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      Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

      review-article
      * , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 6 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 13 , 16 , 17 , 18 , 19 , 17 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 30 , 32 , 33 , 34 , 35 , 35 , 36 , 37 , 38 , 39 , 2 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 15 , 49 , 41 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 57 , 20 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 43 , 67 , 68 , 49 , 69 , 70 , 56 , 71 , 12 , 72 , 64 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 72 , 83 , 33 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 21 , 91 , 92 , 72 , 14 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 43 , 100 , 101 , 102 , 76 , 33 , 103 , 96 , 104 , 105 , 78 , 106 , 107 , 93 , 94 , 108 , 65 , 102 , 109 , 60 , 110 , 111 , 110 , 45 , 112 , 113 , 114 , 115 , 116 , 37 , 38 , 50 , 48 , 43 , 117 , 118 , 63 , 119 , 120 , 121 , 47 , 85 , 122 , 123 , 81 , 26 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 128 , 134 , 135 , 136 , 87 , 117 , 137 , 138 , 70 , 139 , 140 , 43 , 141
      Carcinogenesis
      Oxford University Press

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          Low-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.

          Abstract

          Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

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          Most cited references445

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          Angiogenesis in life, disease and medicine.

          The growth of blood vessels (a process known as angiogenesis) is essential for organ growth and repair. An imbalance in this process contributes to numerous malignant, inflammatory, ischaemic, infectious and immune disorders. Recently, the first anti-angiogenic agents have been approved for the treatment of cancer and blindness. Angiogenesis research will probably change the face of medicine in the next decades, with more than 500 million people worldwide predicted to benefit from pro- or anti-angiogenesis treatments.
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            Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions.

            Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue's homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to "bad luck," that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes. Copyright © 2015, American Association for the Advancement of Science.
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              Angiogenesis in cancer, vascular, rheumatoid and other disease.

              J Folkman (1995)
              Recent discoveries of endogenous negative regulators of angiogenesis, thrombospondin, angiostatin and glioma-derived angiogenesis inhibitory factor, all associated with neovascularized tumours, suggest a new paradigm of tumorigenesis. It is now helpful to think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth. The extent to which the negative regulators are decreased during this switch may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.
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                Author and article information

