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Schubauer-Berigan MK. Invited Perspective: Good Measure-Assessing the Impact of Cancer Hazard Identification on Policies for Cancer Prevention. ENVIRONMENTAL HEALTH PERSPECTIVES 2023; 131:121302. [PMID: 38088578 PMCID: PMC10718083 DOI: 10.1289/ehp14099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 10/25/2023] [Accepted: 11/02/2023] [Indexed: 12/18/2023]
Affiliation(s)
- Mary K. Schubauer-Berigan
- Evidence Synthesis and Classification Branch, International Agency for Research on Cancer, Lyon, France
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Fishbein A, Hammock BD, Serhan CN, Panigrahy D. Carcinogenesis: Failure of resolution of inflammation? Pharmacol Ther 2021; 218:107670. [PMID: 32891711 PMCID: PMC7470770 DOI: 10.1016/j.pharmthera.2020.107670] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2020] [Indexed: 02/06/2023]
Abstract
Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to induce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macrophage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation, including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors, may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans.
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Affiliation(s)
- Anna Fishbein
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Bruce D. Hammock
- Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
| | - Charles N. Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Li B, Tang H, Cheng Z, Zhang Y, Xiang H. The Current Situation and Future Trend of Leukemia Mortality by Sex and Area in China. Front Public Health 2020; 8:598215. [PMID: 33363091 PMCID: PMC7759534 DOI: 10.3389/fpubh.2020.598215] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 11/23/2020] [Indexed: 11/18/2022] Open
Abstract
Leukemia is one of the most common cancers. We conducted this study to comprehensively analyze the temporal trends of leukemia mortality during 2003–2017 and project the trends until 2030. We extracted national-level data on annual leukemia mortality from China Health Statistics Yearbooks (2003–2017). We applied the Joinpoint regression model to assess leukemia mortality trends in urban and rural China by sex during 2003–2017. We also produced sex-specific leukemia mortality using the adjusted Global Burden Disease (GBD) 2016 projection model. In urban areas, age-standardized leukemia mortality decreased significantly among females during 2003–2017 (APC = −0.9%; 95% CI: −1.7, −0.1%). In rural areas, significant decreases of age-standardized leukemia mortality were both found among males (APC = −1.7%; 95% CI: −2.9, −0.5%) and females (APC = −1.6%; 95% CI: −2.6, −0.7%) from 2008 to 2017. Rural-urban and sex disparities of leukemia mortality will continue to exist until the year 2030. According to projection, the leukemia mortality rates of males and rural populations are higher than that of females and urban populations. In 2030, leukemia mortality is projected to decrease to 3.03/100,000 and 3.33/100,000 among the males in urban and rural areas, respectively. In females, leukemia mortality will decrease to 1.87/100,000 and 2.26/100,000 among urban and rural areas, respectively. Our study suggests that more precautionary measures to reduce leukemia mortality are need, and more attention should be paid to rural residents and males in primary prevention of leukemia in China.
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Affiliation(s)
- Baojing Li
- Department of Global Health, School of Health Sciences, Wuhan University, Wuhan, China.,Global Health Institute, Wuhan University, Wuhan, China
| | - Hong Tang
- Department of Global Health, School of Health Sciences, Wuhan University, Wuhan, China.,Global Health Institute, Wuhan University, Wuhan, China
| | - Zilu Cheng
- School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Yuxiao Zhang
- Department of Global Health, School of Health Sciences, Wuhan University, Wuhan, China.,Global Health Institute, Wuhan University, Wuhan, China
| | - Hao Xiang
- Department of Global Health, School of Health Sciences, Wuhan University, Wuhan, China.,Global Health Institute, Wuhan University, Wuhan, China
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The Role of Natural Polyphenols in the Prevention and Treatment of Cervical Cancer-An Overview. Molecules 2016; 21:molecules21081055. [PMID: 27548122 PMCID: PMC6274328 DOI: 10.3390/molecules21081055] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 08/06/2016] [Accepted: 08/08/2016] [Indexed: 12/28/2022] Open
Abstract
Cervical cancer represents the second leading cause of death for women worldwide. The importance of the diet and its impact on specific types of neoplasia has been highlighted, focusing again interest in the analysis of dietary phytochemicals. Polyphenols have shown a wide range of cellular effects: they may prevent carcinogens from reaching the targeted sites, support detoxification of reactive molecules, improve the elimination of transformed cells, increase the immune surveillance and the most important factor is that they can influence tumor suppressors and inhibit cellular proliferation, interfering in this way with the steps of carcinogenesis. From the studies reviewed in this paper, it is clear that certain dietary polyphenols hold great potential in the prevention and therapy of cervical cancer, because they interfere in carcinogenesis (in the initiation, development and progression) by modulating the critical processes of cellular proliferation, differentiation, apoptosis, angiogenesis and metastasis. Specifically, polyphenols inhibit the proliferation of HPV cells, through induction of apoptosis, growth arrest, inhibition of DNA synthesis and modulation of signal transduction pathways. The effects of combinations of polyphenols with chemotherapy and radiotherapy used in the treatment of cervical cancer showed results in the resistance of cervical tumor cells to chemo- and radiotherapy, one of the main problems in the treatment of cervical neoplasia that can lead to failure of the treatment because of the decreased efficiency of the therapy.
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Maru GB, Hudlikar RR, Kumar G, Gandhi K, Mahimkar MB. Understanding the molecular mechanisms of cancer prevention by dietary phytochemicals: From experimental models to clinical trials. World J Biol Chem 2016; 7:88-99. [PMID: 26981198 PMCID: PMC4768127 DOI: 10.4331/wjbc.v7.i1.88] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/04/2015] [Accepted: 11/25/2015] [Indexed: 02/05/2023] Open
Abstract
Chemoprevention is one of the cancer prevention approaches wherein natural/synthetic agent(s) are prescribed with the aim to delay or disrupt multiple pathways and processes involved at multiple steps, i.e., initiation, promotion, and progression of cancer. Amongst environmental chemopreventive compounds, diet/beverage-derived components are under evaluation, because of their long history of exposure to humans, high tolerability, low toxicity, and reported biological activities. This compilation briefly covers and compares the available evidence on chemopreventive efficacy and probable mechanism of chemoprevention by selected dietary phytochemicals (capsaicin, curcumin, diallyl sulphide, genistein, green/black tea polyphenols, indoles, lycopene, phenethyl isocyanate, resveratrol, retinoids and tocopherols) in experimental systems and clinical trials. All the dietary phytochemicals covered in this review have demonstrated chemopreventive efficacy against spontaneous or carcinogen-induced experimental tumors and/or associated biomarkers and processes in rodents at several organ sites. The observed anti-initiating, anti-promoting and anti-progression activity of dietary phytochemicals in carcinogen-induced experimental models involve phytochemical-mediated redox changes, modulation of enzymes and signaling kinases resulting to effects on multiple genes and cell signaling pathways. Results from clinical trials using these compounds have not shown them to be chemopreventive. This may be due to our: (1) inability to reproduce the exposure conditions, i.e., levels, complexity, other host and lifestyle factors; and (2) lack of understanding about the mechanisms of action and agent-mediated toxicity in several organs and physiological processes in the host. Current research efforts in addressing the issues of exposure conditions, bioavailability, toxicity and the mode of action of dietary phytochemicals may help address the reason for observed mismatch that may ultimately lead to identification of new chemopreventive agents for protection against broad spectrum of exposures.
