Tommaso Filippini

A Review and Meta-Analysis of Outdoor Air Pollution and Risk of Childhood Leukemia

Leukemia is the most frequent malignant disease affecting children. To date, the etiology of childhood leukemia remains largely unknown. Few risk factors (genetic susceptibility, infections, ionizing radiation, etc.) have been clearly identified, but they appear to explain only a small proportion of cases. Considerably more uncertain is the role of other environmental risk factors, such as indoor and outdoor air pollution. We sought to summarize and quantify the association between traffic-related air pollution and risk of childhood leukemia, and further examined results according to method of exposure assessment, study quality, leukemia subtype, time period, and continent where studies took place. After a literature search yielded 6 ecologic and 20 case-control studies, we scored the studies based on the Newcastle-Ottawa Scale. The studies assessed residential exposure to pollutants from motorized traffic by computing traffic density in the neighboring roads or vicinity to petrol stations, or by using measured or modeled nitrogen dioxide and benzene outdoor air levels. Because heterogeneity across studies was observed, random-effects summary odds ratios (OR) and 95% confidence intervals (CI) were reported. Whenever possible we additionally conducted stratified analyses comparing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Limiting the analysis to high-quality studies (Newcastle-Ottawa Scale ≥ 7), those using traffic density as the exposure assessment metric showed an increase in childhood leukemia risk in the highest exposure category (OR = 1.07, 95% CI 0.93–1.24). However, we observed evidence of publication bias. Results for NO2 exposure and benzene showed an OR of 1.21 (95% CI 0.97–1.52) and 1.64 (95% CI 0.91–2.95) respectively. When stratifying by leukemia type, the results based upon NO2 were 1.21 (95% CI 1.04–1.41) for ALL and 1.06 (95% CI 0.51–2.21) for AML; based upon benzene were 1.09 (95% CI 0.67–1.77) for ALL and 2.28 (95% CI 1.09–4.75) for AML. Estimates were generally higher for exposures in the postnatal period compared to the prenatal period, and for European studies compared to North American studies. Overall, our results support a link between ambient exposure to traffic pollution and childhood leukemia risk, particularly due to benzene.

Selenium speciation in human serum and its implications for epidemiologic research: a cross-sectional study

Observational studies addressing the relation between selenium and human health, particularly cancer risk, yielded inconsistent results, while most recent randomized trials showed a fairly consistent pattern suggesting null or adverse effects of the metalloid. One of the most plausible explanations for such inconsistencies is inadequate exposure assessment in observational studies, commonly carried out by measuring total Se content without taking into account the specific exposure to the individual chemical forms of the metalloid, whose toxic and nutritional properties may vary greatly. Data on the distribution of these species in human blood and their correlation with overall selenium levels are very limited. The concentrations of organic and inorganic selenium species were analyzed in serum of fifty subjects sampled from the general population of the municipality of Modena, northern Italy, aged from 35 to 70 years. Samples were collected during a 30-month period, and determinations of selenium species were carried out using high pressure liquid chromatography coupled with inductively coupled plasma dynamic reaction cell mass spectrometry. The majority of selenium was found to be present as organic species, but the inorganic forms showed higher levels than expected. These species showed limited correlations with age, sex and body mass index, while the organic forms increased in subjects consuming selenium-containing dietary supplements and decreased in smokers. The length of the sample storage period strongly influenced the distribution of selenium compounds, with a clear tendency towards higher inorganic and lower organic selenium levels over time. In multivariate analysis adjusting for potential confounders, total serum selenium correlated with human serum albumin-bound selenium and, in males, with two organic species of the metalloid (selenocysteine and glutathione peroxidase-bound selenium), while little association existed with the other organic forms and the inorganic ones. These findings highlight the potential for exposure misclassification of observational epidemiologic investigations based on overall selenium content in blood and possibly other tissues, and the critical role of the storage conditions for speciation analysis.

The role of cadmium in obesity and diabetes

Multiple studies have shown an association between environmental exposure to hazardous chemicals including toxic metals and obesity, diabetes, and metabolic syndrome. At the same time, the existing data on the impact of cadmium exposure on obesity and diabetes are contradictory. Therefore, the aim of the present work was to review the impact of cadmium exposure and status on the risk and potential etiologic mechanisms of obesity and diabetes. In addition, since an effect of cadmium exposure on incidence of diabetes mellitus and insulin resistance was suggested by several epidemiologic studies, we carried out a meta-analysis of all studies assessing risk of prevalence and incidence of diabetes. By comparing the highest versus the lowest cadmium exposure category, we found a high risk of diabetes incidence (odds ratio=1.38, 95% confidence interval 1.12-1.71), which was higher for studies using urine as exposure assessment. On the converse, results of epidemiologic studies linking cadmium exposure and overweight or obesity are far less consistent and even conflicting, also depending on differences in exposure levels and the specific marker of exposure (blood, urine, hair, nails). In turn, laboratory studies demonstrated that cadmium adversely affects adipose tissue physiopathology through several mechanisms, thus contributing to increased insulin resistance and enhancing diabetes. However, intimate biological mechanisms linking Cd exposure with obesity and diabetes are still to be adequately investigated.

