Journal of Korean Society of Occupational and Environmental Hygiene (한국산업보건학회지)

Korean Industrial Hygiene Association (한국산업보건학회)
권호 표지
DOI QR코드

DOI QR Code

Adverse Outcome Pathways for Prediction of Chemical Toxicity at Work: Their Applications and Prospects

작업장 화학물질 독성예측을 위한 독성발현경로의 응용과 전망

  • Rim, Kyung-Taek (Chemicals Research Bureau, Occupational Safety&Health Research Institute, Korea Occupational Safety&Health Agency) ;
  • Choi, Heung-Koo (Chemicals Research Bureau, Occupational Safety&Health Research Institute, Korea Occupational Safety&Health Agency) ;
  • Lee, In-Seop (Chemicals Research Bureau, Occupational Safety&Health Research Institute, Korea Occupational Safety&Health Agency)
  • 임경택 (안전보건공단 산업안전보건연구원 산업화학연구실 흡입독성연구센터) ;
  • 최흥구 (안전보건공단 산업안전보건연구원 산업화학연구실 흡입독성연구센터) ;
  • 이인섭 (안전보건공단 산업안전보건연구원 산업화학연구실 흡입독성연구센터)
  • Received : 2019.03.21
  • Accepted : 2019.06.21
  • Published : 2019.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Objectives: An adverse outcome pathway is a biological pathway that disturbs homeostasis and causes toxicity. It is a conceptual framework for organizing existing biological knowledge and consists of the molecular initiating event, key event, and adverse output. The AOP concept provides intuitive risk identification that can be helpful in evaluating the carcinogenicity of chemicals and in the prevention of cancer through the assessment of chemical carcinogenicity predictions. Methods: We reviewed various papers and books related to the application of AOPs for the prevention of occupational cancer. We mainly used the internet to search for the necessary research data and information, such as via Google scholar(http://scholar.google.com), ScienceDirect(www.sciencedirect.com), Scopus(www.scopus. com), NDSL(http: //www.ndsl.kr/index.do) and PubMed(http://www.ncbi.nlm.nih.gov/pubmed). The key terms searched were "adverse outcome pathway," "toxicology," "risk assessment," "human exposure," "worker," "nanoparticle," "applications," and "occupational safety and health," among others. Results: Since it focused on the current state of AOP for the prediction of toxicity from chemical exposure at work and prospects for industrial health in the context of the AOP concept, respiratory and nanomaterial hazard assessments. AOP provides an intuitive understanding of the toxicity of chemicals as a conceptual means, and it works toward accurately predicting chemical toxicity. The AOP technique has emerged as a future-oriented alternative to the existing paradigm of chemical hazard and risk assessment. AOP can be applied to the assessment of chemical carcinogenicity along with efforts to understand the effects of chronic toxic chemicals in workplaces. Based on these predictive tools, it could be possible to bring about a breakthrough in the prevention of occupational and environmental cancer. Conclusions: The AOP tool has emerged as a future-oriented alternative to the existing paradigm of chemical hazard and risk assessment and has been widely used in the field of chemical risk assessment and the evaluation of carcinogenicity at work. It will be a useful tool for prediction, and it is possible that it can help bring about a breakthrough in the prevention of occupational and environmental cancer.

Keywords

SOOSB1_2019_v29n2_141_f0001.png 이미지

Figure 1. Adverse outcome pathway and Selected key events and adverse outcomes

SOOSB1_2019_v29n2_141_f0002.png 이미지

Figure 2. Possible genetic and epigenetic pathways linking occupational/environmental exposures and adverse effects

Table 1. Definitions used in mechanistic frameworks for predicting and assessing toxicity

