State-wise alcohol consumption per capita per week in India [7].
\r\n\t
",isbn:"978-1-83881-922-4",printIsbn:"978-1-83881-921-7",pdfIsbn:"978-1-83881-923-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"dcfc52d92f694b0848977a3c11c13d00",bookSignature:"Dr. Fiaz Ahmad and Prof. Muhammad Sultan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10454.jpg",keywords:"Agricultural Engineering, Technologies, Application, Sustainable Agriculture, Information Technology in Agriculture, Food Security, Renewable Energies, Precision Farming, Smart Agriculture, Farm Mechanization, Robotics, Post Harvest Technologies",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 25th 2020",dateEndSecondStepPublish:"December 23rd 2020",dateEndThirdStepPublish:"February 21st 2021",dateEndFourthStepPublish:"May 12th 2021",dateEndFifthStepPublish:"July 11th 2021",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Ahmad is a researcher in the field of agricultural mechanization and agricultural equipment engineering, in-charge of Farm Machinery Design Laboratory at Bahauddin Zakariya University, with expertise in modeling and simulation. He applied for two patents at the national level.",coeditorOneBiosketch:"Renowned researcher with a focus on developing energy-efficient heat- and/or water-driven temperature and humidity control systems for agricultural storage, greenhouse, agricultural livestock and poultry applications including HVAC, desiccant air-conditioning, adsorption, Maisotsenko cycle (M-cycle), and adsorption desalination.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"338219",title:"Dr.",name:"Fiaz",middleName:null,surname:"Ahmad",slug:"fiaz-ahmad",fullName:"Fiaz Ahmad",profilePictureURL:"https://mts.intechopen.com/storage/users/338219/images/system/338219.jpg",biography:"Fiaz Ahmad obtained his Ph.D. (2015) from Nanjing Agriculture University China in the field of Agricultural Bioenvironmental and Energy Engineering and Postdoc (2020) from Jiangsu University China in the field of Plant protection Engineering. He got the Higher Education Commission, Pakistan Scholarship for Ph.D. studies, and Post-Doctoral Fellowship from Jiangsu Government, China. During postdoctoral studies, he worked on the application of unmanned aerial vehicle sprayers for agrochemical applications to control pests and weeds. He passed the B.S. and M.S. degrees in agricultural engineering from the University of Agriculture Faisalabad, Pakistan in 2007. From 2007 to 2008, he was a Lecturer in the Department of Agricultural Engineering, Bahauddin Zakariya University, Multan-Pakistan. Since 2009, he has been an Assistant Professor in the Department of Agricultural Engineering, BZ University Multan, Pakistan. He is the author of 33 journal articles. He also supervised 6 master students and is currently supervising 5 master and 2 Ph.D. students. In addition, Dr. Ahmad completed three university-funded projects. His research interests include the design of agricultural machinery, artificial intelligence, and plant protection environment.",institutionString:"Bahauddin Zakariya University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}}],coeditorOne:{id:"199381",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sultan",slug:"muhammad-sultan",fullName:"Muhammad Sultan",profilePictureURL:"https://mts.intechopen.com/storage/users/199381/images/system/199381.jpeg",biography:"Muhammad Sultan completed his Ph.D. (2015) and Postdoc (2017) from Kyushu University (Japan) in the field of Energy and Environmental Engineering. He was an awardee of MEXT and JASSO fellowships (from the Japanese Government) during Ph.D. and Postdoc studies, respectively. In 2019, he did Postdoc as a Canadian Queen Elizabeth Advanced Scholar at Simon Fraser University (Canada) in the field of Mechatronic Systems Engineering. He received his Master\\'s in Environmental Engineering (2010) and Bachelor in Agricultural Engineering (2008) with distinctions, from the University of Agriculture, Faisalabad. He