Cancer risk and the complexity of the interactions between environmental and host factors: HENVINET interactive diagrams as simple tools for exploring and understanding the scientific evidence
- Domenico F Merlo1Email author,
- Rosangela Filiberti†1,
- Michael Kobernus†2,
- Alena Bartonova†2,
- Marija Gamulin†3,
- Zeljko Ferencic†4,
- Maria Dusinska†2, 5 and
- Aleksandra Fucic†6
© Merlo et al; licensee BioMed Central Ltd. 2012
Published: 28 June 2012
Development of graphical/visual presentations of cancer etiology caused by environmental stressors is a process that requires combining the complex biological interactions between xenobiotics in living and occupational environment with genes (gene-environment interaction) and genomic and non-genomic based disease specific mechanisms in living organisms. Traditionally, presentation of causal relationships includes the statistical association between exposure to one xenobiotic and the disease corrected for the effect of potential confounders.
Within the FP6 project HENVINET, we aimed at considering together all known agents and mechanisms involved in development of selected cancer types. Selection of cancer types for causal diagrams was based on the corpus of available data and reported relative risk (RR). In constructing causal diagrams the complexity of the interactions between xenobiotics was considered a priority in the interpretation of cancer risk. Additionally, gene-environment interactions were incorporated such as polymorphisms in genes for repair and for phase I and II enzymes involved in metabolism of xenobiotics and their elimination. Information on possible age or gender susceptibility is also included. Diagrams are user friendly thanks to multistep access to information packages and the possibility of referring to related literature and a glossary of terms. Diagrams cover both chemical and physical agents (ionizing and non-ionizing radiation) and provide basic information on the strength of the association between type of exposure and cancer risk reported by human studies and supported by mechanistic studies. Causal diagrams developed within HENVINET project represent a valuable source of information for professionals working in the field of environmental health and epidemiology, and as educational material for students.
Cancer risk results from a complex interaction of environmental exposures with inherited gene polymorphisms, genetic burden collected during development and non genomic capacity of response to environmental insults. In order to adopt effective preventive measures and the associated regulatory actions, a comprehensive investigation of cancer etiology is crucial. Variations and fluctuations of cancer incidence in human populations do not necessarily reflect environmental pollution policies or population distribution of polymorphisms of genes known to be associated with increased cancer risk. Tools which may be used in such a comprehensive research, including molecular biology applied to field studies, require a methodological shift from the reductionism that has been used until recently as a basic axiom in interpretation of data. The complexity of the interactions between cells, genes and the environment, i.e. the resonance of the living matter with the environment, can be synthesized by systems biology. Within the HENVINET project such philosophy was followed in order to develop interactive causal diagrams for the investigation of cancers with possible etiology in environmental exposure.
Causal diagrams represent integrated knowledge and seed tool for their future development and development of similar diagrams for other environmentally related diseases such as asthma or sterility. In this paper development and application of causal diagrams for cancer are presented and discussed.
Cancer incidence and mortality
Environmental exposure complexity and need for action
Moreover, the delayed adverse health effects of exposures occurring during critical windows of vulnerability (e.g., early life, including the prenatal period and puberty) remain largely unknown. One well known exception is in utero exposure to diethylstilbestrol (DES) which increases the risk of benign and malignant pathology in the third generation . Other agents such as ambient air PAHs and PM2.5 have been shown to influence maturation of the immune system during gestation via shifts in cord blood lymphocytes distributions [9, 10]. Whether these shifts will affect cancer risk (or other adverse health outcomes) later in life, need to be proven .
Providing undisputable evidence that environmental exposure to complex mixtures of pollutants results in increased cancer risk is challenging for human epidemiologic and experimental studies conducted in vitro and in laboratory animals. Environmental epidemiology, despite its observational nature, is the scientific discipline attempting to make conclusions on disease etiology in human beings. Experimental studies, conducted under controlled conditions, provide “proof of action” of a given exposure in selected biological (e.g., cell culture) or animal models. The two types of scientific evidence are combined together by the scientific community to classify exposures as carcinogenic, probably/possibly or non carcinogenic to humans. Based on the evidence of carcinogenicity, governments and regulatory agencies should establish and implement effective regulation of environmental exposure. Current regulatory approach is of a reactive type (i.e., human harm must be proven before any action is taken). However, some 80,000 chemicals are in use today and 1,000-2,000 new chemicals are synthesized and enter the environment each year, a figure that is impressive especially if one considers that such chemicals may interact with each others, with physical agents, viruses, and thousands of natural compounds . Cancer incidence reflects lifetime exposure to man-made and naturally occurring carcinogens that are present in the living environment. Most of the evidence of the role played by environmental carcinogens has accumulated during the last century . Epidemiologic and animal studies significantly contributed to the discovery of the major causes of cancer and nowadays it is accepted that cancer risk is connected to the living environment through complex interactions between exposures and host factors, the former playing a major role in cancer development. Host factors, such as single-gene inherited cancer syndrome and the polymorphic distribution of genes for cellular detoxification and DNA-repair processes are known to account for a small proportion of the cancer burden in human populations. A large proportion of cancers are believed to be the consequence of multiple exposures that occur over years or persist for a lifetime . There is also evidence that cancer susceptibility resulting from environmental exposures may be inherited by a child when a carcinogen causes germ cell genetic damage in exposed parents [15, 16].
