Smoking-induced risk of future cardiovascular disease is partly mediated by cadmium in tobacco: Malmö Diet and Cancer Cohort Study

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Abstract

Background

Smoking is a strong risk factor for cardiovascular disease (CVD) and causes exposure to cadmium, which is a pro-atherosclerotic metal. Cadmium exposure has also been shown to increase the risk of CVD, even after adjustment for smoking. Our hypothesis was that part of the risk of CVD in smokers may be mediated by cadmium exposure from tobacco smoke. We examined this hypothesis in a mediation analysis, trying to assess how much of the smoking-induced CVD risk could be explained via cadmium.

Methods

We used prospective data on CVD (incidence and mortality) in a Swedish population-based cohort of 4304 middle-aged men and women (the Malmö Diet and Cancer Study). Blood cadmium was analyzed in base-line samples from 1991, and clinical events were followed up for 16–19 years based on registry data. Mediation analysis was conducted to evaluate the indirect effect (via cadmium) of smoking on CVD. Survival was analyzed by the accelerated failure time (AFT) model and the Aalen additive hazard model.

Results

The mean blood cadmium level in the study population was 0.43 μg/L (median 0.24 μg/L) and increased with recent and current smoking. As expected, shorter survival time (AFT model) and higher incidence rate (Aalen model) were found in current smokers for all CVD outcomes and this effect seemed to be partly mediated by cadmium. For the sum of acute myocardial infarction, bypass grafts and percutaneous coronary intervention, and death in ischemic heart disease, about half of the increased risk of such events in current smokers was mediated via cadmium, with similar results for the AFT and Aalen models.

Conclusions

Cadmium plays an important role in smoking-induced CVDs. This provides evidence for mechanisms and is of importance for both individuals and policy makers.

Electronic supplementary material

The online version of this article (10.1186/s12940-019-0495-1) contains supplementary material, which is available to authorized users.

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Most cited references 35

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The Malmo Diet and Cancer Study. Design and feasibility.

G Berglund, S Elmstáhl, L. Janzon … (1993)

The Malmö Diet and Cancer study is a 10-year prospective case-control study in 45-64-year-old men and women (n = 53,000) living in a city with 230,000 inhabitants. One objective is to clarify whether a western diet is associated with certain forms of cancer whilst taking other life-style factors into account. Another broad question is whether oxidative stress and the activity in DNA-repairing systems influence the impact of diet on the development of all or certain forms of cancer. The study is also to act as a resource available for testing new hypotheses emanating from other studies. Initially food intake, heredity, socio-economic factors, life-style pattern, occupational situation, previous and current diseases, symptoms and medications, will be determined. Viable lymphocytes, granulocytes, erythrocytes, and plasma/serum will be stored in a biological bank together with tumour specimens gathered from cases. The incidence and mortality of all cancer forms will then be followed for 10 years by existing registries. Data from the initial examination in these cases will then be compared with those of control subjects not having developed any form of cancer. A biomarker programme, utilizing the biological bank, has been developed and is aimed at finding predictors and/or precursors of cancer. A high participation rate (> 70%) and a high quality biological bank are prerequisites for a successful project. The experience gathered so far indicates that these goals are feasible.

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Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats.

Günter Oberdörster, Zachary B. Sharp, Viorel Atudorei … (2002)

Studies with intravenously injected ultrafine particles have shown that the liver is the major organ of their uptake from the blood circulation. Measuring translocation of inhaled ultrafine particles to extrapulmonary organs via the blood compartment is hampered by methodological difficulties (i.e., label may come off, partial solubilization) and analytical limitations (measurement of very small amounts). The objective of our pilot study was to determine whether ultrafine elemental carbon particles translocate to the liver and other extrapulmonary organs following inhalation as singlet particles by rats. We generated ultrafine (13)C particles as an aerosol with count median diameters (CMDs) of 20-29 nm (GSD 1.7) using electric spark discharge of (13)C graphite electrodes in argon. Nine Fischer 344 rats were exposed to these particles for 6 h. in whole-body inhalation chambers at concentrations of 180 and 80 microg/m(3); 3 animals each were killed at 0.5, 18, and 24 h postexposure. Six unexposed rats served as controls. Lung lobes, liver, heart, brain, olfactory bulb, and kidney were excised, homogenized, and freeze-dried for analysis of the added (13)C by isotope ratio mass spectrometry. Organic (13)C was not detected in the (13)C particles. The (13)C retained in the lung at 0.5 h postexposure was about 70% less than predicted by rat deposition models for ultrafine particles, and did not change significantly during the 24-h postexposure period. Normalized to exposure concentration, the added (13)C per gram of lung on average in the postexposure period was approximately 9 ng/g organ/microg/m(3). Significant amounts of (13)C had accumulated in the liver by 0.5 h postinhalation only at the high exposure concentration, whereas by 18 and 24 h postexposure the (13)C amount of the livers of all exposed rats was about fivefold greater than the (13)C burden retained in the lung. No significant increase in (13)C was detected in the other organs which were examined. These results demonstrate effective translocation of ultrafine elemental carbon particles to the liver by 1 d after inhalation exposure. Translocation pathways include direct input into the blood compartment from ultrafine carbon particles deposited throughout the respiratory tract. However, since predictive particle deposition models indicate that respiratory tract deposits alone may not fully account for the hepatic (13)C burden, input from ultrafine particles present in the GI tract needs to be considered as well. Such translocation to blood and extrapulmonary tissues may well be different between ultrafine carbon and other insoluble (metal) ultrafine particles.