SOOSB1_2019_v29n2_141_t0001.png 이미지

Table 2. Guide to assessing genetic and epigenetic data for risk assessment

SOOSB1_2019_v29n2_141_t0002.png 이미지

Table 3. External links about AOP sources

SOOSB1_2019_v29n2_141_t0003.png 이미지

References

  1. Allen TEH, Goodman JM, Gutsell S, Russell PJ. Defining molecular initiating events in the adverse outcome pathway framework for risk assessment. Chem Res Toxicol 2014;27(12):2100-2112(DOI: 10.1021/tx500345j)
  2. American Cancer Society(ACS). Known and probable human carcinogens. [serial online] 2018 [Accessed 2019 March 20]. Available from: URL:https://www.cancer.org/cancer/cancer-causes/general-info/known-and-probable-human-carcinogens.html
  3. Andersen ME, Al-Zoughool M, Croteau M, Westphal M, Krewski D. The future of toxicity testing. J Toxicol Environ Health B 2010;13:163-196(doi: 10.1080/10937404.2010.483933.)
  4. Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, et al. Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 2010;29:730-741(doi: 10.1002/etc.34.)
  5. Anna Bal-Pricea, Pamela J. Lein, Kimberly P. Keil, Sunjay Sethi, Timothy Shafer, et al. Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity. Neuro Toxicology 2017;59:240-255(doi: 10.1016/j.neuro.2016.05.010.)
  6. Balls M. Why modification of the LD50 test will not be enough. Lab Anim 1991;25:198-206 https://doi.org/10.1258/002367791780808310
  7. Bell J, Healey N. The causes of major hazard incidents and how to improve risk control and health and safety management: a review of the existing literature. Buxton, Health and Safety Laboratory, 2006
  8. Benowitz NL. Emerging nicotine delivery products. Implications for public health. Ann Am Thorac Soc 2014;11:231-235(doi: 10.1513/AnnalsATS.201312-433PS)
  9. BeruBe K. Medical waste tissues-breathing life back into respiratory research. Altern. Lab Anim 2013;41(6):429-434 https://doi.org/10.1177/026119291304100604
  10. Bessems JG, Loizou G, Krishnan K, Clewell HJ, Bernasconi C, et al. PBTK modelling platforms and parameter estimation tools to enable animal-free risk assessment: recommendations from a joint EPAA-EURL ECVAM ADME workshop. Regul Toxicol Pharmacol 2014;68:119-139(doi: 10.1016/j.yrtph.2013.11.008.)
  11. Boekelheide K, Andersen ME. A mechanistic redefinition of adverse effects-a key step in the toxicity testing paradigm shift. ALTEX 2010;27:243-252 https://doi.org/10.14573/altex.2010.4.243
  12. Bollati V, Baccarelli, A. Environmental epigenetics. Heredity (Edinib) 2010;105(1):105-112(doi: 10.1038/hdy.2010.2.)
  13. Cahn Z, Siegel M. Electronic cigarettes as a harm reduction strategy for tobacco control: A step forward or a repeat of past mistakes? J Public Health Policy 2011;32:16-31(doi: 10.1057/jphp.2010.41.)
  14. Carpenter DO, Arcaro K, Spink DC. Understanding the human health effects of chemical mixtures. Environ Health Perspect 2002;110(Suppl 1):25-42 https://doi.org/10.1289/ehp.02110s125
  15. Celli B, Halbert RJ, Isonaka S, Schau B. Population impact of different definitions of airway obstruction. Eur Respir J 2003;22:268-273 https://doi.org/10.1183/09031936.03.00075102
  16. Chapman K, Creton S, Kupferschmidt H, Bond GR, Wilks MF, et al., The value of acute toxicity studies to support the clinical management of overdose and poisoning: a cross-discipline consensus. Regul Toxicol Pharmacol 2010;58(3):354-359 https://doi.org/10.1016/j.yrtph.2010.07.003
  17. ChemSafetyPro. Chemical risk assessment: overview and examples. [serial online] 2018 [Accessed 2019 March 20]. Available from: URL:https://www.chemsafetypro.com/Topics/CRA/introduction_to_chemical_risk_assessment_overview_principles.html
  18. Clewell H. Use of mode of action in risk assessment: past, present, and future. Regul Toxicol Pharmacol 2005;42:3-14 https://doi.org/10.1016/j.yrtph.2005.01.008