                Journal
                Carcinogenesis
                Carcinogenesis
                carcin
                carcin
                Carcinogenesis
                Oxford University Press (UK )
                0143-3334
                1460-2180
                June 2015
                19 June 2015
                19 June 2015
                : 36
                : Suppl 1 , Assessing the Carcinogenic Potential of Low-Dose Exposures to Chemical Mixtures in the Environment: The Challenge Ahead
                : S254-S296
                Affiliations
                California Pacific Medical Center Research Institute , 2100 Webster Street #401, San Francisco, CA 94115, USA,
                1Getting to Know Cancer , Room 229A, 36 Arthur Street, Truro, Nova Scotia B2N 1X5, Canada,
                2Lancaster Environment Centre, Lancaster University , Bailrigg, Lancaster LA1 4AP, UK,
                3Institute for Health and the Environment, University at Albany , 5 University Pl., Rensselaer, NY 12144, USA,
                4Getting to Know Cancer , Guelph N1G 1E4, Canada,
                5School of Biotechnology, Faculty of Agriculture Biotechnology and Food Sciences, Sultan Zainal Abidin University , Tembila Campus, 22200 Besut, Terengganu, Malaysia,
                6Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Navarra , Pamplona 31008, Spain,
                7Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey , Piscataway, NJ 08854, USA,
                8Instituto de Biomedicina de Sevilla, Consejo Superior de Investigaciones Cientificas . Hospital Universitario Virgen del Rocio, Univ. de Sevilla., Avda Manuel Siurot sn. 41013 Sevilla, Spain,
                9Department of Experimental and Clinical Medicine, University of Firenze , Florence 50134, Italy,
                10School of Biological Sciences, University of Reading , Hopkins Building, Reading, Berkshire RG6 6UB, UK,
                11Department of Nutrition, University of Oslo , Oslo, Norway,
                12Department of Biochemistry and Biology, University of Bath , Claverton Down, Bath BA2 7AY, UK,
                13Department of Public Health Sciences, College of Medicine, Pennsylvania State University , Hershey, PA 17033, USA,
                14Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency , 40126 Bologna, Italy,
                15Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health , Oslo N-0403, Norway,
                16Planet Biotechnologies Inc. , St Albert, Alberta T8N 5K4, Canada,
                17Department of Molecular and Cellular Biochemistry, University of Kentucky , Lexington, KY 40508, USA,
                18Spanish National Cancer Research Centre, CNIO, Melchor Fernandez Almagro , 3, 28029 Madrid, Spain,
                19Department of Medicine, McGill University , Montreal, Quebec H4A 3J1, Canada,
                20Istituto di Genetica Molecolare, CNR , Via Abbiategrasso 207, 27100 Pavia, Italy,
                21Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Bethesda, MD 20892–3375, USA,
                22Department of Cellular and Physiological Sciences, Life Sciences Institute, Faculty of Medicine, The University of British Columbia , Vancouver, British Columbia V5Z 1M9, Canada,
                23Department of Biology, Jackson State University, Jackson , MS 39217, USA,
                24Department of Molecular and Environmental Toxicology, University of Wisconsin-Madison , Madison, WI 53706, USA,
                25Department of Anatomy and Cell Biology, University of Western Ontario , London, Ontario N6A 3K7, Canada,
                26Stanford University Department of Medicine, Division of Oncology, Stanford, CA 94305 , USA,
                27Superfund Research Program, National Institute of Environmental Health Sciences , Research Triangle Park, NC 27560, USA,
                28Department of Medicine, Oncology and Pathology , Stanford University, Stanford, CA 94305, USA,
                29Department of Natural Science, The City University of New York at Hostos Campus , Bronx, NY 10451, USA,
                30Department of Environmental and Radiological Health Sciences, Colorado State University , Fort Collins, CO 80523–1680, USA,
                31Department of Head and Neck Surgery/Head and Neck Cancer Research, Johns Hopkins University School of Medicine , Baltimore, MD 21205, USA,
                32Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan , Italy,
                33Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, National Autonomous University of Mexico, Mexico City 04510 , México,
                34Department of Bioscience and Biotechnology, Sejong University , Seoul 143–747, Korea,
                35Department of Biomedical Sciences, University of Cagliari , 09124 Cagliari, Italy,
                36Department of Pathology, Kuwait University , Safat 13110, Kuwait,
                37Department of Biotechnology and Biosciences, University of Milano-Bicocca , 20126 Milan, Italy,
                38SYSBIO Centre of Systems Biology , Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy,
                39Human Safety and Environmental Research, Department of Health Sciences, College of North Atlantic, Doha 24449, State of Qatar ,
                40Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University , Maastricht 6200, The Netherlands,
                41Department of Molecular Biology, School of Osteopathic Medicine, Rowan University , Stratford, NJ 08084, USA,
                42Hacettepe University, Center for Stem Cell Research and Development , Ankara 06640, Turkey,
                43Department of Biochemistry and Cancer Biology, Meharry Medical College , Nashville, TN 37208, USA,
                44Center for Radiological Research, Columbia University Medical Center , New York, NY 10032, USA,
                45Instituto de Alta Investigacion, Universidad de Tarapaca , Arica, Chile,
                46School of Biological Sciences, University of Reading , Reading, RG6 6UB, UK,
                47Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School , Ann Arbor, MI 48109, USA,
                48Environmental Risk and Health Unit, Flemish Institute for Technological Research , 2400 Mol, Belgium,
                49Department of Surgery, Pathology, Immunology, Duke University Medical Center , Durham, NC 27710, USA,