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Brophy JT, Keith MM, Park R, Watterson A, Gilbertson M, Dematteo R. Breast cancer and the environment: why research and preventive action are needed. Curr Oncol 2013; 20:e488-90. [PMID: 24155646 DOI: 10.3747/co.20.1681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
In the February 2013 issue of Current Oncology, Dr. Steven Narod1 critiqued the 2012 study by Brophy et al. [...]
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Affiliation(s)
- James T Brophy
- University of Stirling, Occupational and Environmental Health Research Group, Centre for Public Health and Population Health Research and Department of Sociology, Anthropology, and Criminology, University of Windsor, Tecumseh, ON, E-mail:
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What Are the Real Causes of Cancer? INTERNATIONAL JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH 2013. [DOI: 10.1179/oeh.2006.12.1.81] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Huff J, Ladou L. Aspartame Bioassay Findings Portend Human Cancer Hazards. INTERNATIONAL JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH 2013; 13:446-8. [DOI: 10.1179/oeh.2007.13.4.446] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Ladou J, Teitelbaum DT, Egilman DS, Frank AL, Kramer SN, Huff J. American College of Occupational and Environmental Medicine (ACOEM): A Professional Association in Service to Industry. INTERNATIONAL JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH 2013; 13:404-26. [DOI: 10.1179/oeh.2007.13.4.404] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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White MC, Peipins LA, Watson M, Trivers KF, Holman DM, Rodriguez JL. Cancer prevention for the next generation. J Adolesc Health 2013; 52:S1-7. [PMID: 23601606 PMCID: PMC4402978 DOI: 10.1016/j.jadohealth.2013.02.016] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Revised: 02/27/2013] [Accepted: 02/28/2013] [Indexed: 12/15/2022]
Abstract
Given the continued growth in the number of persons with cancer in the United States, the primary prevention of cancer remains an urgent public health priority. As the field of cancer prevention continues to mature and scientific knowledge evolves, it is imperative to challenge the status quo and embrace new approaches to cancer prevention. In this commentary, we summarize recent trends and some of the scientific advances that have been made over the past few decades regarding the complex process of cancer development and the interaction of individual and social risk factors. We examine some of the assumptions and terminology that have characterized cancer prevention approaches for more than a quarter century and the impact of these assumptions and our use of terminology. We propose that it is possible for today's youth to experience lower cancer incidence rates as adults compared with previous generations. To accomplish this goal, a more transdisciplinary and multifaceted approach is needed, adapted as appropriate for different populations and stages of life. The greatest improvements in cancer prevention may occur as a result of innovative, multilevel interventions that build on the expanding scientific evidence base.
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Affiliation(s)
- Mary C White
- Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia 3034, USA.
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Espina C, Porta M, Schüz J, Aguado IH, Percival RV, Dora C, Slevin T, Guzman JR, Meredith T, Landrigan PJ, Neira M. Environmental and occupational interventions for primary prevention of cancer: a cross-sectorial policy framework. ENVIRONMENTAL HEALTH PERSPECTIVES 2013; 121:420-6. [PMID: 23384642 PMCID: PMC3620754 DOI: 10.1289/ehp.1205897] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Accepted: 01/31/2013] [Indexed: 05/10/2023]
Abstract
BACKGROUND Nearly 13 million new cancer cases and 7.6 million cancer deaths occur worldwide each year; 63% of cancer deaths occur in low- and middle-income countries. A substantial proportion of all cancers are attributable to carcinogenic exposures in the environment and the workplace. OBJECTIVE We aimed to develop an evidence-based global vision and strategy for the primary prevention of environmental and occupational cancer. METHODS We identified relevant studies through PubMed by using combinations of the search terms "environmental," "occupational," "exposure," "cancer," "primary prevention," and "interventions." To supplement the literature review, we convened an international conference titled "Environmental and Occupational Determinants of Cancer: Interventions for Primary Prevention" under the auspices of the World Health Organization, in Asturias, Spain, on 17-18 March 2011. DISCUSSION Many cancers of environmental and occupational origin could be prevented. Prevention is most effectively achieved through primary prevention policies that reduce or eliminate involuntary exposures to proven and probable carcinogens. Such strategies can be implemented in a straightforward and cost-effective way based on current knowledge, and they have the added benefit of synergistically reducing risks for other noncommunicable diseases by reducing exposures to shared risk factors. CONCLUSIONS Opportunities exist to revitalize comprehensive global cancer control policies by incorporating primary interventions against environmental and occupational carcinogens.
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Affiliation(s)
- Carolina Espina
- Department of Public Health and Environment, World Health Organization (WHO), Geneva, Switzerland
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Benigni R, Bossa C, Tcheremenskaia O. Nongenotoxic carcinogenicity of chemicals: mechanisms of action and early recognition through a new set of structural alerts. Chem Rev 2013; 113:2940-57. [PMID: 23469814 DOI: 10.1021/cr300206t] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Romualdo Benigni
- Istituto Superiore di Sanita' Environment and Health Department, Viale Regina Elena 299, 00161 Rome, Italy.
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Brophy JT, Keith MM, Watterson A, Park R, Gilbertson M, Maticka-Tyndale E, Beck M, Abu-Zahra H, Schneider K, Reinhartz A, DeMatteo R, Luginaah I. Breast cancer risk in relation to occupations with exposure to carcinogens and endocrine disruptors: a Canadian case-control study. Environ Health 2012; 11:87. [PMID: 23164221 PMCID: PMC3533941 DOI: 10.1186/1476-069x-11-87] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 11/06/2012] [Indexed: 05/20/2023]
Abstract
BACKGROUND Endocrine disrupting chemicals and carcinogens, some of which may not yet have been classified as such, are present in many occupational environments and could increase breast cancer risk. Prior research has identified associations with breast cancer and work in agricultural and industrial settings. The purpose of this study was to further characterize possible links between breast cancer risk and occupation, particularly in farming and manufacturing, as well as to examine the impacts of early agricultural exposures, and exposure effects that are specific to the endocrine receptor status of tumours. METHODS 1005 breast cancer cases referred by a regional cancer center and 1146 randomly-selected community controls provided detailed data including occupational and reproductive histories. All reported jobs were industry- and occupation-coded for the construction of cumulative exposure metrics representing likely exposure to carcinogens and endocrine disruptors. In a frequency-matched case-control design, exposure effects were estimated using conditional logistic regression. RESULTS Across all sectors, women in jobs with potentially high exposures to carcinogens and endocrine disruptors had elevated breast cancer risk (OR = 1.42; 95% CI, 1.18-1.73, for 10 years exposure duration). Specific sectors with elevated risk included: agriculture (OR = 1.36; 95% CI, 1.01-1.82); bars-gambling (OR = 2.28; 95% CI, 0.94-5.53); automotive plastics manufacturing (OR = 2.68; 95% CI, 1.47-4.88), food canning (OR = 2.35; 95% CI, 1.00-5.53), and metalworking (OR = 1.73; 95% CI, 1.02-2.92). Estrogen receptor status of tumors with elevated risk differed by occupational grouping. Premenopausal breast cancer risk was highest for automotive plastics (OR = 4.76; 95% CI, 1.58-14.4) and food canning (OR = 5.70; 95% CI, 1.03-31.5). CONCLUSIONS These observations support hypotheses linking breast cancer risk and exposures likely to include carcinogens and endocrine disruptors, and demonstrate the value of detailed work histories in environmental and occupational epidemiology.