  19. Clewell HJ, Gentry PR, Gearhart JM, Allen BC, Andersen ME. Considering pharmacokinetic and mechanistic information in cancer risk assessments for environmental contaminants: examples with vinyl chloride and trichloroethylene. Chemosphere 1995;31(1):2561-2578 https://doi.org/10.1016/0045-6535(95)00124-Q
  20. Clippinger AJ, Allen D, Jarabek AM, Corvaro M, Gaca M, et al., Alternative approaches for acute inhalation toxicity testing to address global regulatory and non-regulatory data requirements: an international workshop report. Toxicol in vitro 2018a;48:53-70 (doi: 10.1016/j.tiv.2017.12.011.)
  21. Clippinger AJ, Allen D, Behrsing H, BeruBe KA, Bolger MB, et al. Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity. Toxicol in Vitro 2018b;52:131-145(doi: 10.1016/j.tiv.2018.06.009.)
  22. Cohen SM, Arnold LL. Chemical carcinogenesis. Toxicol Sci 2011;120(Suppl 1):S76-92. https://doi.org/10.1093/toxsci/kfq365
  23. Collins FS, Gray GM, Bucher JR. Toxicology. Transforming environmental health protection. Science 2008;319:906-907 https://doi.org/10.1126/science.1154619
  24. Duffus JH, Nordberg M, Templeton DM. Glossary of terms used in toxicology. 2nd edition. Research Triangle Park, Pure and Applied Chemistry 2007; p. 1153
  25. Edwards SW, Tan YM, Villeneuve DL, Meek ME, Mc Queen CA. Adverse outcome pathways-organizing toxicological information to improve decision making. J Pharmacol Exp Ther 2016;356:170-181 https://doi.org/10.1124/jpet.115.228239
  26. European chemicals agency(ECHA). Weight of evidence. [serial online] 2018 [Accessed 2019 March 20]. Available from: URL:https://echa.europa.eu/support/registration/how-to-avoid-unnecessary-testingon-animals/weight-of-evidence
  27. Gallo V, Egger M, McCormack V, Farmer PB, Ioannidis JP, et al. Strengthening the reporting of observational studies in epidemiology-Molecular Epidemiology STROBE-ME: an extension of the STROBE statement. J Clin Epidemiol 2011;64(12):1350-1363 https://doi.org/10.1016/j.jclinepi.2011.07.010
  28. Gerloff K, Landesmann B, Worth A, Munn S, Palosaari T, et al. The Adverse Outcome Pathway approach in nanotoxicology. Comput Toxicol 2017;1:3-11 https://doi.org/10.1016/j.comtox.2016.07.001
  29. Gollapudi BB, Johnson GE, Hernandez LG, Pottenger LH, Dearfield KL, et al. Quantitative approaches for assessing dose-response relationships in genetic toxicology studies. Environ Mol Mutagen 2013;54:8-18 https://doi.org/10.1002/em.21727
  30. Groh KJ, Carvalho RN, Chipman JK, Denslow ND, Halder M, et al. Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology. Chemosphere 2015;120:764-777 https://doi.org/10.1016/j.chemosphere.2014.09.068
  31. Hartung T, McBride M. Food for Thought ... on mapping the human toxome. ALTEX 2011;28:83-93 https://doi.org/10.14573/altex.2011.2.083
  32. Hernandez AF, Tsatsakis AM. Human exposure to chemical mixtures: challenges for the integration of toxicology with epidemiology data in risk assessment. Food Chem Toxicol 2017;103:188-193(doi: 10.1016/j.fct.2017.03.012.)
  33. Hill AB. The Environment and disease: Association or caution? Proc R Soc Med 1965;58:295-300
  34. IARC. Agents classified by the IARC monographs, volumes 1-122 [serial online] 2018 [Accessed 2019 March 20]. Available from: URL:https://monographs.iarc.fr/agents-classified-by-the-iarc/
  35. IOMC. Manual for the public health management of chemical incidents. Geneva, WHO, 2009
  36. Jarabek AM. The application of dosimetry models to identify key processes and parameters for default dose-response assessment approaches. Toxicology Letters 1995;79(1-3):171-184 https://doi.org/10.1016/0378-4274(95)03368-U
  37. Jefferson M, Chung PWH, Kletz TA. Learning the lessons from past accidents. London, IChemE Services:1997. p. 217-226
  38. Jennings P. Stress response pathways, toxicity pathways and adverse outcome pathways. Arch Toxicol 2013;87(1):13-14 https://doi.org/10.1007/s00204-012-0974-4