worked for Kyushu University International Institute for Carbon-Neutral Energy Research (WPI-I2CNER) for two years. Currently, he is working as an Assistant Professor at the Department of Agricultural Engineering, Bahauddin Zakariya University (Pakistan). He has supervised 10+ M.Eng./Ph.D. students so far and 10+ M.Eng./Ph.D. students are currently working under his supervision. He has published more than 70+ journal articles, 70+ conference articles, and a few magazine articles, with the addition of 2 book chapters and 2 edited/co-edited books. Dr. Sultan is serving as a Leading Guest Editor of a special issue in the Sustainability (MDPI) journal (IF 2.58). In addition, he is appointed as a Regional Editor for the Evergreen Journal of Kyushu University. His research is focused on developing energy-efficient heat- and/or water-driven temperature and humidity control systems for agricultural storage, greenhouse, livestock, and poultry applications. His research keywords include HVAC, desiccant air-conditioning, evaporative cooling, adsorption cooling, energy recovery ventilator, adsorption heat pump, Maisotsenko cycle (M-cycle), wastewater, energy recovery ventilators; adsorption desalination; and agricultural, poultry and livestock applications.",institutionString:"Bahauddin Zakariya University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"252211",firstName:"Sara",lastName:"Debeuc",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/252211/images/7239_n.png",email:"sara.d@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"68819",title:"Genetic Polymorphism and Alcohol Metabolism",doi:"10.5772/intechopen.88907",slug:"genetic-polymorphism-and-alcohol-metabolism",body:'\nAlcohol abuse and alcoholism represent substantial problems that affect a large portion of individuals throughout the world. More than 200 disease and injury conditions are caused by alcohol consumption due to liver cirrhosis, cancer and various injuries [1]. According to Organization for Economic Cooperation and Development (OECD) report released in May 2015, alcoholism has been increased by about 55% between 1992 and 2012. It is a quickly rising concern among the youth of the country. According to WHO [2], alcohol per capita consumption increased in China and India (China: 4.1, 7.1 and 7.2 liters in 2005, 2010 and 2016 respectively; India: 2.4, 4.3 and 5.7 liters in 2005, 2010 and 2016 respectively). By 2025, the highest increase in per capita alcohol consumption is expected in India and China covering largest population of South-East Asia and Western Pacific region. Table 1 indicates Indian scenario of alcohol consumption.
\nState/UT | \nToddy and country liquor (ml) | \nBeer, imported alcohol, wine (ml) | \nState/UT | \nToddy and country liquor (ml) | \nBeer, imported alcohol, wine (ml) | \n
---|---|---|---|---|---|
Andaman and Nicobar Island | \n656 | \n532 | \nLakshadweep | \n0 | \n0 | \n
Andhra Pradesh | \n561 | \n104 | \nMadhya Pradesh | \n133 | \n12 | \n
Arunachal Pradesh | \n749 | \n346 | \nMaharashtra | \n65 | \n19 | \n
Assam | \n304 | \n19 | \nManipur | \n155 | \n6 | \n
Bihar | \n266 | \n17 | \nMeghalaya | \n74 | \n49 | \n
Chandigarh | \n37 | \n42 | \nMizoram | \n29 | \n2 | \n
Chhattisgarh | \n120 | \n27 | \nNagaland | \n159 | \n23 | \n
Dadra and Nagar Haveli | \n2533 | \n498 | \nOrissa | \n146 | \n20 | \n
Daman and Diu | \n252 | \n1079 | \nPondicherry | \n154 | \n144 | \n
Delhi | \n55 | \n86 | \nPunjab | \n141 | \n50 | \n
Goa | \n47 | \n108 | \nRajasthan | \n80 | \n43 | \n
Gujarat | \n53 | \n3 | \nSikkim | \n41 | \n307 | \n
Haryana | \n89 | \n43 | \nTamil Nadu | \n20 | \n85 | \n
Himachal Pradesh | \n149 | \n73 | \nTripura | \n163 | \n2 | \n
Jammu and Kashmir | \n32 | \n7 | \nUttar Pradesh | \n34 | \n5 | \n
Jharkhand | \n320 | \n14 | \nUttarakhand | \n38 | \n43 | \n
Karnataka | \n23 | \n102 | \nWest Bengal | \n74 | \n12 | \n
Kerala | \n94 | \n102 | \n\n | \n | \n |
State-wise alcohol consumption per capita per week in India [7].