                50Department of Biomedical Sciences, Faculty of Medicine and Health Sciences , 43400 Universiti Putra Malaysia, Serdang, Selangor, Malaysia,
                51Department of Life Sciences, College of Health and Life Sciences and the Health and Environment Theme, Institute of Environment, Health and Societies, Brunel University Kingston Lane , Uxbridge, Middlesex UB8 3PH, UK,
                52National Institute for Environmental Studies , 16-2 Onogawa, Tsukuba, Ibraki 3058506, Japan,
                53Department of Geriatric Medicine, Kyoto University Hospital 54 Kawaharacho , Shogoin, Sakyo-ku Kyoto, 606–8507, Japan,
                54Department of Urology, Kasr Al-Ainy School of Medicine, Cairo University , El Manial, Cairo 11559, Egypt,
                55Department of Life Sciences, Tzu-Chi University , Hualien 970, Taiwan,
                56School of Biotechnology, Yeungnam University , Gyeongbuk 712-749, South Korea,
                57Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences , Little Rock, AR 72205, USA,
                58Department of Environmental Health, Indiana University, School of Public Health , Bloomington, IN 47405, USA,
                59Department of Cytokinetics, Institute of Biophysics Academy of Sciences of the Czech Republic , Brno, CZ-61265, Czech Republic,
                60Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada , Ottawa, Ontario K1A 0K9, Canada,
                61Department of Medicine, University of Louisville , Louisville, KY 40202, USA,
                62Robley Rex VA Medical Center , Louisville, KY 40202, USA,
                63Department of Applied Medical Sciences, University of Southern Maine , 96 Falmouth St., Portland, ME 04104, USA,
                64Mouse Models of Cancer Therapies Group, Vall d’Hebron Institute of Oncology (VHIO) , 08035 Barcelona, Spain,
                65Lombardi Comprehensive Cancer Center, Georgetown University Medical Center , Washington DC 20057, USA,
                66Cancer Research UK. Cambridge Institute, University of Cambridge , Robinson Way, Cambridge CB2 0RE, UK,
                67Department of Cell Biology, Pharmamar-SAU , Avda. De los Reyes, 1. 28770-Colmenar Viejo, Madrid, Spain,
                68Departments of Obstetrics and Gynecology and Pathology, Pennsylvania State University College of Medicine , Hershey PA 17033, USA,
                69Department of Biochemistry, Rush University , Chicago, IL 60612, USA,
                70Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University , Corvallis, OR 97331, USA,
                71Department of Medicine/Medical Oncology, Rutgers Cancer Institute of New Jersey , New Brunswick, NJ 08903, USA,
                72Laboratory for Cell Genetics, Vrije Universiteit Brussel , 1050 Brussels, Belgium,
                73Catalan Institution for Research and Advanced Studies (ICREA) , Barcelona 08010, Spain,
                74School of Public Health, Curtin University , Bentley, WA 6102, Australia,
                75Public Health and Clinical Services Division, Department of Health, Government of Western Australia, WA 6004, Australia ,
                76Department of Urology, University of California Davis , Sacramento, CA 95817, USA,
                77Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University , Taipei 11031, Taiwan,
                78School of Biomedical Sciences, The Chinese University of Hong Kong , Shatin, NT, Hong Kong SAR, The People’s Republic of China,
                79Faculty of Medicine, University of Otago , Dunedin 9054, New Zealand,
                80Department of Biomedical Engineering and Cancer Biology, Vanderbilt University , Nashville, TN 37235, USA,
                81Department of Experimental Oncology, Mediterranean Institute of Oncology , Via Penninazzo 7, Viagrande (CT) 95029, Italy,
                82Center for Experimental Molecular Medicine, Academic Medical Center , Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands,
                83Division of Environmental Health Sciences, School of Public Health, University of California , Berkeley, CA 94720-7360, USA,
                84Inflammation and Cancer Research, National Cancer Institute (NCI) (Retired) , National Institutes of Health , Bethesda, MD 20892, USA,
                85Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples , 80131 Naples, Italy,
                86Centre De Recherche En Cancerologie, De Lyon, Lyon, U1052-UMR5286, France,
                87United States Army Institute of Public Health, Toxicology Portfolio-Health Effects Research Program, Aberdeen Proving Ground , Edgewood, MD 21010-5403, USA,
                88Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia , Via Adamello 16, 20139 Milano, Italy,
                89Department of Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer Center , Richmond, VA 23298, USA,
                90Institut De Recerca Hospital Vall D’Hebron, Passeig Vall d’Hebron , 119–129, 08035 Barcelona, Spain,
                91University of Puerto Rico, Medical Sciences Campus , School of Public Health, Nutrition Program, San Juan 00921, Puerto Rico,
                92Department of Biological Chemistry, Medical School, University of Athens, Institute of Molecular Medicine and Biomedical Research , 10676 Athens, Greece,
                93White River Junction Veterans Affairs Medical Center, White River Junction , VT 05009, USA,
                94Geisel School of Medicine at Dartmouth , Hanover, NH 03755, USA,
                95Advanced Molecular Science Research Centre (Centre for Advanced Research), King George’s Medical University , Lucknow, Uttar Pradesh 226 003, India,
                96Departments of Neurosurgery and Biochemistry and Massey Cancer Center, Virginia Commonwealth University , Richmond, VA 23298, USA,
                97Integrated Laboratory Systems Inc., in support of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods , RTP, NC 27709, USA,
                98Analytische, Milieu en Geochemie, Vrije Universiteit Brussel , Brussel B1050, Belgium,
                99Department of Obstetrics and Gynecology, University of Melbourne , Victoria 3052, Australia,
                100Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 3126, Saudi Arabia ,
                101School of Engineering and Materials Science, Queen Mary University of London , Mile End Road, London, E1 4NS, UK,
                102Department of Biochemistry and Molecular Biology, Dalhousie University , Halifax, Nova Scotia B3H 4R2, Canada,