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Application of toxicological risk assessment principles to the chemical constituents of cigarette smoke.

J. Fowles, E Dybing (2003)

To provide a hazard prioritisation for reported chemical constituents of cigarette smoke using toxicological risk assessment principles and assumptions. The purpose is to inform prevention efforts using harm reduction. International Agency for Research on Cancer Monographs; California and US Environmental Protection Agency cancer potency factors (CPFs) and reference exposure levels; scientific journals and government reports from the USA, Canada, and New Zealand. This was an inclusive review of studies reporting yields of cigarette smoke constituents using standard ISO methods. Where possible, the midpoint of reported ranges of yields was used. Data on 158 compounds in cigarette smoke were found. Of these, 45 were known or suspected human carcinogens. Cancer potency factors were available for 40 of these compounds and reference exposure levels (RELs) for non-cancer effects were found for 17. A cancer risk index (CRI) was calculated by multiplying yield levels with CPFs. A non-cancer risk index (NCRI) was calculated by dividing yield levels with RELs. Gas phase constituents dominate both CRI and NCRI for cigarette smoke. The contribution of 1,3-butadiene (BDE) to CRI was more than twice that of the next highest contributing carcinogen (acrylonitrile) using potencies from the State of California EPA. Using those potencies from the USEPA, BDE ranked third behind arsenic and acetaldehyde. A comparison of CRI estimates with estimates of smoking related cancer deaths in the USA showed that the CRI underestimates the observed cancer rates by about fivefold using ISO yields in the exposure estimate. The application of toxicological risk assessment methods to cigarette smoke provides a plausible and objective framework for the prioritisation of carcinogens and other toxicant hazards in cigarette smoke. However, this framework does not enable the prediction of actual cancer risk for a number of reasons that are discussed. Further, the lack of toxicology data on cardiovascular end points for specific chemicals makes the use of this framework less useful for cardiovascular toxicity. The bases for these priorities need to be constantly re-evaluated as new toxicology information emerges.

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Author and article information

Contributors

Huiqi Li:

ORCID: http://orcid.org/0000-0002-1127-0829

+46 31 786 6265 , huiqi.li@amm.gu.se

Björn Fagerberg: bjorn.fagerberg@wlab.gu.se

Gerd Sallsten: gerd.sallsten@amm.gu.se

Yan Borné: yan.borne@med.lu.se

Bo Hedblad: bo.hedblad@med.lu.se

Gunnar Engström: gunnar.engstrom@med.lu.se

Lars Barregard: lars.barregard@amm.gu.se

Eva M. Andersson: eva.m.andersson@amm.gu.se

Journal

Journal ID (nlm-ta): Environ Health

Journal ID (iso-abbrev): Environ Health

Title: Environmental Health

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-069X

Publication date (Electronic): 14 June 2019

Publication date PMC-release: 14 June 2019

Publication date Collection: 2019

Volume: 18

Electronic Location Identifier: 56

Affiliations

[1 ]ISNI 0000 0000 9919 9582, GRID grid.8761.8, Occupational and Environmental Medicine, , Sahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, ; P.O. Box 414, 405 30 Gothenburg, Sweden

[2 ]ISNI 0000 0000 9919 9582, GRID grid.8761.8, Department of Molecular and Clinical Medicine, Wallenberg Laboratory for Cardiovascular and Metabolic Research, , University of Gothenburg and Sahlgrenska University Hospital, ; Gothenburg, Sweden

[3 ]Cardiovascular Epidemiology, Department of Clinical Sciences in Malmö, Lund University and Skåne University Hospital, Malmö, Sweden

Author information

Huiqi Li http://orcid.org/0000-0002-1127-0829

Article

Publisher ID: 495

DOI: 10.1186/s12940-019-0495-1

PMC ID: 6570857

PubMed ID: 31200698

SO-VID: 5ec25c6c-3178-40c7-b9b4-96a8a27ae9b5

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 28 March 2019

Date accepted : 31 May 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004359, Vetenskapsrådet;

Award ID: 2014-2265

Award Recipient : Gunnar Engström

Funded by: FundRef http://dx.doi.org/10.13039/501100006636, Forskningsrådet om Hälsa, Arbetsliv och Välfärd;

Award ID: 2014-0171

Award Recipient : Gerd Sallsten

Funded by: FundRef http://dx.doi.org/10.13039/501100005754, Sahlgrenska Universitetssjukhuset;

Award ID: ALF 74580

Award Recipient : Lars Barregard

Funded by: FundRef http://dx.doi.org/10.13039/501100003793, Hjärt-Lungfonden;

Award ID: 2015-0469

Award Recipient : Yan Borné

Custom metadata

ScienceOpen disciplines: Public health

Keywords: smoking,cadmium,cardiovascular diseases,mediation analysis,prospective cohort

Data availability:

ScienceOpen disciplines: Public health

Keywords: smoking, cadmium, cardiovascular diseases, mediation analysis, prospective cohort

Smoking-induced risk of future cardiovascular disease is partly mediated by cadmium in tobacco: Malmö Diet and Cancer Cohort Study

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Tobacco Prevention & Cessation

Most cited references 35

The Malmo Diet and Cancer Study. Design and feasibility.

Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats.

Application of toxicological risk assessment principles to the chemical constituents of cigarette smoke.

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