Despite the fact that our knowledge of the biologic mechanisms underlying cancer development has been extensively improved, the mechanisms by which environmental contaminants contribute to cancer risk, and particularly how they interact, remain largely under investigated in humans .
Is it waiting for a “proof of harm” the right approach to protect human health by reducing exposure? The USA President’s Cancer Panel  assessed the state of environmental research on cancer, policy and programs receiving testimony from 45 invited experts from academia, government, industry, the environmental and cancer communities, and the public. The Panel made recommendations for policy, research, program, industry, and other actions aimed at minimizing the impact of environmental factors on cancer. A precautionary oriented approach instead of the reactionary approach currently used is recommended by the President’s Cancer Panel as the cornerstone of a new cancer prevention strategy based on primary prevention. Such a recommended approach should “shift the burden of proving safety to manufacturers prior to new chemical approval, in mandatory post-market studies for new and existing agents, and in renewal applications for chemical approval”. The European Commission has anticipated, to some extent, the US by adopting in 2007 a precautionary approach to chemical regulation. The Registration, Evaluation, Authorization, and Restriction of Chemical Substances (REACH) is a major reform that requires industry to take a main role in managing risks from chemicals by providing safety information on its products. The final goal of REACH is to protect human health as well as the environment through better and earlier recognition of intrinsic properties of chemicals.
The HENVINET approach to environmental cancers
The Health and Environment Network (HENVINET) was funded by the Commission of the European Communities within the 6th Framework Programme on Research, Technological Development and Demonstration. The main objective of HENVINET was that of establishing a long-term co-operation between researchers, policy makers and stakeholders in the area of environment and health research and assessment. To protect the health of populations and individuals, environmental and health policies need to integrate environmental and health knowledge: HENVINET is meant to support such informed policy making process. Based on the four priority health diseases of the European Environment and Health Action Plan 2004-2010 (EHAP) (i.e., asthma and allergies, cancer, neurodevelopmental disorders and endocrine disrupting effects), HENVINET has reviewed, exploited and disseminated knowledge on environmental health issues . EHAP is aimed at improving the health of European citizens, a goal requiring knowing exactly what impact environmental damage has on human health. EHAP was designed to provide the European Union (EU) with reliable information on that impact and to step up cooperation between stakeholders in the environment, health and research fields.
HENVINET interactive cause-effect diagrams
List of cancers and environmental exposure considered within HENVINET
DDT and DDE
Lung cancer and
Fruits and vegetables consumption
Intake of calcium and Vitamin D
Intake of folic acid
Low frequency electromagnetic fields
Low level ionizing radiation
UV light, artificial light
Cosmetics (including sun screen)
Glossary and references
A glossary and selected references are made available to users to ensure fluent browsing and transparency. The glossary is an important tool aimed at assuring a consistent terminology across the exposure-cancer diagrams (e.g., meaning of reported biological effects, biological activity). Diagrams were specifically developed to allow users to actively explore the depicted exposure-effect interactions within the continuum between cancer initiation and detection. Their appearance is shown in Figure 6 as an example for exposure to radiofrequency and its association with brain tumours, one the hottest and most controversial topic in environmental health. The reader, after selecting a specific environmental exposure within a given cancer type, access a diagram showing the known risk factors, the evidence of susceptibility available, the reported mechanisms of action for a given environmental exposure/agent, and the quantitative measure of the exposure-effect association estimated by recent systematic review. The glossary and the reference list can be both accessed through a link placed on the left side of the interactive diagrams accessible on the HENVINET portal (Figure 6).