                103Department of Pathology, Stony Brook School of Medicine, Stony Brook University, The State University of New York, Stony Brook, NY 11794-8691 , USA,
                104Charles University in Prague, Third Faculty of Medicine , CZ-100 00 Prague 10, Czech Republic,
                105School of Biological Sciences, The University of Reading , Whiteknights, Reading RG6 6UB, England,
                106Department of Pathology, Wayne State University , Detroit, MI 48201, USA,
                107Computer Science Department, Southern Illinois University , Carbondale, IL 62901, USA,
                108Human Genetics Unit, Department of Pathology, Faculty of Medicine, Kuwait University , Jabriya 13110, Kuwait,
                109Department of Molecular and Experimental Medicine, The Scripps Research Institute , La Jolla, CA 92037, USA,
                110Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies, Polyclinic Plexus, University of Palermo, Palermo 90127, Italy ,
                111Sbarro Institute for Cancer Research and Molecular Medicine, Temple University , Philadelphia, PA 19122, USA,
                112Department of Pharmacology and Toxicology, University of Vienna , Vienna A-1090, Austria,
                113Institute of Cancer Research, Department of Medicine, Medical University of Vienna , Wien 1090, Austria,
                114Departments of Pharmacology and Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute , Atlanta, GA 30322, USA,
                115Division of Hematology and Oncology, Department of Pediatrics, Children’s Healthcare of Atlanta , GA 30322, USA,
                116Department of Pediatrics, Emory University School of Medicine, Emory University , Atlanta, GA 30322, USA,
                117Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill , NC 27599, USA,
                118Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104, USA,
                119Program in Genetics and Molecular Biology, Graduate Division of Biological and Biomedical Sciences, Emory University , Atlanta, GA 30322, USA,
                120Population Health and Prevention, Research, Prevention and Cancer Control, Cancer Care Ontario , Toronto, Ontario, M5G 2L7, Canada,
                121Departments of Epidemiology and Occupational and Environmental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, M5T 3M7, Canada ,
                122Department of Cardiac, Thoracic and Vascular Sciences, Unit of Occupational Medicine, University of Padova , Padova 35128, Italy,
                123Department of Anatomy, Physiology and Biochemistry, The Swedish University of Agricultural Sciences , PO Box 7011, VHC, Almas Allé 4, SE-756 51, Uppsala, Sweden,
                124Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 , Thailand,
                125Department of Anatomy, College of Medicine, Yeungnam University, Daegu 705–717, South Korea,
                126Department of Hygiene, Kawasaki Medical School, Matsushima Kurashiki, Okayama 701-0192 , Japan,
                127Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, United States Food and Drug Administration , Jefferson, AR 72079, USA,
                128INSERM U1113, team 3 ‘Cell Signalling and Communication in Kidney and Prostate Cancer’, University of Strasbourg, Faculté de Médecine , 67085 Strasbourg, France,
                129INRS-Institut Armand-Frappier, 531 Boulevard des Prairies , Laval, QC H7V 1B7, Canada,
                130Department of Biology, Geology and Environmental Sciences, Alma Mater Studiorum Università di Bologna , Via Francesco Selmi, 3, 40126 Bologna, Italy,
                131Center for Applied Biomedical Research, S. Orsola-Malpighi University Hospital , Via Massarenti, 9, 40126 Bologna, Italy,
                132National Institute of Biostructures and Biosystems, Viale Medaglie d’ Oro , 305, 00136 Roma, Italy,
                133Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences , PO Box 7028, 75007 Uppsala, Sweden,
                134Department of Cell and Developmental Biology, University of California , Irvine, CA 92697, USA,
                135Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University , Atlanta, GA 30314, USA,
                136Harvard Medical School/Brigham and Women’s Hospital , Boston, MA 02115, USA,
                137Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences , PO Box 7028, 75007 Uppsala, Sweden,
                138Baylor College of Medicine , Houston, TX 77030, USA,
                139Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, 26506,USA
                140Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University , PO Box 24923, Safat 13110, Kuwait and
                141Department of Surgery, The Ohio State University College of Medicine, The James Comprehensive Cancer Center , Columbus, OH 43210, USA
                Author notes
                *To whom correspondence should be addressed. William H.Goodson III, California Pacific Medical Center Research Institute, 2100 Webster Street #401, San Francisco, CA 94115, USA. Tel: +41 59 233925; Fax: +41 57 761977; Email: whg3md@ 123456att.net
                Correspondence may also be addressed to Leroy Lowe. Tel: +90 28 935362; Fax: +90 28 935610; Email: leroy.lowe@ 123456gettingtoknowcancer.org

                Part of the special issue on ‘Assessing the Carcinogenic Potential of Low-Dose Exposures to Chemical Mixtures in the Environment: The Challenge Ahead’

                Disclaimer

                This manuscript is the work product of a large group of researchers collectively representing a diverse array of institutions and a significant number of sponsors; however, the statements, opinions and conclusions expressed herein do not necessarily represent the views or positions of these institutions and sponsors.

                Conflict of interest statement: None declared

                Article
                10.1093/carcin/bgv039
                4480130
                26106142
                03ef96a4-1dcd-4224-a4c5-feb71dfdf1aa
                © The Author 2015. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 7 August 2014
                : 23 January 2015
                : 31 January 2015
                Page count
                Pages: 43
                Categories
                Review

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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