Approximately 80% of the college students consume alcohol which can have short- and long-term consequences including increased risk of accidental injury, risky sexual behavior, and lower education attainment. Alcohol use stimulates the Hypothalamic-Pituitary-Adrenal (HPA) axis and causes stress-like cortisol responses [3, 4]. Frequent stimulation of the HPA by alcohol may alter the function of the system, setting the stage for reduced activity to stressors and increased likelihood of alcohol use disorder. Moreover, abnormal stress physiology is related to greater addiction severity, cravings, and poor treatment outcome alcohol use disorder [5]. More than 90% of people who drink heavily develop fatty liver, a type of liver disease. Yet only 20% will go on to develop the more severe alcoholic liver disease and liver cirrhosis [6]. Environmental factors and genetic differences in the way alcohol is metabolized, also contribute to the development of alcoholic pancreatitis [8]. Genetic factors, for example, variation in enzyme activity that metabolize alcohol and environmental factors, for example, quantity of alcohol and overall nutrition a person consume play an important role in the etiology of alcoholic liver disorders including liver cancer. It has been reported that in the population of Central India who consume alcohol are at risk for liver disorders due to ALDH2, GSTM1 and GSTT1 gene polymorphism [9, 10].
\nThis article mainly focuses on the consequences of alcohol consumption at genetic level that ultimately affect alcohol metabolism resulting in various health disorders.
\nThere are two categories of alcoholic beverages, fermented (beer and wine) and distilled (whiskey, rum, gin, vodka etc.) and the concentration of ethanol differs across preparation. Yeast fermented alcoholic drinks generally contain less concentration of alcohol since yeast stops growing at about 15% ethanol concentration while strong alcoholic drinks/liquors are prepared through distillation [11].
\nMost alcoholic beverages mainly contain ethanol and water. Some beverages like beer, wine, spirit contain volatile and non-volatile substances along with ethanol. Volatile compounds include hydrocarbons, aliphatic carbon compounds, monocarboxylic acids esters, compounds having sulfur and nitrogen, benzene etc. Dibasic carboxylic acids, tribasic carboxylic acids, coloring agents, inorganic salts polyphenols, tannic acid etc. are the non-volatile substances [12]. Contaminants and toxins found are nitrosamines, mycotoxins, ethyl carbamate, pesticides, thermal processing contaminants, benzene, and inorganic contaminants include lead, cadmium, arsenic, copper, chromium, inorganic anions, and organometals [12].
\nRegardless of how much a person consume, the body can only metabolize a certain amount of alcohol every hour. That amount varies widely among individuals and depending on liver size and body mass [13]. The effects of alcohol on various tissues depend on blood alcohol concentration (BAC) over time. The time of alcohol absorption, distribution, metabolism and excretion determines BAC [14]. After absorption from small intestine, alcohol reaches liver for metabolism. The rate of BAC rise depends on how quickly alcohol is emptied from the stomach and its metabolism during first pass through stomach and liver [15, 16]. BAC depends on various factors viz. the presence of food in the stomach, alcoholic beverages, the rate of alcohol drinking and genetic polymorphism of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Depending upon age, diet, alcohol consumption and smoking, the rate of alcohol elimination varies from individual to individual [17].
\nIn the developing world, alcohol use is one of the prevalent habit and is responsible for liver cancer [18, 19, 20]. Heavy drinking along with smoking increase the risk of developing cancers [21]. Observations suggest that some people develop cancer even at moderate daily alcohol consumption indicating that alcohol metabolism is genetically determined [22]. Also, those who typically consumed more than two drinks per drinking day were at increased risk of high blood pressure, high triglycerides, increased abdominal girth, and elevated blood glucose. Further, excessive per-occasion consumption is the primary risk factor for both acute and chronic alcohol-related problems [23].
\nThe pharmacologic and potentially pathologic effects of alcohol depend on the concentration of ethanol and its metabolites in the body, and on the duration of exposure to these substances. Alcohol is metabolized in the body by various mechanisms, that is, oxidative pathways involving alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), cytochrome P450, and catalase enzymes (which either add oxygen or remove hydrogen) and non-oxidative pathways.
\nMost of the alcohol that people drink is metabolized in the liver. First, alcohol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH). Acetaldehyde is highly toxic to the body, even in low concentrations. In the second step, acetaldehyde is further metabolized by ALDH to acetate and eventually to acetyl CoA, which then is broken down into water and carbon dioxide for easy elimination (Figure 1). Thus depending on the nutritional, hormonal, energetic status, the acetyl CoA is converted to CO2, ketone bodies, fatty acid and Cholesterol [14].
\nOxidative pathway of alcohol metabolism [17].