Health risk assessment of environmental selenium: Emerging evidence and challenges (Review)

New data have been accumulated in the scientific literature in recent years which allow a more adequate risk assessment of selenium with reference to human health. This new evidence comes from environmental studies, carried out in populations characterized by abnormally high or low selenium intakes, and from high-quality and large randomized controlled trials with selenium recently carried out in the US and in other countries. These trials have consistently shown no beneficial effect on cancer and cardiovascular risk, and have yielded indications of unexpected toxic effects of selenium exposure. Overall, these studies indicate that the minimal amount of environmental selenium which is source of risk to human health is much lower than anticipated on the basis of older studies, since toxic effects were shown at levels of intake as low as around 260 µg/day for organic selenium and around 16 µg/day for inorganic selenium. Conversely, populations with average selenium intake of less than 13–19 µg/day appear to be at risk of a severe cardiomyopathy, Keshan disease. Overall, there is the need to reconsider the selenium standards for dietary intake, drinking water, outdoor and indoor air levels, taking into account the recently discovered adverse health effects of low-dose selenium overexposure, and carefully assessing the significance of selenium-induced proteomic changes.

Meta‐Analysis of Potassium Intake and the Risk of Stroke

Background The possibility that lifestyle factors such as diet, specifically potassium intake, may modify the risk of stroke has been suggested by several observational cohort studies, including some recent reports. We performed a systematic review and meta‐analysis of existing studies and assessed the dose–response relation between potassium intake and stroke risk. Methods and Results We reviewed the observational cohort studies addressing the relation between potassium intake, and incidence or mortality of total stroke or stroke subtypes published through August 6, 2016. We carried out a meta‐analysis of 16 cohort studies based on the relative risk (RR) of stroke comparing the highest versus lowest intake categories. We also plotted a pooled dose–response curve of RR of stroke according to potassium intake. Analyses were performed with and without adjustment for blood pressure. Relative to the lowest category of potassium intake, the highest category of potassium intake was associated with a 13% reduced risk of stroke (RR=0.87, 95% CI 0.80–0.94) in the blood pressure–adjusted analysis. Summary RRs tended to decrease when original estimates were unadjusted for blood pressure. Analysis for stroke subtypes yielded comparable results. In the spline analysis, the pooled RR was lowest at 90 mmol of potassium daily intake (RRs=0.78, 95% CI 0.70–0.86) in blood pressure–adjusted analysis, and 0.67 (95% CI 0.57–0.78) in unadjusted analysis. Conclusions Overall, this dose–response meta‐analysis confirms the inverse association between potassium intake and stroke risk, with potassium intake of 90 mmol (≈3500 mg)/day associated with the lowest risk of stroke.

The Epidemiology of Selenium and Human Health

Few issues involving nutritional and environmental epidemiology have received as much interest as the relation between selenium (Se) intake and human health, as reflected by the large body of evidence from observational and experimental studies with reference to cancer and other clinical endpoints. Se deficiency may play a major role in favoring the onset of a human cardiomyopathy, Keshan disease. Se overexposure has been linked to skin and advanced prostate cancers in recent randomized controlled trials, in contrast with earlier hypotheses of protective effects of Se intake against cancer generally, and prostate cancer in particular. Overexposure has also been linked to higher risk for diabetes and amyotrophic lateral sclerosis. For cardiovascular disease risk, such as ischemic heart disease and stroke, little evidence of any modifying effect of Se exposure has been provided by epidemiologic studies. The results of these studies should be used in public health to set better standards for intake of organic and inorganic Se species, focusing on experimental studies with individual Se compounds more than overall exposure to the element, in order to improve reliability and reduce bias in the studies.

Lead, cadmium and mercury in cerebrospinal fluid and risk of amyotrophic lateral sclerosis: A case-control study.

Exposure to neurotoxic chemicals such as pesticides, selenium, and heavy metals have been suggested to play a role in the etiology of amyotrophic lateral sclerosis (ALS). We assessed exposure to lead, cadmium, and mercury in 38 ALS patients (16 men and 22 females) and 38 hospital-admitted controls by using their cerebrospinal fluid (CSF) content as biomarker. We determined CSF heavy metal levels with inductively coupled plasma sector field mass spectrometry, according to a methodology specifically developed for this biological matrix. ALS patients had higher median values for Pb (155 vs. 132ng/L) but lower levels for Cd (36 vs. 72ng/L) and Hg (196 vs. 217ng/L). In the highest tertile of exposure, ALS odds ratio was 1.39 (95% CI 0.48-4.25) for Pb, 0.29 (0.08-1.04) for Cd and 3.03 (0.52-17.55) for Hg; however, no dose-response relation emerged. Results were substantially confirmed after conducting various sensitivity analyses, and after stratification for age and sex. Though interpretation of these results is limited by the statistical imprecision of the estimates, and by the possibility that CSF heavy metal content may not reflect long-term antecedent exposure, they do not lend support to a role of the heavy metals cadmium, lead and mercury in ALS etiology.