Evaluation of knowledge: the online questionnaires
Causal diagram evaluation
HENVINET cancer causal diagrams were actually a new experience for experts as they offer a simultaneous overview of all xenobiotics described in the etiology of selected site specific cancers.
Discrepancy between the state of the art (e.g. existing knowledge) and answers of experts shows that knowledge is not equally communicated to different professional areas, policy makers and the general public.
Discussion and conclusions
How to develop knowledge communication and self-learning interaction between science and policymaking system?
The complexity of the causal relations between exposure to environmental agents, their interactions, as well as the role played by host factors such as age at exposure (e.g., in utero exposure), gender, and polymorphisms of genes involved in the activation-detoxification of xenobiotics, cell cycle, in DNA repair and apoptosis, is not taken into account in current legislation. Environmental health regulatory policies should adopt a new approach which includes the knowledge of complexity. HENVINET interactive causal diagrams are an opportunity for collaboration between the scientific and regulatory communities and the society with its variety of populations, cultures, and environmental differences. The analysis of causal diagrams and the development of specific web sites which enable such an opportunity for an interactive dialogue may represent a starting point for accomplishing effective legislation aimed at protecting health and the environment. Policymakers have to learn the potential of present knowledge and timely deal with the scientific evidence generated by human and laboratory studies that investigate early health effects and or molecular markers that occur and can be measured along the pathways from exposure to disease manifestation. Within this modern and highly technological research framework a precautionary approach can be applied to environment and health issues (not just as an alternative to cost-benefit analysis), with the aim of improving future legislation. The recognition of environmental threats and the prediction of possible associated cancer risks will allow putting scientific facts directly in a regulatory perspective, raise public confidence in science and administration.
This work was supported by the EU project HENVINET 6th Framework Programme, Coordination Action (Contract no. GOCE-CT-2006-037019), http://www.henvinet.eu.
This article has been published as part of Environmental Health Volume 11 Supplement 1, 2012: Approaching complexities in health and environment. The full contents of the supplement are available online at http://www.ehjournal.net/supplements/11/S1.
- Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide. IARC CancerBase No. 10. Lyon, France: International Agency for Research on Cancer. 2010, Available from: http://globocan.iarc.frGoogle Scholar
- Karim-Kosa HE, de Vriesa E, Soerjomatarama I, Lemmensa V, Sieslingc S, Coebergh JWW: Recent trends of cancer in Europe: A combined approach of incidence, survival and mortality for 17 cancer sites since the 1990s. EJC. 2008, 1345-89.Google Scholar
- SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Edited by: Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, Altekruse SF, Feuer EJ, Huang L, Mariotto A, Miller BA, Lewis DR, Eisner MP, Stinchcomb DG, Edwards BK. 2009, Bethesda, MD, USA, based on November 2008 SEER data submission, posted to the SEER web site, [http://seer.cancer.gov/csr/1975_2006/]
- American Cancer Society: Cancer facts and figures. 2009, ACS, AtlantaGoogle Scholar
- Steliarova-Foucher E, Stiller , Kaatsch P, Berrino F, Coebergh JW, Lacour Band, Parkin M: The Lancet. 2004, 2097-2105.Google Scholar
- Rudel RA, Perovich LJ: Endocrine disrupting chemicals in indoor and outdoor air. Atmos Environ. 2009, 43 (1): 170-181. 10.1016/j.atmosenv.2008.09.025.View ArticleGoogle Scholar
- Diaminti-Kandarakis ED, Bourguignon J-P, Guidice LC, Hauser R, Prins GS, Soto AM: Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Re. 2009, 293-42.Google Scholar
- Titus-Ernstoff L, Troisi R, Hatch EE, Hyer M, Wise LA, Palmer JR: Offspring of women exposed in utero to diethylstilbestrol (DES): a preliminary report of benign and malignant pathology in the third generation. Epidemiology. 2008, 19 (2): 251-7. 10.1097/EDE.0b013e318163152a.View ArticleGoogle Scholar