  39. Kang DS, Yang JH, Kim HS, Koo BK, Lee CM, et al. Application of the Adverse Outcome Pathway Framework to Risk Assessment for Predicting Carcinogenicity of Chemicals. J Cancer Prev 2018; 23(3):126-133 https://doi.org/10.15430/JCP.2018.23.3.126
  40. Kimber I, Pooleb A, Basketter DA. Skin and respiratory chemical allergy: confluence and divergence in a hybrid adverse outcome pathway. Toxicol Res 2018;7:586-605 https://doi.org/10.1039/C7TX00272F
  41. Kimber I, Dearmana RJ, Basketter DA, Boverhof DR. Chemical respiratory allergy: Reverse engineering an adverse outcome pathway. Toxicology 2014;318:32-39 https://doi.org/10.1016/j.tox.2014.02.001
  42. Korean Statistical Information Service Age specific pneumonia mortality in South Korea during 1995-2015. [serial online] 2016 [Accessed 2019 March 20]. Available from: URL:http://kosis.kr/statisticsList/statisticsList_01List.jsp?vwcd=MT_ZTITLE&parmTabId=M_01_01
  43. Krewski D, Acosta D, Andersen M, Anderson H, Bailar JC, et al. Toxicity testing in the 21st century: a vision and a strategy. J Toxicol Environ Health B Crit Rev 2010;13:51-138 https://doi.org/10.1080/10937404.2010.483176
  44. Krewski D, Westphal M, Al-Zoughool M, Croteau MC & Andersen ME. New directions in toxicity testing. Annual Review of Public Health 2011;32:161-78 (doi: 10.1146/annurev-publhealth-031210-101153.)
  45. Langley G, Austin CP, Balapure AK, Birnbaum LS, Bucher JR. et al. The Humane Society Institute for Science and Policy - Animal Studies Repository 2015 Lessons from Toxicology: Developing a 21st-Century Paradigm for Medical Research
  46. Leem JH, Chung KH. Combined approaches using adverse outcome pathways and big data to find potential diseases associated with humidifier disinfectant. Environ Health Toxicol 2017;32:e2017003 https://doi.org/10.5620/eht.e2017003
  47. Leist M, Ghallab A, Graepel R, Marchan R, Hassan R, et al. Adverse outcome pathways: Opportunities, limitations and open questions. Arch Toxicol 2017;91(3):477-505
  48. MacKay C., Davies M, Summerfield V, Maxwell G. From Pathways to People: Applying the Adverse Outcome Pathway(AOP) for skin sensitization to risk assessment. Altex-Alter Animal Exper 2013;30(4):473-486
  49. McNeill A. Should clinicians recommend e-cigarettes to their patients who smoke? Yes. Ann Fam Med 2016;14:300-301(doi: 10.1370/afm.1962.)
  50. Meek ME, Boobis A, Cote I, Dellarco V, Fotakis G, et al. New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis. J Appl Toxicol 2014;34(1):1-18 https://doi.org/10.1002/jat.2949
  51. Meernik C, Goldstein AO. Should clinicians recommend e-cigarettes to their patients who smoke? No. Ann Fam Med 2016;14:302-303 https://doi.org/10.1370/afm.1961
  52. Murti CK. Biological effects of chemical disasters: human victims. In: Bourdeau P, Green G, editors. eds. Methods for assessing and reducing injury from chemical accidents. Chichester, Wiley, 1989
  53. Myatt GJ, Ahlberg E, Akahori Y, Allen D, Amberg A, et al. In silico toxicology protocols. Regul Toxicol Pharmacol 2018;96:1-17(doi: 10.1016/j.yrtph.2018.04.014.)
  54. National Research Council (US). Committee on Occupational Health and Safety in the Care and Use of Nonhuman Primates. Occupational health and safety in the care and use of nonhuman primates. Washington, DC, National Academies Press, 2003
  55. National Research Council. Toxicity testing in the 21st century: A vision and a strategy. 2007, National Academic Press: Washington, DC. 2007
  56. Nymark P, Kohonen P, Hongisto V, Grafstrom RC. Toxic and genomic influences of inhaled nanomaterials as a basis for predicting adverse outcome. Ann Am Thorac Soc 2018;15(2):S91-S97(doi: 10.1513/AnnalsATS.201706-478MG.)
  57. OECD. Guidance document on developing and assessing adverse outcome pathways. OECD Environment, Health and Safety Publications. Series on Testing and Assessment No. 184. ENV/JM/MONO (2013)6. [serial online] 2013 [Accessed 2019 March 20]. Available from: URL:http://www.oecd.org/chemicalsafety/