Dietary intake of cadmium, chromium, copper, manganese, selenium and zinc in a Northern Italy community

This study provides the dietary intakes of six trace elements (cadmium, chromium, copper, manganese, selenium and zinc), generally characterized by both nutritional and toxicological features depending on their exposure. Being diet the most relevant source of exposure to trace elements in non-professionally exposed subjects, we measured content of these trace elements in foods composing the typical Italian diet using inductively coupled plasma-mass spectrometry, and assessing dietary habits using a validated semi-quantitative food frequency questionnaire we eventually estimated dietary daily intake of trace elements in a Northern Italian community. In the 890 analyzed food samples, the main contributors to cadmium intake are cereals, vegetables and sweets, while cereals, beverages and vegetable are to primary source of manganese. The primary contributors for copper are cereals, fresh fruits and vegetables, while for chromium are beverages, cereals and meat. The main source of selenium intake are cereals and meat, followed by fish, seafood and milk and dairy products, while of zinc intake are meat, cereals, milk and dairy products. In our Italian population sample, the estimated median (interquartile range) dietary daily intakes are 5.00 (3.17-7.65), 56.70 (36.08-86.70) and 66.53 (40.04-101.32) μg/day for cadmium, chromium and selenium, and corresponding figures are 0.98 (0.61-1.49), 2.34 (1.46-3.52) and 8.50 (5.21-12.48) mg/day for copper, manganese and zinc. The estimated intakes are generally within the average intake reported in other European populations, and in such cases well above the daily dietary intakes recommended by national international agencies, avoiding the risk of excess or deficiency. The present estimated intake data can be used to examine a specific trace element of interest and would afford enhanced health protection from those trace elements characterized by both nutritional and toxicological effects.

Incidence of amyotrophic lateral sclerosis in the province of Novara, Italy, and possible role of environmental pollution

Abstract Objective and methods: Based on nationwide death certificates, a cluster of amyotrophic lateral sclerosis (ALS) has been reported in the area of Briga (Novara province, northern Italy), known for its severe environmental contamination. We further investigated this finding, by following up with the collection of recent incidence ALS data in 2002–2012 of Novara province, also to assess the possible long-term effects of environmental pollution in that area. Results: In the whole Novara province we identified 106 ALS cases, of which 35 were from the Briga area. Incidence rates of Novara province were 3.98, 5.14 and 2.97 for the total population, males and females, respectively, compared with the Briga area where they were 4.65, 4.27 and 4.98, respectively. The ratio of observed-to-expected ALS cases in the Briga area, using incidence of the rest of Novara province as a reference, was 1.17 (95% CI 0.81–1.62), with a value of 0.83 (95% CI 0.47–1.37) in males and 1.68 (95% CI 1.03–2.60) in females. Conclusions: Overall, our study did not confirm previous findings of an excess ALS incidence in an area characterised by severe environmental heavy metal pollution, and it suggests the need to interpret with caution clusters identified through mortality data.

Cadmium and atherosclerosis: A review of toxicological mechanisms and a meta-analysis of epidemiologic studies

Abstract Cadmium has been proposed to be the one of the factors of atherosclerosis development, although the existing data are still controversial. The primary objective of the present study is the review and the meta‐analysis of studies demonstrating the association between Cd exposure and atherosclerosis as well as review of the potential mechanisms of such association. We performed a systematic search in the PubMed‐Medline database using the MeSH terms cadmium, cardiovascular disease, atherosclerosis, coronary artery disease, myocardial infarction, stroke, mortality and humans up through December 20, 2017. Elevated urinary Cd levels were associated with increased mortality for cardiovascular disease (HR = 1.34, 95% CI: 1.07–1.67) as well as elevated blood Cd levels (HR = 1.78, 95% CI: 1.24–2.56). Analysis restricted to never smokers showed similar, though more imprecise, results. Consistently, we also observed an association between Cd exposure markers (blood and urine) and coronary heart disease, stroke, and peripheral artery disease. Moreover, Cd exposure was associated with atherogenic changes in lipid profile. High Cd exposure was associated with higher TC levels (OR = 1.48, 95% CI: 1.10–2.01), higher LDL‐C levels (OR = 1.31, 95% CI 0.99–1.73) and lower HDL‐C levels (OR = 1.96, 95% CI: 1.09–3.55). The mechanisms of atherogenic effect of cadmium may involve oxidative stress, inflammation, endothelial dysfunction, enhanced lipid synthesis, up‐regulation of adhesion molecules, prostanoid dysbalance, as well as altered glycosaminoglycan synthesis.