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Affiliation(s)
- James T Brophy
- Occupational and Environmental Health Research Group, Centre for Public Health and Population Health Research, University of Stirling, Stirling, Scotland, FK9 4LA, UK
- Department of Sociology, Anthropology, and Criminology, University of Windsor, 401 Sunset Avenue, Windsor, ON, N9B 3P4, Canada
| | - Margaret M Keith
- Occupational and Environmental Health Research Group, Centre for Public Health and Population Health Research, University of Stirling, Stirling, Scotland, FK9 4LA, UK
- Department of Sociology, Anthropology, and Criminology, University of Windsor, 401 Sunset Avenue, Windsor, ON, N9B 3P4, Canada
| | - Andrew Watterson
- Occupational and Environmental Health Research Group, Centre for Public Health and Population Health Research, University of Stirling, Stirling, Scotland, FK9 4LA, UK
| | - Robert Park
- Education and Information Division, National Institute for Occupational Safety and Health (NIOSH), 4676 Columbia Parkway, Cincinnati, Ohio, 45226, USA
| | - Michael Gilbertson
- Occupational and Environmental Health Research Group, Centre for Public Health and Population Health Research, University of Stirling, Stirling, Scotland, FK9 4LA, UK
| | - Eleanor Maticka-Tyndale
- Department of Sociology, Anthropology, and Criminology, University of Windsor, 401 Sunset Avenue, Windsor, ON, N9B 3P4, Canada
| | - Matthias Beck
- Queen’s University Belfast, University Road, Belfast, Northern Ireland, BT7 1NN, UK
| | - Hakam Abu-Zahra
- Windsor Regional Cancer Centre, 2220 Kildare Road, Windsor, ON, N8W 2X3, Canada
| | - Kenneth Schneider
- Windsor Regional Cancer Centre, 2220 Kildare Road, Windsor, ON, N8W 2X3, Canada
| | - Abraham Reinhartz
- Occupational Health Clinics for Ontario Workers, 15 Gervais Drive, Suite 601, Don Mills, ON, M3C1Y8, Canada
| | - Robert DeMatteo
- Occupational Health Clinics for Ontario Workers, 15 Gervais Drive, Suite 601, Don Mills, ON, M3C1Y8, Canada
| | - Isaac Luginaah
- Department of Geography, Social Science Centre, University of Western Ontario, London, ON, N6A 5C2, Canada
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Benigni R, Bossa C, Tcheremenskaia O. In vitro cell transformation assays for an integrated, alternative assessment of carcinogenicity: a data-based analysis. Mutagenesis 2012; 28:107-16. [DOI: 10.1093/mutage/ges059] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Huff J. Long-term toxicology and carcinogenicity of 2,4,6-trichlorophenol. CHEMOSPHERE 2012; 89:521-525. [PMID: 22748215 DOI: 10.1016/j.chemosphere.2012.05.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Revised: 03/13/2012] [Accepted: 05/04/2012] [Indexed: 06/01/2023]
Abstract
Carcinogenesis bioassays were conducted by giving 2,4,6-trichlorophenol [2,4,6-TCP] in feed to groups of 50 male and female Fischer rats and male B6C3F1 mice for two years. Dietary concentrations were 0 [20/group], 5000 [0.5%], or 10,000 [1%] ppm. Female mice began with 10,000 and 20,000 ppm but after 38 weeks were lowered due to reduced body weights to 2500 and 5000 ppm for 67 weeks; exposures averaged 5200 and 10,400 ppm. Adverse effects at two years were leukocytosis and monocytosis of peripheral blood and hyperplasia of bone marrow in both sexes of rats. In mice, liver toxicity, including individual liver cell abnormalities, focal areas of cellular alteration, and focal and nodular areas of hyperplasia were commonly present. Regarding carcinogenic activity, TCP caused leukemias/lymphomas in male rats, and possibly in female rats and female mice as well, and induced liver tumors in male and female mice. Using NTP categories of evidence indicates 'clear evidence of carcinogenicity' for male rats [hematopoietic system tumors]; 'equivocal evidence of carcinogenicity' for female rats [hematopoietic system tumors]; 'clear evidence of carcinogenicity' for male and female mice [liver tumors].
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Affiliation(s)
- James Huff
- National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
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Shamovsky I, Ripa L, Blomberg N, Eriksson LA, Hansen P, Mee C, Tyrchan C, O'Donovan M, Sjö P. Theoretical Studies of Chemical Reactivity of Metabolically Activated Forms of Aromatic Amines toward DNA. Chem Res Toxicol 2012; 25:2236-52. [DOI: 10.1021/tx300313b] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Igor Shamovsky
- Department of Medicinal Chemistry, R&I iMed, AstraZeneca R&D, Pepparedsleden 1, S-431 83 Mölndal, Sweden
| | - Lena Ripa
- Department of Medicinal Chemistry, R&I iMed, AstraZeneca R&D, Pepparedsleden 1, S-431 83 Mölndal, Sweden
| | - Niklas Blomberg
- Department of Medicinal Chemistry, R&I iMed, AstraZeneca R&D, Pepparedsleden 1, S-431 83 Mölndal, Sweden
| | - Leif A. Eriksson
- Department of Chemistry and Molecular Biology, University of Gothenburg, S-412 96 Göteborg, Sweden
| | - Peter Hansen
- Department of Medicinal Chemistry, R&I iMed, AstraZeneca R&D, Pepparedsleden 1, S-431 83 Mölndal, Sweden
| | - Christine Mee
- Genetic Toxicology, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom
| | - Christian Tyrchan
- Department of Medicinal Chemistry, CVGI iMed, AstraZeneca R&D, Pepparedsleden 1, S-431 83 Mölndal, Sweden
| | - Mike O'Donovan
- Genetic Toxicology, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom
| | - Peter Sjö
- Department of Medicinal Chemistry, R&I iMed, AstraZeneca R&D, Pepparedsleden 1, S-431 83 Mölndal, Sweden
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Kar S, Roy K. First report on development of quantitative interspecies structure-carcinogenicity relationship models and exploring discriminatory features for rodent carcinogenicity of diverse organic chemicals using OECD guidelines. CHEMOSPHERE 2012; 87:339-355. [PMID: 22225702 DOI: 10.1016/j.chemosphere.2011.12.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2011] [Revised: 12/08/2011] [Accepted: 12/08/2011] [Indexed: 05/31/2023]
Abstract
Different regulatory agencies in food and drug administration and environmental protection worldwide are employing quantitative structure-activity relationship (QSAR) models to fill the data gaps related with properties of chemicals affecting the environment and human health. Carcinogenicity is a toxicity endpoint of major concern in recent times. Interspecies toxicity correlations may provide a tool for estimating sensitivity towards toxic chemical exposure with known levels of uncertainty for a diversity of wildlife species. In this background, we have developed quantitative interspecies structure-carcinogenicity correlation models for rat and mouse [rodent species according to the Organization for Economic Cooperation and Development (OECD) guidelines] based on the carcinogenic potential of 166 organic chemicals with wide diversity of molecular structures, spanning a large number of chemical classes and biological mechanisms. All the developed models have been assessed according to the OECD principles for the validation of QSAR models. Consensus predictions for carcinogenicity of the individual compounds are presented here for any one species when the data for the other species are available. Informative illustrations of the contributing structural fragments of chemicals which are responsible for specific carcinogenicity endpoints are identified by the developed models. The models have also been used to predict mouse carcinogenicities of 247 organic chemicals (for which rat carcinogenicities are present) and rat carcinogenicities of 150 chemicals (for which mouse carcinogenicities are present). Discriminatory features for rat and mouse carcinogenicity values have also been explored.