  58. OECD. Test No. 433: Acute inhalation toxicity-fixed concentration procedure. OECD Guidelines for the testing of chemicals, Section 4. 2017
  59. OECD. Adverse Outcome pathway knowledge base (AOP-KB). Series on Testing and Assessment No. 184. ENV/JM/MONO(2013)6. [serial online] 2018a [Accessed 2019 March 20]. Available from: URL: https://aopkb.oecd.org/background.html
  60. OECD. Adverse outcome pathways, molecular screening and toxicogenomics. [serial online] 2018b [Accessed 2019 March 20]. Available from: URL:http://www.oecd.org/chemicalsafety/testing/adverse-outcome-pathways-molecular-screening-and-toxic-ogenomics.htm
  61. OECD portal site(topics_adverse outcome pathways, molecular screening and toxicogenomics) [serial online] 2019 [Accessed 2019 March 20]. Available from:https://www.oecd.org/chemicalsafety/testing/adverse-outcome-pathways-molecular-screening-and-toxicogenomics.htm
  62. OECD. Proposal for a template, and guidance on developing and assessing the completeness of adverse outcome pathways. Paris, OECD Publishing, 2012
  63. OECD. Users' handbook supplement to the guidance document for developing and assessing adverse outcome pathways. Paris, OECD Publishing, 2016
  64. Oliveira PA, Colaco A, Chaves R, Guedes-pinto H, De-La-Cruz PLF, et al. Chemical carcinogenesis. An Acad Bras Cienc 2007;79:593-616 https://doi.org/10.1590/S0001-37652007000400004
  65. Pletz J, Sanchez-Bayo F, Tennekes HA. Dose-response analysis indicating time-dependent neurotoxicity caused by organic and inorganic mercuryimplications for toxic effects in the developing brain. Toxicology 2016;347-349:1-5(doi: 10.1016/j.tox.2016.02.006.)
  66. Scheffler S, Dieken H, Krischenowski O, Aufderheide M. Cytotoxic evaluation of e-liquid aerosol using different lung-derived cell models. Int J Environ Res Public Health 2015;12:12466-12474 https://doi.org/10.3390/ijerph121012466
  67. Scheffler S, Dieken H, Krischenowski O, Forster C, Branscheid D, et al. Evaluation of e-cigarette liquid vapor and mainstream cigarette smoke after direct exposure of primary human bronchial epithelial cells. Int J Environ Res Public Health 2015;12:3915-3925 https://doi.org/10.3390/ijerph120403915
  68. Schulte PA, Whittaker C, Curran CP. Considerations for Using Genetic and Epigenetic Information in Occupational Health Risk Assessment and Standard Setting. J Occup Environ Hyg. 2015;12 Suppl 1(sup1):S69-S81.(doi:10.1080/15459624.2015.1060323.)
  69. Schultz TW. Adverse outcome pathways: a way of linking chemical structure to in vivo toxicological hazards. In In Silico Toxicology: Principles and Applications (ed. M.T.D. Cronin & J.C. Madden), p. 346-371. Cambridge, UK: The Royal Society of Chemistry
  70. Hartung T & McBride M(2011). Food for Thought on mapping the human toxome. ALTEX 2010;28:83-93 https://doi.org/10.14573/altex.2011.2.083
  71. Seidle T, Robinson S, Holmes T, Creton S, Prieto P, et al. Cross-sector review of drivers and available 3Rs approaches for acute systemic toxicity testing. Toxicological Sciences, 2010;116(2):382-396 https://doi.org/10.1093/toxsci/kfq143
  72. Shivalingappa PC, Hole R, Westphal CV, Vij N. Airway exposure to e-cigarette vapors impairs autophagy and induces aggresome formation. Antioxid Redox Signal 2016;24:186-204 https://doi.org/10.1089/ars.2015.6367
  73. Silins I, Hogberg J. Combined toxic exposures and human health: biomarkers of exposure and effect. Int J Environ Res Public Health 2011;8:629-647 https://doi.org/10.3390/ijerph8030629
  74. Song JA, Park HJ, Yang MJ, Jung KJ, Yang HS, et al. Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy. Food Chem Toxicol 2014;69:267-275 https://doi.org/10.1016/j.fct.2014.04.027
  75. Sugimura T. Multistep carcinogenesis: a 1992 perspective. Science 1992;258:603-607 https://doi.org/10.1126/science.1411570
  76. Sugimura T. Nutrition and dietary carcinogens. Carcinogenesis 2000;21:387-395 https://doi.org/10.1093/carcin/21.3.387