- Hertz-Picciotto I, Herr CE, Yap PS, Dostal M, Shumway RH, Ashwood P, Lipsett M, Joad JP, Pinkerton KE, Šrám RJ: Air pollution and lymphocyte phenotype proportions in cord blood. Environ Health Perspect. 2005, 113: 1391-1398. 10.1289/ehp.7610.View ArticleGoogle Scholar
- Herr CEW, Dostal M, Ghosh R, Ashwood P, Lipsett M, Pinkerton KE, Sram R, Hertz-Picciotto I: Air pollution exposure during critical time periods in gestation and alterations in cord blood lymphocyte distribution: a cohort of livebirths. Environmental Health. 2010, 9: 46-10.1186/1476-069X-9-46. doi:10.1186/1476-069X-9-46View ArticleGoogle Scholar
- Merlo DF, Wild CP, Kogevinas M, Kyrtopoulos S, Kleinjans J: NewGeneris: A European Study on Maternal Diet during Pregnancy and Child Health. Cancer Epidemiol Biomarkers Prev. 2009, 18 (1): 5-10. 10.1158/1055-9965.EPI-08-0876.View ArticleGoogle Scholar
- Kennedy D: Toxic dilemmas. Science. 2007, 318: 1217-10.1126/science.1151604.View ArticleGoogle Scholar
- Doll R: Epidemiological evidence of the effects of behaviour and the environment on the risk of human cancer. Recent Results Cancer Res. 1998, 154: 3-21. 10.1007/978-3-642-46870-4_1.View ArticleGoogle Scholar
- President’s Cancer Panel: 2008–2009 Annual Report. U.S. 2010. Department of Health and Human Services, National Institutes of Health, National Cancer InstituteGoogle Scholar
- Fleming J, Huang T, Toland A: The role of parental and grandparental epigenetic alterations in familial cancer risk. Perspect Cancer Res. 2008, 68 (22): 9116-21.View ArticleGoogle Scholar
- Bird A: Perceptions of epigenetics. Nature. 2007, 447: 396-398. 10.1038/nature05913.View ArticleGoogle Scholar
- REACH: Environment Directorate General, European Commission: REACH in brief [Internet]. 2007, Brussels (Belgium): EC, [cited 2009 May 19], [http://ec.europa.eu/environment/chemicals/reach/pdf/2007_02_reach_in_brief.pdf]Google Scholar
- EHAP: European Parliament resolution on the European Environment and Health Action Plan 2004-2010. Official Journal of the European Union. 2005, C 304 E: 267-269.Google Scholar
- Pershagen G, Akerblom G, Axelson O, Clavensjo B, Damber L, Desai G, Enflo A, Lagarde F, Mellander H, Svartengren M, Swedjemark G: Residential Radon Exposure and Lung Cancer in Sweden. New Eng J Med. 1994, 330: 59-164. 10.1056/NEJM199401063300111.View ArticleGoogle Scholar
- Catelinois O, Rogel A, Laurier D, Billon S, Hemon D, Verger P, Tirmarche M: Lung cancer Attributed to Indoor Radon Exposure in France: Impact of the Risk Models and Uncertainty Analysis. Environ Health Perspect. 2006, 114: 1361-1366. 10.1289/ehp.9070.View ArticleGoogle Scholar
- Kreienbrock L, Kreuzer M, Gerken M, Dingerkus G, Wellmann J, Keller G, Krewski D, Lubin JH, Zielinski JM, Alavanja M, Catalan VS, Field RV, Klotz JB, Letourneau EG, Lynch CF, Lyon JI, Sandler DP, Schoenberg JB, Steck DJ, Stolwijk JA, Weinberg C, Wilcox HB: Residential Radon and Risk of Lung Cancer: a Combined Analysis of 7 North American Case-Control Studies. Epidemiology. 2005, 16 (2): 137-145. 10.1097/01.ede.0000152522.80261.e3.View ArticleGoogle Scholar
- Janssen MPM: Modeling ventilation and radon in new Dutch dwellings. Indoor Air. 2003, 13 (2): 118-127. 10.1034/j.1600-0668.2003.00157.x.View ArticleGoogle Scholar
- Barros-Dios JM, Barriero MA, Ruano-Ravina A, Figueiras A: Exposure to residential Radon and lung cancer in Spain: A populaton-based case-control study. Am J Epidemiol. 2002, 156: 548-555. 10.1093/aje/kwf070.View ArticleGoogle Scholar
- Coskeran T, Denman A, Phillips P, Gillmore G, Tornberg R: A New Methodology for Cost-Effectiveness Studies of Domestic radon remediation Programmes: Quality-adjusted Life-years Gained Within Primary Care Trusts in Central England. Sci Tot Env. 2006, 366 (1): 32-46. 10.1016/j.scitotenv.2005.12.020.View ArticleGoogle Scholar
- Horner MJ: SEER 9 areas and U.S. Mortality Files. National Center for Health Statistics, Centers for Disease Control and Prevention. 2010, based on November 2008 SEER data submission, posted to the SEER web site, [http://seer.cancer.gov/csr/1975_2006/]Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.