbons (PAHs): rain was collected in three sampling sites (high traffic, restricted traffic and a low traffic zone) in Como. Solid phase micro extraction (SPME) was used for the extraction to reduce required sample volumes, allowing the acquisition of more samples in time. Rain samples highlighted a spatial and temporal variability along a traffic gradient in the Como city, especially for the most abundant PAH, e.g. phenanthrene. Air concentrations were then estimated from rain concentrations. The results show that this is a cheap and promising method, although requiring rainfall/snowfall conditions, that can be used to perform monitoring campaign of air concentrations at a higher temporal and spatial resolution than the adopted standard methods (e.g. high-volume air samplers). The results could be employed for evaluation of the exposure, emission profiles and calibration of fate models.

Micropollutants in Lake Como water in the context of circular economy: A snapshot of water cycle contamination in a changing pollution scenario.

In this work we evaluated the contamination of the water cycle in Como Bay by measuring 38 selected pharmaceuticals in two main wastewater treatment plant in Switzerland and in Italy, two influents (River Breggia and Cosia), lake water (epilimnion and hypolimnion), as well as potable water. The collection of comparative information on the presence and environmental fate of these substances contributes to set specific environmental quality standard (EQS). The results presented show that the contamination of the lake reflects national health policies, which deeply influence the usage of chemicals. The outcomes of this study give an overall picture of contamination in the area, showing that concentrations of the measured compounds are generally low and under the commonly adopted ecotoxicological and toxicological thresholds. Only in a few cases did the contamination appear to be noteworthy, for some of the most persistent compounds (antibiotic macrolides, diclofenac, irbesartan, carbamazepine and dihydrocarbamazepine, bezafibrate, furosemide and hydrochlorothiazide). Some concern can be also be raised for the presence of antibiotics (clarithromycin) in drinking water, although at very low levels, due to the problem of antibiotic resistance.

Risk assessment of a mixture of emerging contaminants in surface water in a highly urbanized area in Italy.

A complex mixture of emerging contaminants (ECs) occurs in the environment, with potential effects for aquatic organisms and human health. This study assessed the environmental risk of a mixture of ECs detected in the most urbanized and industrialized area of Italy. Water samples were collected in the Lambro river basin to the north and south of Milan, and were analyzed by liquid chromatography tandem mass spectrometry. The Environmental Risk Assessment (ERA) was performed calculating the Risk Quotients (RQs) for each EC as the ratio of Measured Concentrations (MECs) and Predicted No Effect Concentrations. The ERA was also conducted for the whole mixture of ECs by considering the RQs of the components. The results confirmed that ECs are ubiquitous in urbanized areas. The ERA for the single pollutants identified a panel of substances of environmental concern (estrogens, amoxicillin, clarythromycin, triclosan and nicotine). The ERA for the mixture indicated a potential cumulative risk for the substances that individually could be considered safe, highlighting the importance of taking the whole mixture of ECs into account for the ERA. This information may help establish EU regulations for ECs and environmental quality standards for regulatory purposes.

Bone mineral density changes in relation to environmental PCB exposure.

BACKGROUND: Bone toxicity has been linked to organochlorine exposure following a few notable poisoning incidents, but epidemiologic studies in populations with environmental organochlorine exposure have yielded inconsistent results. OBJECTIVES: The aim of this study was to investigate whether organochlorine exposure was associated with bone mineral density (BMD) in a population 60-81 years of age (154 males, 167 females) living near the Baltic coast, close to a river contaminated by polychlorinated biphenyls (PCBs). METHODS: We measured forearm BMD in participants using dual energy X-ray absorptiometry; and we assessed low BMD using age- and sex-standardized Z-scores. We analyzed blood samples for five dioxin-like PCBs, the three most abundant non-dioxin-like PCBs, and p,p'-dichloro-phenyldichloroethylene (p,p'-DDE). RESULTS: In males, dioxin-like chlorobiphenyl (CB)-118 was negatively associated with BMD; the odds ratio for low BMD (Z-score less than -1) was 1.06 (95% confidence interval, 1.01-1.12) per 10 pg/mL CB-118. The sum of the three most abundant non-dioxin-like PCBs was positively associated with BMD, but not with a decreased risk of low BMD. In females, CB-118 was positively associated with BMD, but this congener did not influence the risk of low BMD in women. CONCLUSIONS: Environmental organochlorine exposures experienced by this population sample since the 1930s in Sweden may have been sufficient to result in sex-specific changes in BMD.

Assessment of the dietary exposure to non-dioxin-like PCBs of the Italian general population.

The dietary intake of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) has been estimated using the sum of six indicator PCBs (Sigma(6)(PCBs)) in the Italian general population. Data from a national food consumption survey were combined with the mean concentration values of the individual six indicator PCBs (IUPAC Nos. 28, 52, 101, 138, 153, and 180) in foodstuffs available on the European market. Mean concentrations were estimated from the raw data set provided by the European Commission (DG SANCO). The purpose was to describe the distribution of NDL-PCB dietary intake in the Italian population, and to investigate to what extent the variability in dietary habits may cause higher exposures to the aforesaid contaminants. Results indicated a mean dietary intake of Sigma(6)(PCBs) corresponding to 24.6, 16.1, and 10.9 ng kg-bw(-1) day(-1) for toddlers (0.5-6 years old, excluding breastfeeding), children (7-12 year old), and adults (13-94 years old), respectively. Fish and fishery products and milk and dairy products were the major contributors to the total dietary intake. The highest exposures due to variation in dietary habits were in general two-three times higher than the corresponding mean values and they were generally due to a higher fish consumption rate. The NDL-PCB dietary intake decreased with age until about 10-12 years; afterwards it appeared to remain constant. The tolerable daily intake (TDI) has not been established for these contaminants; however, action and maximum allowed levels in feeding stuffs and food recently established by the European Commission for dioxin-like PCBs could also protect consumers from exposure to NDL-PCBs.