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Affiliation(s)
- Supratik Kar
- Drug Theoretics and Cheminformatics Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India
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Huff J, Melnick R. Environmental justice and primary prevention of cancer: the odyssey and legacy of lorenzo tomatis. New Solut 2012; 22:7-17. [PMID: 22436205 DOI: 10.2190/ns.22.1.b] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Lorenzo Tomatis [1929-2007] devoted his private and professional life to the betterment of mankind. As a physician, scientist, and humanitarian he championed against the plight of social injustice and promoted the obvious benefits of primary prevention of diseases compared to treatments that prevent or delay disease progression, especially occupational cancers. An avowed student and scholar of literature, the arts, the history of medicine and science, and chemical carcinogenesis, he believed in and wrote about these issues throughout his storied life. Some of his achievements, with excerpts from his writings, especially on primary prevention and on social injustice, are highlighted herein.
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Affiliation(s)
- James Huff
- NIEHS, P.O. Box 12233, Research Triangle Park, NC 27709, USA.
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Benigni R. Alternatives to the carcinogenicity bioassay for toxicity prediction: are we there yet? Expert Opin Drug Metab Toxicol 2012; 8:407-17. [PMID: 22360376 DOI: 10.1517/17425255.2012.666238] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION For decades, traditional toxicology has been the ultimate source of information on the carcinogenic potential of chemicals; however, with increasing demand on regulation of chemicals and decreasing resources for testing, opportunities to accept 'alternative' approaches have dramatically expanded. The need for tools able to identify carcinogens in shorter times and at a lower cost in terms of animal lives and money is still an open issue, and the present strategies and regulations for carcinogenicity prescreening do not adequately protect human health. AREAS COVERED This paper briefly summarizes the theories on the early steps of carcinogenesis and presents alternative detection methods for carcinogens based on genetic toxicology, structure-activity relationships and cell transformation assays. EXPERT OPINION There is evidence that the combination of Salmonella and structural alerts for the DNA-reactive carcinogens, and in vitro cell transformation assays for nongenotoxic carcinogens, permits the identification of a very large proportion of carcinogens. If implemented, this alternative strategy could improve considerably the protection of human health.
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Affiliation(s)
- Romualdo Benigni
- Environment and Health Department, Istituto Superiore di Sanita, Viale Regina Elena 299 00161, Rome, Italy.
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20
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Liu L, Winter KM, Stevenson L, Morris C, Leach DN. Wheat bran lipophilic compounds with in vitro anticancer effects. Food Chem 2012. [DOI: 10.1016/j.foodchem.2011.07.023] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Affiliation(s)
- James Huff
- National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
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Abstract
Studies of occupational exposures have made major contributions to our understanding of human carcinogenesis. About one third of the factors identified as definite or probable human carcinogens were first investigated in the workplace and these exposures exact a considerable toll on working populations. There are many additional workplace exposures that are suspect carcinogens that require further evaluation to ensure a safe work environment. Information from occupational investigations is also relevant to the general population because many occupational exposures can be found outside the workplace. Much of our understanding about occupational cancer has been obtained from studies largely composed of white men in developed countries. The movement of industry from developed to developing countries underscores the need for future investigations to include more diverse populations.
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Affiliation(s)
- Aaron Blair
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
- Occupational Cancer Research Centre, Cancer Care Ontario, Toronto, ON, Canada
| | - Loraine Marrett
- Occupational Cancer Research Centre, Cancer Care Ontario, Toronto, ON, Canada
| | - Laura Beane Freeman
- Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
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Abstract
The leading 20th century proponent for primary prevention of environmental cancer was Dr. Lorenzo Tomatis, the former Director of the International Agency for Research on Cancer and founder of the IARC Monographs program. This paper is dedicated to the memory of Dr. Tomatis--eminent scientist, scholar, teacher, humanitarian, and public health champion--and includes many perspectives that he promoted throughout his career, with original quotations from some of his scientific writings on primary prevention of environmental cancer. Any attempt by us to simply summarize his views would only detract from the power and logic of his language."Cancer still remains a mainly lethal disease. Primary prevention remains the most relevant approach to reduce mortality through a reduction in incidence".
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Affiliation(s)
- Ronald L Melnick
- Ron Melnick Consulting, LLC, 111 Roundtree Rd, Chapel Hill, NC 25514, USA
| | - James Huff
- National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
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Affiliation(s)
- David C Christiani
- Department of Environmental Health, Harvard School of Public Health, Boston, USA
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Benigni R, Bossa C. Mechanisms of Chemical Carcinogenicity and Mutagenicity: A Review with Implications for Predictive Toxicology. Chem Rev 2011; 111:2507-36. [PMID: 21265518 DOI: 10.1021/cr100222q] [Citation(s) in RCA: 254] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Romualdo Benigni
- Istituto Superiore di Sanita’, Environment and Health Department, Viale Regina Elena, 299 00161 Rome, Italy
| | - Cecilia Bossa
- Istituto Superiore di Sanita’, Environment and Health Department, Viale Regina Elena, 299 00161 Rome, Italy
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Huff J, Chan P, Melnick R. Clarifying carcinogenicity of ethylbenzene. Regul Toxicol Pharmacol 2010; 58:167-9; discussion 170-2. [PMID: 20723573 PMCID: PMC2989615 DOI: 10.1016/j.yrtph.2010.08.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2010] [Accepted: 08/08/2010] [Indexed: 11/18/2022]
Abstract
Ethylbenzene has been evaluated for carcinogenic activity in Fischer rats and B6C3F1 mice exposed by inhalation (Chan et al., 1998; Chan, 1999) and in Sprague-Dawley rats after oral exposure (Maltoni et al., 1985,1997). Bioassay findings are summarized below to expand on those not stated clearly or completely in Saghir et al. (2010). Overall in these three studies animals exposed to ethylbenzene had increased tumors in rats for kidneys, testes, head (including rare neuroesthesioepitheliomas), and total malignant tumors, whilst in mice tumor incidences were increased in the lung and liver (Huff, 2002). Thus ethylbenzene was carcinogenic by two exposure routes to both sexes of two species of rodents, two strains of rats, and one strain of mice, causing collectively tumors in five different target organs and a composite of "total malignant" tumors.