Acetaldehyde has the power to cause tremendous damage regardless of its short life. This is particularly evident in the liver, where major alcohol metabolism occurs [17]. Minor alcohol metabolism also takes place in the pancreas [24] and the brain, causing damage to cells and tissues [13]. Additionally, small amount of alcohol is metabolized to acetaldehyde in the gastrointestinal tract, exposing it to damaging effects [22]. The International Agency for Research on Cancer [25] asserts that acetaldehyde should be classified as a carcinogen, it promotes cancer in several ways, for example, by interfering with replication of DNA and by inhibiting a process by which the body repairs damaged DNA [22]. Studies have shown that people who are exposed to large amounts of acetaldehyde are at greater risk for developing cancer of the mouth and throat [22].
\nAcetaldehyde possesses the ability to bind to various proteins like enzymes, microsomal proteins and microtubules. It combines with neurotransmitter dopamine and form salsolinol that cause alcohol dependence and also form DNA adducts, for example, 1,N2-propanodeoxyguanosine which is carcinogenic [17]. However it is also reported that acetaldehyde concentrations in the brain are not high enough to produce these effects [26]. This is because the brain has a unique blood–brain barrier, which protects it from toxic products circulating in the bloodstream. However, it is possible that due to alcohol metabolism, acetaldehyde is produced in the brain by catalase [27, 28] and CYP2E1 [29].
\nAcetaldehyde may also be responsible for some of the behavioral and physiological effects previously attributed to alcohol [30]. For example, when acetaldehyde is administered to lab animals, it leads to in-coordination, memory impairment and sleepiness effects often associated with alcohol [26]. Deficiency of aldehyde dehydrogenase (ALDH2) leads to accumulation of acetaldehyde which results in facial flushing or blotches associated with erythema on the face, neck, shoulders, and in some cases, the entire body [31].
\nOxidation of acetaldehyde produce acetate which is later oxidized to carbon dioxide (CO2) in the heart, brain and skeletal muscles. Acetate is also metabolized to acetyl CoA, which is involved in lipid and cholesterol biosynthesis in the mitochondria of peripheral and brain tissues. Acetate causes depression in the central nervous system and also affects various metabolic processes [17].
\nEthanol is non-oxidatively metabolized by two pathways; first reaction is catalyzed by the enzyme fatty acid ethyl ester (FAEE) synthase leads to the formation of molecules known as FAEEs. In the second pathway, reaction with the enzyme phospholipase D (PLD) results in the formation of a phospholipid known as phosphatidyl ethanol [32]. This pathway is a critical component in cellular communication.
\nAlcohol metabolism involves both oxidative and non-oxidative inter related pathways. When ethanol oxidation is inhibited through enzyme inhibition, non-oxidative metabolism is increased along with increase in FAEEs in the liver and pancreas [33].
\nAlcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the main enzymes of alcohol metabolism. Both the enzymes have several forms encoded by different genes. Enzymes with different characteristics having different ethnic distributions are because of variants of these genes. Since these enzyme variants work efficiently than others suggesting some people can metabolize alcohol more quickly, for example, a fast ADH enzyme or a slow ALDH enzyme may increase acetaldehyde level resulting in deleterious health effects including alcohol dependence [34].
\nA null allele is a mutant copy of a gene at a locus that completely lack normal function. This can result in to complete absence of the gene product (protein, RNA), or the expression of a non-functional gene product. At the phenotypic level, a null allele is indistinguishable from a deletion of the entire locus [35].
\nBecause of genetic difference in these enzymes, alcohol related problems are either higher or lower in some ethnic groups, for example, ADH1B*2, a variant of ADH is common in people of China, Japan and Korea but rare in Europe and Africa [36]. Another version of the ADH enzyme ADH1B*3, occurs in 15–25% of African Americans [37]. These enzymes protect against alcoholism [38] by elevating the level of acetaldehyde that make drinking unpleasant [39]. Two variations of the ALDH enzyme, ALDH1A1*2 and ALDH1A1*3, may be associated with alcoholism in African-American people [40].
\nAlong with genetic factors, environmental factors are also important for alcoholism and alcohol-related health problems, for example, alcohol consumption increased from 2.5 to 13% in Japanese alcoholics who carried the protective ADH1B*2 gene [41]. There is no difference in the rate of alcohol metabolism and enzyme pattern between Native Americans and Whites, more Native American people die of alcoholism than any other ethnic group in the United States [42]. This suggests that a rate of alcoholism and alcohol-related problems depends on environmental and genetic factors.