Monitoring emerging contaminants in the drinking water of Milan and assessment of the human risk.

Emerging Contaminants (ECs) are ubiquitous in waters, arousing concern because of their potential risks for human health and the environment. This study investigated the presence of multiple classes of ECs in 21 wells over the drinking water network of Milan, in the most inhabited and industrialized area of Italy, and assessed the risks for consumers. Samples were analyzed using liquid chromatography coupled to mass spectrometry. Human risk assessment (HRA) was conducted by comparing the measured concentrations with drinking water thresholds from guidelines or calculated in this study; first considering the exposure to each single EC and then the entire mixture. Thirteen ECs were measured in the low ng/L range, and were generally detected in less than half of the wells. Pharmaceuticals, perfluorinated substances, personal care products, and anthropogenic markers were the most frequently detected. The results of the HRA excluded any risks for consumers in each scenario considered. This is one of the most comprehensive studies assessing the presence of a large number of ECs in the whole drinking water network of a city, and the risks for human health. Results improve the limited information on ECs sources and occurrence in drinking water and help establishing guidelines for regulatory purposes.

Perfuorooctane Sulfonate (PFOS), Perfluorooctanoic Acid (PFOA), Brominated Dioxins (PBDDs) and Furans (PBDFs) in Wild and Farmed Organisms at Different Trophic Levels in the Mediterranean Sea.

The present study shows the results of perfuorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), brominated dioxins (PBDDs) and furans (PBDFs) measured in several marine fish and seafood of commercial interest at different trophic levels of the food chain. The aims were to investigate the level of the contamination in Mediterranean aquatic wildlife, and in farmed fish, to assess human exposure associated to fishery products consumption. Samples of wild fish were collected during three different sampling campaigns in different Food and Agriculture Organization (FAO) 37 areas of the Mediterranean Sea. In addition, farmed fish (gilthead sea bream and European sea bass) from off-shore cages from different marine aquaculture plants. Results showed contamination values of PFOS and PFOA were lower than those detected in sea basins other than the Mediterranean Sea. Concentration values of PFOS were generally higher than those of PFOA; moreover, levels in farmed fish were lower than in wild samples from the Mediterranean Sea. Intake of PFOS and PFOA through fishery products consumption was estimated to be 2.12 and 0.24 ng/kg·BW·day, respectively, for high consumers (95th percentile). Results of 2,3,7,8-substituted congeners of PBDDs and PBDFs were almost all below the limit of detection (LOD), making it difficult to establish the contribution of these compounds to the total contamination of dioxin-like compounds in fish and fishery products.

PCB contamination in farmed and wild sea bass (Dicentrarchus labrax L.) from a coastal wetland area in central Italy.

Food consumption is by far the main exposure route for polychlorinated biphenyls (PCBs) for the general population, and fish and fishery products seem to be the main contributors to the total dietary intake of these pollutants. In recent years some investigations have suggested that farmed fish may be more significantly contaminated than wild fish, because of polluted feed. This study measured the levels of PCBs in wild and farmed sea bass (Dicentrarchus labrax L.), one of the most valuable and popular fish in the Italian diet, and assessed the exposure to these pollutants through fish intake. Concentrations of summation operator (Sigma59PCBs) and dioxin-like PCBs (DL-PCBs), as toxic equivalency (TEQ), in fish samples, ranged from 2.2 to 32ngg(-1) and from 0.1 to 4.0pg TEQ((2006) DL-PCBs)g(-1) whole weight, respectively. Farmed sea bass were as average two times more contaminated. Even if the concentrations of DL-PCBs were below the regulation limits, intake of these compounds from nine fish meals per month can in itself exceed the WHO Provisional Tolerable Monthly Intake (PTMI).

Effects of free sugars on blood pressure and lipids: a systematic review and meta-analysis of nutritional isoenergetic intervention trials.

BACKGROUND: Sugar has been suggested as a central risk factor in the development of noncommunicable diseases. OBJECTIVE: We assessed the evidence of the effects of free sugars compared with complex carbohydrates on selected cardiovascular disease risk factors. DESIGN: We conducted a systematic review and meta-analysis of intervention trials to compare diets that provide a given amount of energy from free sugars with a control diet that provides the same amount of energy from complex carbohydrates. The primary outcomes were: blood pressure, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triacylglycerols, apolipoproteins A-I and B, or very low-density lipoprotein cholesterol. Body weight was also recorded but was not a primary outcome of the studies. RESULTS: In all, 28 studies involving 510 volunteers were included. When free sugars were substituted for complex carbohydrates, no significant increases were detected in systolic or diastolic blood pressure, and no heterogeneity was observed. There were significant increases in HDL cholesterol, LDL cholesterol, and triacylglycerols, although for LDL cholesterol and triacylglycerols there was significant heterogeneity between studies and evidence of publication bias. After adjustment for missing studies, these increases lost significance. Subgroup analyses showed that diets providing the largest total energy intake and energy exchange enhanced the effect of free sugars on total and LDL cholesterol and triacylglycerols. The increase of triacylglycerols was no longer significant when studies with the highest risk of bias were excluded or when only randomized trials were considered. Free sugars had no effect on body weight. CONCLUSIONS: In short- or moderate-term isoenergetic intervention trials, the substitution of free sugars for complex carbohydrates had no effect on blood pressure or body weight and an unclear effect on blood lipid profile. Further independent trials are required to assess whether the reduction of free sugars improves cardiovascular disease risk factors. This review was registered at http://www.crd.york.ac.uk/prospero as CRD42016042930.