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Affiliation(s)
- James Huff
- National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
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Benigni R, Bossa C, Giuliani A, Tcheremenskaia O. Exploring in vitro/in vivo correlation: lessons learned from analyzing phase I results of the US EPA's ToxCast Project. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS 2010; 28:272-286. [PMID: 21069615 DOI: 10.1080/10590501.2010.525781] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
The research on alternative toxicological methods provides, among other things, a privileged viewpoint on one of the central issues of modern biomedical research--the relationship between (a) biological phenomena observed at the level of tissues and organisms and (b) their cellular and molecular bases as studied in isolated systems in vitro. The newly released ToxCast Phase 1 results, subject to initial analysis, converge with evidence from other fields (e.g., research on drug design with intensive use of omics technologies, traditional research on alternative tests) in indicating a low degree of the in vitro/in vivo correlation overall. In addition, this and other approaches point to the need for combining biological and chemical information in exploring the in vitro to in vivo connection.
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Affiliation(s)
- Romualdo Benigni
- Environmental and Healt Department, Istituto Superiore di Sanita', Rome, Italy.
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Helguera AM, Pérez-Machado G, Cordeiro MNDS, Combes RD. Quantitative structure-activity relationship modelling of the carcinogenic risk of nitroso compounds using regression analysis and the TOPS-MODE approach. SAR AND QSAR IN ENVIRONMENTAL RESEARCH 2010; 21:277-304. [PMID: 20544552 DOI: 10.1080/10629361003773930] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Worldwide, legislative and governmental efforts are focusing on establishing simple screening tools for identifying those chemicals most likely to cause adverse effects without experimentally testing all chemicals of regulatory concern. This is because even the most basic biological testing of compounds of concern, apart from requiring a huge number of test animals, would be neither resource nor time effective. Thus, alternative approaches such as the one proposed here, quantitative structure-activity relationship (QSAR) modelling, are increasingly being used for identifying the potential health hazards and subsequent regulation of new industrial chemicals. This paper follows up on our earlier work that demonstrated the use of the TOPological Substructural MOlecular DEsign (TOPS-MODE) approach to QSAR modelling for predictions of the carcinogenic potency of nitroso compounds. The data set comprises 56 nitroso compounds which have been bio-assayed in female rats and administered by the oral water route. The QSAR model was able to account for about 81% of the variance in the experimental activity and exhibited good cross-validation statistics. A reasonable interpretation of the TOPS-MODE descriptors was achieved by means of bond contributions, which in turn afforded the recognition of structural alerts (SAs) regarding carcinogenicity. A comparison of the SAs obtained from different data sets showed that experimental factors, such as the sex and the oral administration route, exert a major influence on the carcinogenicity of nitroso compounds. The present and previous QSAR models combined together provide a reliable tool for estimating the carcinogenic potency of yet untested nitroso compounds and they should allow the identification of SAs, which can be used as the basis of prediction systems for the rodent carcinogenicity of these compounds.
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Affiliation(s)
- A M Helguera
- Department of Chemistry, Central University of Las Villas, Santa Clara, Villa Clara, Cuba.
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Chemopreventive effects of 13alpha,14alpha-epoxy-3beta-methoxyserratan-21beta-ol (PJJ-34), a serratane-type triterpenoid, in a rat multi-organ carcinogenesis bioassay. Cancer Lett 2009; 289:161-9. [PMID: 19747769 DOI: 10.1016/j.canlet.2009.08.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2008] [Revised: 07/02/2009] [Accepted: 08/04/2009] [Indexed: 11/24/2022]
Abstract
A novel serratane-type triterpenoid, 13alpha,14alpha-epoxy-3beta-methoxyserratan-21beta-ol (PJJ-34) derived from cuticles of Picea jezoensis Carr. var. jezoensis, has proved to be highly effective at suppressing carcinogenesis both in vitro and in vivo. To investigate possible anti-carcinogenic efficacy at the whole-body level, male Fischer 344 rats were subjected to an established rat multi-organ carcinogenesis bioassay (DMBDD model). After initiation with five carcinogens, groups 1-3 (20 in each) were intragastrically (i.g.) administered PJJ-34 dissolved in 1 ml of 0.5% CMC (5 times/week) at doses of 0, 5 and 10mg/kg body weight (b.w.), respectively, until the end of week 30. PJJ-34 did not show apparent toxicity. Incidences of adenomas (100-->75%) and carcinomas (63-->30%) in the lung were significantly decreased in the 5mg/kg b.w. group, and multiplicity of alveolar hyperplasias and total lung tumors (adenomas+carcinomas) were significantly reduced by both 5 and 10mg/kg. The incidence of colorectal tumors was also significantly decreased in the 10mg/kg group (63-->28%) along with the multiplicity. Rat liver pre-neoplastic lesions, glutathione S-transferase placental form (GST-P) foci, and tumor development in the other organs were not affected. Immunohistochemical indices for proliferating cell nuclear antigen (PCNA) and cyclin D1 in normal alveolar epithelium of the lung were significantly suppressed at both doses. In conclusion, PJJ-34 is chemopreventive against lung and colon carcinogenesis without exerting apparent toxicity, and suppression of cell proliferation could play a key role in the underlying mechanisms.