  77. Sullivan KM, Enoch SJ, Ezendam J, Roggen KEL, Cochrane S. An adverse outcome pathway for sensitization of the respiratory tract by low-molecular-weight chemicals: Building evidence to support the utility of In Vitro and In Silico methods in a regulatory context. Applied In Vitro Toxicology 2017;3(3)
  78. Tang S, Cui H, Yao L, Hao X, Shen Y, et al. Increased cytokines response in patients with tuberculosis complicated with chronic obstructive pulmonary disease. PLoS One 2013;8(4):e62385 https://doi.org/10.1371/journal.pone.0062385
  79. Taylor M, Carr T, Oke O, Jaunky T, Breheny D, et al. E-cigarette aerosols induce lower oxidative stress in vitro when compared to tobacco smoke. Toxicol Mech Methods 2016;26(6):465-476 https://doi.org/10.1080/15376516.2016.1222473
  80. Terron A, Bal-Pric A, Paini A, Monnet-Tschudi F, Bennekou SH, et al. An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition. Archives of Toxicology 2018;92(1):41-82 (doi: 10.1007/s00204-017-2133-4.)
  81. Tollefsen KE, Scholz S, Cronin MT, Edwards SW, de Knecht J, et al. Applying Adverse Outcome Pathways(AOPs) to support Integrated Approaches to Testing and Assessment(IATA). Regul Toxicol Pharmacol 2014;70:629-640 https://doi.org/10.1016/j.yrtph.2014.09.009
  82. U.S. EPA. Human health risk assessment. [serial online] 2018 [Accessed 2019 March 20]. Available from: URL:https://www.epa.gov/risk/human-health-risk-assessment
  83. US EPA. Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001FMarch. [serial online] 2005 [Accessed 2019 March 20]. Available from: URL:http://www.epa.gov/raf/publications/pdfs/CANCER_GUIDELINES_FINAL_3-25-05.PDF
  84. US EPA. Risk and Technology Review(RTR) Risk Assessment Methodologies: For Review by the EPA's Science Advisory Board. Case Studies - MACT I Petroleum Refining Sources Portland Cement Manufacturing(EPA-452/R-09-006). 2009
  85. van der Veen JW, Soeteman-Hernandez LG, Ezendam J, Stierum R, Kuper FC, et al. Anchoring molecular mechanisms to the adverse outcome pathway for skin sensitization: Analysis of existing data. Crit Rev Toxicol 2014;44(7):590-599 https://doi.org/10.3109/10408444.2014.925425
  86. Villeneuve DL, Crump D, Garcia-Reyero N, Hecker M, Hutchinson TH, et al. Adverse outcome pathway (AOP) development I: strategies and principles. Toxicol Sci 2014a;142(2):312-320(doi: 10.1093/toxsci/kfu199.)
  87. Villeneuve DL, Crump D, Garcia-Reyero N, Hecker M, Hutchinson TH, et al. Adverse outcome pathway development II: best practices Toxicol Sci 2014b; 142(2):321-330(doi: 10.1093/toxsci/kfu200.)
  88. Vinken M. The adverse outcome pathway concept: A pragmatic tool in toxicology. Toxicology 2013;312:158-165 https://doi.org/10.1016/j.tox.2013.08.011
  89. WHO. Environmental Health Criteria 240: Principles and methods for the risk assessment of chemicals in food. World Health Organization, Geneva. [serial online] 2009 [Accessed 2019 March 20]. Available from: http://www.who.int/entity/foodsafety/chem/principles/en/index.html
  90. Worth A, Barroso J, Bremer S, Burton J, Casati S, et al. Alternative methods for regulatory toxicology-a state-of-the-art review. European Union Reference Laboratory for Alternatives to Animal Testing(EURL ECVAM), Systems Toxicology Unit, Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra, Italy. 2014
  91. Zbinden G, Flury-Roversi M. Significance of the LD50 test for the toxicological evaluation of chemical substances. Arch. Toxicol 1981;47(2):77-99 https://doi.org/10.1007/BF00332351
  92. Zheng F, Zhang MG, Song J, Chen FZ. Analysis on risk of multi-factor disaster and disaster control in oil and gas storage tank. Procedia Eng 2018;211:1058-1064 https://doi.org/10.1016/j.proeng.2017.12.110
  93. Zvinavashe E, van den Berg H, Soffers AE, Vervoort J, Freidig A, et al. QSAR models for predicting in vivo aquatic toxicity of chlorinated alkanes to fish. Chem Res Toxicol 2008;21:739-745(doi: 10.1021/tx700367c.)