\nThe major pathway of oxidative metabolism of ethanol in the liver involves ADH present in the cytosol. During oxidation an electron carrier nicotinamide adenine dinucleotide (NAD) is reduced to NADH providing reduced cytosolic environment in the liver cells. Because of byproduct like highly reactive and toxic free radicals and acetaldehyde, the liver cells become more vulnerable to damage [17]. Control of ADH activity is complex and involves: (a) dissociation of the product NADH which is a rate limiting step and (b) product inhibition by NADH and acetaldehyde [14].
\nADH comprises of a complex family. In humans on the basis of kinetic and structural properties, enzyme ADH has been categorized into five classes. Most of them are found in liver, stomach and lungs except ADH5 found in most tissues [17]. If alcohol concentration is high, it is eliminated at a higher rate because of high activity of enzymes viz. class II ADH encoded by ADH4 gene and β3-ADH encoded by ADH1B*3 gene [43].
\nAldehyde dehydrogenase (ALDH2) rapidly metabolizes acetaldehyde (produced by alcohol oxidation) to acetate and NADH. NADH is then oxidized through electron transport chain, or respiratory chain enzymes [17]. Among various isozymes of ALDH, only the cytosolic ALDH1 and the mitochondrial ALDH2 can metabolize acetaldehyde [44, 45].
\nGenetic polymorphism in ADH1B and ADH1C gene locations is associated with different levels of enzyme activity [46]. In different population ADH1B occur at different frequencies. For example, in Caucasian and black populations it is predominant, whereas in Chinese, Japanese and in some people of Jewish ancestry ADH1B*2 frequency is higher. In case of Caucasian populations, ADH1C*1 and ADH1C*2 appear with equal frequency [47]. People of Jewish descent carrying the ADH1B*2 allele show only marginally (<15%) higher alcohol elimination rates compared to people with ADH1B*1. Also, African Americans [48] and native Americans with the ADH1B*3 allele metabolize alcohol at a faster rate than those with ADH1B*1 [49].\n
\nVariants in both ADH and ALDH2 genes can influence alcohol metabolism by either increasing turnover of ethanol to acetaldehyde or deactivating oxidization function of acetaldehyde to harmless acetic acid [34, 50]. This can result in accumulation of acetaldehyde, which is a known mutagen and carcinogen that cause DNA damage and promote esophageal squamous cell carcinoma (ESCC) development [51]. In addition, ADH and ALDH2 alleles may influence individual alcohol consumption habits and risk of alcoholism development.
\nInformation on alcohol consumption, sex, and family history is essential in risk analyses of alcohol-related variants for several reasons. First, alcohol consumption could be a strong confounding variable and effect modifier in comparing genotypes and the risk of ESCC because genotypes and alcohol consumption are interrelated. Second, alcohol-related enzymes do not play a major role in ESCC development among alcohol nondrinkers, or females who drink lesser alcohol than males. Also the adverse role of loss-of-functional ADH and ALDH variants will increase in alcohol drinkers. Third, the mechanism of tumorigenesis may not be same with and without a family history of the esophageal cancer [52, 53].
\nThe allelic variants ALDH2*1 and ALDH2*2 resulted from genetic polymorphism of ALDH2 gene is inactive showing no acetaldehyde metabolism in vitro. After alcohol consumption level of acetaldehyde is high in people having heterozygous or homozygous condition for ALDH2*2 allele [44, 45] and therefore experience negative physiological responses to alcohol.
\nCytochrome P450 enzymes are present in almost all tissues of the body and play important roles in hormone synthesis and breakdown including estrogen and testosterone, cholesterol synthesis and vitamin D metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, for example, drugs and bilirubin, principally in the liver [54]. The cytochrome P450 isozymes, including CYP2E1, 1A2, and 3A4 which are present predominantly in the microsomes or endoplasmic reticulum, also contribute to alcohol oxidation in the liver. However, CYP2E1 is active only after a person consume large amount of alcohol, and catalase metabolizes only a small fraction of alcohol in the body [47]. This enzyme is induced when alcohol concentration is high and it metabolizes alcohol in to acetaldehyde. It also oxidizes alcohol in tissue like brain where ADH activity is low. It produces ROS which increase the risk of tissue damage [17]. When alcohol is metabolized by CYP2E1, highly reactive oxygen containing molecules or reactive oxygen species (ROS) is produced. ROS can damage proteins and DNA or interact with other substances to create carcinogenic compounds [55].