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Vineis P, Xun W. The emerging epidemic of environmental cancers in developing countries. Ann Oncol 2009; 20:205-12. [DOI: 10.1093/annonc/mdn596] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Morales Helguera A, Pérez González M, Dias Soeiro Cordeiro MN, Cabrera Pérez MÁ. Quantitative Structure−Carcinogenicity Relationship for Detecting Structural Alerts in Nitroso Compounds: Species, Rat; Sex, Female; Route of Administration, Gavage. Chem Res Toxicol 2008; 21:633-42. [DOI: 10.1021/tx700336n] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Aliuska Morales Helguera
- Department of Chemistry and Molecular Simulation and Drug Design Group, Chemical Bioactive Center, Central University of Las Villas, Santa Clara, 54830, Villa Clara, Cuba, and REQUIMTE, Chemistry Department, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Maykel Pérez González
- Department of Chemistry and Molecular Simulation and Drug Design Group, Chemical Bioactive Center, Central University of Las Villas, Santa Clara, 54830, Villa Clara, Cuba, and REQUIMTE, Chemistry Department, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Maria Natália Dias Soeiro Cordeiro
- Department of Chemistry and Molecular Simulation and Drug Design Group, Chemical Bioactive Center, Central University of Las Villas, Santa Clara, 54830, Villa Clara, Cuba, and REQUIMTE, Chemistry Department, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Miguel Ángel Cabrera Pérez
- Department of Chemistry and Molecular Simulation and Drug Design Group, Chemical Bioactive Center, Central University of Las Villas, Santa Clara, 54830, Villa Clara, Cuba, and REQUIMTE, Chemistry Department, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
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Vineis P, Melnick R. A Darwinian perspective: right premises, questionable conclusion. A commentary on Niall Shanks and Rebecca Pyles' "evolution and medicine: the long reach of "Dr. Darwin"". Philos Ethics Humanit Med 2008; 3:6. [PMID: 18269763 PMCID: PMC2265736 DOI: 10.1186/1747-5341-3-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2007] [Accepted: 02/12/2008] [Indexed: 05/25/2023] Open
Abstract
As Dobzhansky wrote, nothing in biology makes sense outside the context of the evolutionary theory, and this truth has not been sufficiently explored yet by medicine. We comment on Shanks and Pyles' recently published paper, Evolution and medicine: the long reach of "Dr. Darwin", and discuss some recent advancements in the application of evolutionary theory to carcinogenesis. However, we disagree with Shanks and Pyles about the usefulness of animal experiments in predicting human hazards. Based on the darwinian observation of inter-species and inter-individual variation in all biological functions, Shanks and Pyles suggest that animal experiments cannot be used to identify hazards to human health. We claim that while the activity of enzymes may vary among individuals and among species, this does not indicate that critical events in disease processes occurring after exposure to hazardous agents differ qualitatively between animal models and humans. In addition, the goal is to avoid human disease whenever possible and with the means that are available at a given point in time. Epidemics of cancer could have been prevented if experimental data had been used to reduce human exposures or ban carcinogenic chemicals. We discuss examples.
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Affiliation(s)
- Paolo Vineis
- Department of Epidemiology and Community Health, Imperial College London, St Mary's Campus, Norfolk Place, W2 1PG, London, UK
| | - Ronald Melnick
- Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
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Huff J, Melnick R. In Memoriam: Lorenzo Tomatis 1929-2007. ENVIRONMENTAL HEALTH PERSPECTIVES 2008; 116:A16-A17. [PMID: 18197277 PMCID: PMC2199285 DOI: 10.1289/ehp.116-a16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
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Fernander AF, Shavers VL, Hammons GJ. A biopsychosocial approach to examining tobacco-related health disparities among racially classified social groups. Addiction 2007; 102 Suppl 2:43-57. [PMID: 17850613 DOI: 10.1111/j.1360-0443.2007.01954.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
AIMS To articulate a broader, multi-causal model that incorporates psychosocial and environmental factors that can differ systematically across racially classified social groups (RCSGs) and impact biological pathways related to the development of tobacco-related diseases. METHODS This paper is built upon a review of the existing scientific literature on selected biopsychosocial factors (diet/nutrition, obesity, alcoholic intake, psychosocial stress, occupational/environmental exposures and exposure to other diseases and illnesses) and tobacco use in examining the biological contributions to differences in tobacco-related health outcomes among RCSGs. FINDINGS Recent work has focused on RCSG genetic variations as a possible explanation for differences in tobacco-related health disparities. It is argued in this paper that, given the genetic heterogeneity 'within' RCSGs, it is unlikely that across RCSG genetic variations are likely to be the major source of differences impacting biological pathways in tobacco-related health outcomes. The evidence shows that results, even at the level of within-population genetic variations, have been limited and often inconsistent. A conceptual framework is proposed to account for biological pathways related to the development of tobacco-related diseases. CONCLUSIONS Determinants of tobacco-related health disparities are not understood clearly. The contribution of biological factors may be important. Current efforts to determine biological differences in tobacco use and related diseases among RCSGs have focused primarily on genetic variations. However, this approach has limitations. An alternative biopsychosocial framework that examines the potential biological mechanisms through which life experiences and behavior might affect tobacco use and health outcomes in these population groups is needed, including those of life-style (e.g. diet/nutrition, obesity, physical exercise, alcohol consumption), psychosocial (e.g. stress and coping), occupational/environmental exposures and the presence of other diseases/illnesses.
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Affiliation(s)
- Anita F Fernander
- Behavioral Science Department, College of Medicine, University of Kentucky, Lexington, KY, USA
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Benigni R. Social sexual inequality and sex difference in cancer incidence. ENVIRONMENTAL RESEARCH 2007; 104:128-34. [PMID: 17084838 DOI: 10.1016/j.envres.2006.09.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2005] [Revised: 08/28/2006] [Accepted: 09/27/2006] [Indexed: 05/12/2023]
Abstract
Socioeconomic factors play many roles in influencing health including overall health status, lifestyle and occupational exposures, and access to preventive, diagnostic and treatment services. This paper reviews evidence on the geographical distribution of the sex differences in cancer incidence and life expectancy. The analyses reported are at the regional (Italy), continental (Europe), and world-wide scales. In agreement with other contributions on the social epidemiology of cancer, these results indicate that there is a close link between the health of the populations, and socioeconomic and cultural factors, and support the notion that environment contributes strongly to total cancer incidence. Thus, the emphasis for reducing cancer incidence needs to focus more on reducing environmental contributions. In order to improve the health status of the populations, not only applications of the present etiologic knowledge are necessary (for example, it is estimated that around up to 50% of cancers are nowadays technically preventable), but also further research on environmental topics should be stimulated. Within this perspective the indicators of health differences between genders-which are demonstrated to be very sensitive to socioeconomic and cultural factors--can play a very useful role for monitoring environmental factors, and for health planning by agencies and governments.
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Affiliation(s)
- Romualdo Benigni
- Environment and Health Department, Istituto Superiore di Sanita, Viale Regina Elena 299-00161 Rome, Italy.
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Huff J. Benzene-induced cancers: abridged history and occupational health impact. INTERNATIONAL JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH 2007; 13:213-21. [PMID: 17718179 PMCID: PMC3363002 DOI: 10.1179/oeh.2007.13.2.213] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Benzene-induced cancer in humans was first reported in the late 1920s. Carcinogenesis findings in animals were not reported conclusively until 1979. Industry exploited this "discrepancy" to discredit the use of animal bioassays as surrogates for human exposure experience. The cardinal reason for the delay between first recognizing leukemia in humans and sought-after neoplasia in animals centers on poor design and conduct of experimental studies. The first evidence of carcinogenicity in animals manifested as malignant tumors of the zymbal glands (sebaceous glands in the ear canal) of rats, and industry attempted to discount this as being irrelevant to humans, as this organ is vestigial and not present per se in humans. Nonetheless, shortly thereafter benzene was shown to be carcinogenic to multiple organ sites in both sexes of multiple strains and multiple species of laboratory animals exposed via various routes. This paper presents a condensed history of the benzene bioassay story with mention of benzene-associated human cancers.