\nCYP2E1 enzyme is an important member of the cytochrome P450 family. It is a naturally ethanol-inducible enzyme involved in alcohol metabolism. Polymorphism in RsaI/PstI in the promoter gene region increases transcriptional activity of the gene which may play an important role in the development of esophageal carcinoma [56].
\n\nCYP2E1 c1/c1 genotype found at increased risk for gastric cardia cancer (GCC). Individuals with this genotype and have a history of heavy cigarette smoking were at increased risk for GCC. This suggests that the interaction of the CYP2E1 polymorphism with smoking has a great influence on susceptibility to GCC [57]. Polymorphisms in CYP2E1 involved in the metabolism of carcinogens tobacco and alcohol, leads to Head and Neck Squamous Cell Carcinoma (HNSCC). Haplotype analysis revealed that haplotype T-A was associated with a greater than 10-fold increase in risk for HNSCC. Use of alcohol or tobacco interact with CYP2E1 variant genotypes or with GSTM1 or XRCC1 and increases the risk of HNSCC suggest the importance of gene–gene and gene–environment interactions in the development of HNSCC [58].
\nThere was no risk of ESCC found associated with CYP2A6, CYP2E1, GSTM1 polymorphism suggest an opposite role of GSTP1 and GSTT1 polymorphisms for ESCC [59]. Gene polymorphism in GSTM1, GSTT1, GSTP1, CYP1A1 and CYP2E1 represent risk-modifying factors for ethanol related diseases in Brazilian alcoholics and controls with similar ethnic backgrounds. Also the persons with these genotypes are genetically more prone to the development of alcoholic pancreatitis and alcoholic cirrhosis, respectively [60, 61, 62, 63].
\nCatalase (in peroxisomes) is capable of oxidizing ethanol in vitro in the presence of a hydrogen peroxide (H2O2) generating system, such as the enzyme complex NADPH oxidase or the enzyme xanthine oxidase. It converts hydrogen peroxide into water and molecular oxygen. Quantitatively, however, this is considered a minor pathway of alcohol oxidation, except in the fasted state [64].
\nCAT pathway plays a prominent role in the oxidation of ethanol in the brain [17]. A common polymorphism in the promoter region of the catalase gene CAT c.-262C > T (rs1001179) influences the susceptibility to alcohol dependence and severity of alcohol dependence [65]. It was found that CAT levels were significantly higher in subjects carrying CAT -262 T allele [66, 67]. There is one study showing CAT activity and alcohol intake are interrelated [68], but the impact of this polymorphism in alcohol dependence needs to be investigated for proper conclusions [67].
\nHeat (thermal) inactivation is one of several physical approaches that may be employed to inactivate viruses suspended in solutions or deposited on surfaces. Unlike chemical inactivation approaches that often display greater efficacy for lipid-enveloped viruses than for nonenveloped viruses, heat inactivation has been found to display effectiveness for both enveloped and nonenveloped viruses [1]. Heating appears to open the viral capsid, exposing the genomic material to nucleases present in the immediate environment [2, 3]. Therefore, the capsid conformation appears to be the main determinant of heat inactivation susceptibility [3, 4], not the envelope status.
\nIn the past, heat inactivation has more typically been evaluated in liquid inactivation studies. In these studies, a solution of known virus titer is heated at a given temperature for a given amount of time and the final titer is measured (Scheme 1). A decimal reduction value (D) in units of time required for one log10 decrease in titer is then calculated. Such studies are appropriate when evaluating the effectiveness of inactivation processes aimed at virus infectivity reduction in solutions (e.g., pasteurization). When the susceptibility of viruses deposited on a surface to heating is to be evaluated, such studies are most appropriately performed using carriers (Scheme 1) [5, 6]. A known amount of virus is applied to the carriers (small representative pieces of a given material type) and allowed to dry in the absence or presence of a matrix (such as blood, saline, or culture medium). After a given drying time, the carriers and virus deposited thereon are subjected to a given duration of heating at a given temperature. The remaining infectious virus is recovered from the carriers and is measured and, again, a log10 reduction value and corresponding D value may be determined.
\nHigh-level flow diagrams for carrier (A) and liquid (B) inactivation study design.