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Affiliation(s)
- James Huff
- National Institute of Environmental Health Sciences, Research Triangle Park, NC 27514, USA.
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Huff J, Lunn RM, Waalkes MP, Tomatis L, Infante PF. Cadmium-induced cancers in animals and in humans. INTERNATIONAL JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH 2007; 13:202-12. [PMID: 17718178 PMCID: PMC3399253 DOI: 10.1179/oeh.2007.13.2.202] [Citation(s) in RCA: 237] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Discovered in the early 1800s, the use of cadmium and various cadmium salts started to become industrially important near the close of the 19th century, rapidly thereafter began to flourish, yet has diminished more recently. Most cadmium used in the United States is a byproduct from the smelting of zinc, lead, or copper ores, and is used to manufacture batteries. Carcinogenic activity of cadmium was discovered first in animals and only subsequently in humans. Cadmium and cadmium compounds have been classified as known human carcinogens by the International Agency for Research on Cancer and the National Toxicology Program based on epidemiologic studies showing a causal association with lung cancer, and possibly prostate cancer, and studies in experimental animals, demonstrating that cadmium causes tumors at multiple tissue sites, by various routes of exposure, and in several species and strains. Epidemiologic studies published since these evaluations suggest that cadmium is also associated with cancers of the breast, kidney, pancreas, and urinary bladder. The basic metal cationic portion of cadmium is responsible for both toxic and carcinogenic activity, and the mechanism of carcinogenicity appears to be multifactorial. Available information about the carcinogenicity of cadmium and cadmium compounds is reviewed, evaluated, and discussed.
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Affiliation(s)
- James Huff
- National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27514, USA.
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Abstract
During the annual Ramazzini Days, the Mayor of Carpi confers the Ramazzini Award on scientists deemed by the Collegium Ramazzini to have made outstanding contributions to furthering the aims of Bernardino Ramazzini in safeguarding public health. Dr. Lorenzo Tomatis was the Ramazzini Award recipient in 2005, and the presentation of the award was a highlight of the Symposium. The Ramazzini Lecture given by Dr. Tomatis follows.
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Affiliation(s)
- Lorenzo Tomatis
- International Society of Doctors for the Environment, Arezzo, Italy.
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Kang JS, Wanibuchi H, Morimura K, Totsuka Y, Yoshimura I, Fukushima S. Existence of a no effect level for MeIQx hepatocarcinogenicity on a background of thioacetamide-induced liver damage in rats. Cancer Sci 2006; 97:453-8. [PMID: 16734722 PMCID: PMC11159755 DOI: 10.1111/j.1349-7006.2006.00201.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
As exposure to heterocyclic amines might increase the risk of liver cancer, we investigated the carcinogenic potential of MeIQx under conditions of liver damage caused by TAA. Male, 6-week-old F344 rats (n = 280) were divided into 14 groups; groups 1-7 received TAA (0.03% in drinking water) and groups 8-14 received water for the first 12 weeks. Thereafter, the animals received MeIQx at doses from 0, 0.001, 0.01, 0.1, 1, 10 to 100 p.p.m. (groups 1-7 and 8-14, respectively) in pellet basal diet for 16 weeks. All survivors were killed at week 28 for assessment of numbers and areas of GST-P positive foci, considered to be pre-neoplastic lesions of the liver. Values were increased significantly in all the groups receiving TAA-->MeIQx compared to MeIQx alone (P < 0.01). Numbers of GST-P positive foci were significantly increased in groups 7 and 14 (treated with 100 p.p.m. MeIQx) as compared to 0 p.p.m.-MeIQx (groups 1 and 8) (P < 0.01), along with areas in group 14 compared to group 8 (P < 0.01). However, with the maximum likelihood method, the data for numbers of GST-P positive foci (groups 1-7 and groups 8-14) fitted the hockey stick regression model, representing no differences from groups 1-5 and from groups 8-13, despite a linear dose-dependent increase of MeIQx-DNA adducts from 0.1 to 100 p.p.m. We conclude that there is a no effect level for MeIQx hepatocarcinogenicity, even on a background of TAA-induced liver damage.
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Affiliation(s)
- Jin Seok Kang
- Department of Pathology, Osaka City University Medical School,1-4-3 Asahi-machi, Osaka, 545-8585, Japan
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Wei M, Hori TA, Ichihara T, Wanibuchi H, Morimura K, Kang JS, Puatanachokchai R, Fukushima S. Existence of no-observed effect levels for 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline on hepatic preneoplastic lesion development in BN rats. Cancer Lett 2006; 231:304-8. [PMID: 16399231 DOI: 10.1016/j.canlet.2005.02.029] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2004] [Accepted: 02/10/2005] [Indexed: 10/25/2022]
Abstract
There is increasing evidence that dose-response curve of genotoxic carcinogen is nonlinear and a practical threshold dose exists. However, little is known about differences in the dose-response relationship of genotoxic carcinogen among different strain rats. Herein, we showed that low doses of genotoxic carcinogen 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx) had no effects on induction of liver glutathione S-transferase placental form (GST-P)-positive foci in both BN and F344 rats, and therefore demonstrated the existence of no-observed effect level for hepatocarcinogenicity of this genotoxic carcinogen irrespective of strains. These findings further support our notion that a practical threshold dose for MeIQx hepatocarcinogenicity exists in rats.
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Affiliation(s)
- Min Wei
- Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
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Abstract
Following the Supreme Court's Daubert v Merrell Dow Pharmaceuticals, Inc decision, courts have struggled in reviewing scientific evidence and appear to have appreciated insufficiently the nature of scientific reasoning. To assist their evidentiary reviews, courts need to appreciate both scientific complexity and ignorance about human toxicity caused by the universe of chemical substances. Conscientious, well-motivated, respectable experts can come to different conclusions about scientific evidence without making obvious mistakes and without being charlatans. So that justice is done between parties, courts need to allow for reasonable scientific disagreement to avoid excluding from trials respectable experts and all relevant scientific evidence. The public health community can assist courts to understand ranges of scientific evidence and to recognize the reasonableness of scientific disagreements.
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Affiliation(s)
- Carl Cranor
- Department of Philosophy, University of California, 900 University Ave., Riverside, CA 92521, USA.
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Doi K, Wanibuchi H, Salim EI, Morimura K, Kinoshita A, Kudoh S, Hirata K, Yoshikawa J, Fukushima S. Lack of large intestinal carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine at low doses in rats initiated with azoxymethane. Int J Cancer 2005; 115:870-8. [PMID: 15751028 DOI: 10.1002/ijc.20960] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), an abundant food-derived heterocyclic amine (HCA), has attracted particular attention as a human colon carcinogen. Humans are in fact exposed to continuous low doses of HCAs during lifetime. Therefore, we focused on rat large intestinal carcinogenicity of PhIP at levels that mimic practical human exposure. A total of 192 6-week-old male F344 rats were subcutaneously injected twice with 15 mg/kg body weight azoxymethane (AOM), then continuously fed various doses (0, 0.001, 0.01, 0.1, 1, 10, 50 and 200 ppm) of PhIP in the diet. At week 16, aberrant crypt foci (ACF) were quantitatively analyzed. At week 36, tumor occurrence was pathologically analyzed. Then immunohistochemical examinations were performed. PhIP was found to enhance strongly AOM-initiated rat large intestinal tumorigenesis at high doses (50 and 200 ppm), while lower doses (0.001-10 ppm) had no apparent effects. High doses also caused variation in tumor histologic types and their distribution throughout the large intestinal segments. Frequencies of ACF/cm(2) did not meaningfully vary between the groups. Cellular proliferation activity in normal-appearing colonic mucosa was significantly increased at high doses. These novel findings may provide evidence of a low-dose potential for PhIP, with a no-observed effect level speculated to be 10 ppm in the present initiation-promotion experimental model.
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Affiliation(s)
- Kenichiro Doi
- Department of Pathology, Osaka City University Medical School, Osaka, Japan
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Melnick RL. ADaubertMotion: A Legal Strategy to Exclude Essential Scientific Evidence in Toxic Tort Litigation. Am J Public Health 2005; 95 Suppl 1:S30-4. [PMID: 16030335 DOI: 10.2105/ajph.2004.046250] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
In the US Supreme Court's Daubert v Merrell Dow Pharmaceuticals, Inc decision, federal judges were directed to examine the scientific method underlying expert evidence and admit that which is scientifically reliable and relevant. However, if a judge does not have adequate training or experience in dealing with scientific uncertainty, understand the full value or limit of currently used methodologies, or recognize hidden assumptions, misrepresentations of scientific data, or the strengths of scientific inferences, he or she may reach an incorrect decision on the reliability and relevance of evidence linking environmental factors to human disease. This could lead to the unfair exclusion of valid scientific evidence, particularly that which is essential to a plaintiff's case in toxic tort litigation.
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Affiliation(s)
- Ronald L Melnick
- Environmental Toxicology Program, National Institute for Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA.
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Benigni R. Structure-activity relationship studies of chemical mutagens and carcinogens: mechanistic investigations and prediction approaches. Chem Rev 2005; 105:1767-800. [PMID: 15884789 DOI: 10.1021/cr030049y] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Romualdo Benigni
- Istituto Superiore di Sanita', Experimental and Computational Carcinogenesis, Department of Environment and Primary Prevention, Viale Regina Elena 299-00161 Rome, Italy.
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48
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Fukushima S, Wanibuchi H, Morimura K, Nakae D, Tsuda H, Imaida K, Shirai T, Tatematsu M, Tsukamoto T, Hirose M, Furukawa F. Lack of potential of low dose N-nitrosodimethylamine to induce preneoplastic lesions, glutathione S-transferase placental form-positive foci, in rat liver. Cancer Lett 2005; 222:11-5. [PMID: 15837536 DOI: 10.1016/j.canlet.2004.08.035] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2004] [Revised: 08/19/2004] [Accepted: 08/31/2004] [Indexed: 11/17/2022]
Abstract
Induction of liver lesions in male F344 rats by the genotoxic and carcinogenic N-nitrosodimethylamine (NDMA) was studied at a wide range of dose levels, i.e. from 0.001 to 10 ppm, in drinking water for 16 weeks. Dose related and statistically significant increase of glutathione S-transferase placental form-positive foci, endpoint markers for hepatocarcinogenesis in rats, at 1 and 10 ppm dose groups was obtained, but no increment in foci could be detected with the lower doses (0.001, 0.01, and 0.1 ppm). This finding of a no-observed effect level supports our hypothesis that a threshold, at least in practical terms, exists in carcinogenesis proposed on the basis of extensive wide range dose-dependence studies of other genotoxic carcinogens.
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Affiliation(s)
- Shoji Fukushima
- Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
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Maronpot RR, Flake G, Huff J. Relevance of animal carcinogenesis findings to human cancer predictions and prevention. Toxicol Pathol 2004; 32 Suppl 1:40-8. [PMID: 15209402 DOI: 10.1080/01926230490425003] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Use of laboratory animals to identify carcinogenic potential of chemicals, mixtures, and other agents has a modern history of greater than 40 years from which much useful scientific and public health information can be derived. While laboratory animals differ from humans in some respects that may affect responses to hazardous exposures, use of such models is based on experimental evidence indicating that there are more genetic, genomic, physiological, biochemical, and metabolic similarities than differences among mammalian species. Issues of concordance of responses between rodent species and between rodents and humans as well as repeatability and site-specificity are important considerations in evaluating laboratory animal carcinogenicity results. Variables in experimental design such as animal strain, diet, route of exposure, and study, duration as well as single-site versus multisite carcinogenic responses all influence interpretation and intelligent use of study data. Similarities and differences in site-specific laboratory animal and corresponding human cancers should also be considered in study evaluation. Recent attempts to explore genetically engineered mice and to humanize the mouse for more relevant identification of carcinogen hazard identification have yielded mixed results. In the end we are confronted by the realization that virtually all animal cancer models are useful but imperfect surrogates for humans. Assuming the percentage of chemicals currently in commerce that are estimated to be potent animal or human carcinogens is quite low, the task of identifying agents with significant carcinogenic potential is daunting and important. The biological conundrum of scientific debate regarding the relevance of carcinogenicity studies in laboratory animals is likely to continue. Nonetheless public health considerations must take precedence when deciding human safety issues.
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Affiliation(s)
- R R Maronpot
- National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
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Fukushima S, Wanibuchi H, Morimura K, Wei M, Nakae D, Konishi Y, Tsuda H, Takasuka N, Imaida K, Shirai T, Tatematsu M, Tsukamoto T, Hirose M, Furukawa F. Lack of initiation activity in rat liver of low doses of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. Cancer Lett 2003; 191:35-40. [PMID: 12609707 DOI: 10.1016/s0304-3835(02)00631-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
It has been generally accepted that genotoxic carcinogens have no threshold in exerting their potential for cancer induction. However, the non-threshold theory can be challenged for cancer risk assessment in humans. Here we examined low dose carcinogenicity of a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), using an in vivo medium-term bioassay to detect initiating activity for rat hepatocarcinogenesis. With MeIQx initiation at various doses followed by administration of phenobarbital, a well known hepatopromoter, no induction of glutathione S-transferase placental form-positive foci, assessed as preneoplastic lesions, was noted at doses of 0.001-1 ppm. The results imply a no-observed effect level for hepatocarcinogenicity with this genotoxic agent.
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Affiliation(s)
- Shoji Fukushima
- Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
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