There have been relatively few studies that have evaluated heat inactivation of viruses on carriers [5, 6, 7, 8, 9, 10, 11], and we are aware of only a single study directly comparing liquid and carrier heat inactivation in a side-by-side format [11]. The prevailing opinion has been that viruses are more susceptible to heating in liquid than when deposited on surfaces and that dry heat efficacy is related to residual moisture or relative humidity [7, 9, 10, 11, 12]. In order to clarify the relative susceptibilities of model enteroviruses to liquid and carrier inactivation, we have evaluated poliovirus-1 (PV-1; family Picornaviridae) and adenovirus type 5 (Ad5; family Adenoviridae) inactivation in two liquid matrices (medium containing 5% serum [medium] or undiluted fetal bovine serum [serum]) or when deposited on two carrier materials (stainless steel [Steel] or glass). The two enteroviruses may be transmitted by the fecal-oral route and therefore ability to inactivate viruses dried onto surfaces following deposition from contaminated water is of public health interest. See Box 1 for information about poliovirus, adenovirus and associated disease.
\nPoliovirus, adenovirus, and associated disease. The majority of PV-1 infections result in an abortive flu-like prodrome or are asymptomatic. In ~5% of infections, a meningitic phase follows the prodrome as the virus displays a predilection for the nervous system [13]. Spinal poliomyelitis with varying degrees of flaccid weakness follows shortly in some cases, while a bulbar form with minimal limb involvement but higher mortality can also occur. Interestingly, the “summer plague” of poliomyelitis that was experienced between 1916 and the advent of vaccination in the mid-1950s has been attributed in part to improvements in community sanitation [13] occurring around the turn of the century. The herd immunity that previously existed due to early infection coinciding with presence of maternal antibodies was lost when sanitation improved. Acquisition of the infection later in childhood was associated with a greater chance for poliomyelitis. Poliomyelitis still occurs in certain underdeveloped regions of the world, despite efforts at global eradication.
\nAdenoviruses can cause respiratory and gastrointestinal infections. Adenovirus types 40 and 41 represent common cases of infantile gastroenteritis, although most of the 41 types of adenovirus may be recovered from the feces of patients. These enteroviruses may be spread by the fecal-oral route. Contamination of water supplies and fomites (environmental surfaces) can lead to transmission of the enteritis from infected to noninfected individuals [14].
\nPoliovirus type 1 (PV-1), strain Chat, was propagated in rhesus monkey kidney LLC-MK2 derivative cells (American Type Culture Collection CCL-7.1). The virus was diluted in Roswell Park Memorial Institute (RPMI) medium supplemented with 5% newborn calf serum (NCS, source: ThermoFisher Scientific, Waltham, MA) and added to T-75 flasks of the LLC-MK2 cells. The flasks were incubated at 36 ± 2°C with 5 ± 1% CO2 for 90 min to allow for viral adsorption, after which they were refed with growth medium. Incubation was continued at 36 ± 2°C with 5 ± 1% CO2 until 90% of the cells exhibited viral cytopathic effect (CPE). The flasks were frozen at −80°C and then thawed at room temperature. The medium from the flasks was collected and clarified by centrifugation at 2000 rpm for 15 min and the resulting supernatant was aliquoted and stored at −80°C until use. The certified titer of the stock PV-1 was determined to be 6.79 log10 tissue culture infective dose50 per mL (TCID50/mL) in MA-104 cells (Charles River Laboratories, Germantown, MD).
\nAdenovirus type 5 (Ad5), strain Adenoid 75, was propagated in human lung epithelial A549 cells (American Type Culture Collection CCL-185). The virus was diluted in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 5% fetal bovine serum (FBS, source: ThermoFisher Scientific, Waltham, MA) and added to T-75 flasks of the A549 cells. The flasks were incubated at 36 ± 2°C with 5 ± 1% CO2 for 90 min to allow for viral adsorption, after which they were refed with the growth medium. Incubation was continued at 36 ± 2°C with 5 ± 1% CO2 until 100% of the cells exhibited viral CPE. The flasks were frozen at −80°C and then thawed at room temperature. The medium from the flasks was collected and clarified by centrifugation at 2000 rpm for 15 min and the resulting supernatant was aliquoted and stored at −80°C until use. The certified titer of the stock Ad5 virus stock was determined to be 7.01 log10 TCID50/mL in A549 cells.
\nGlass carriers consisted of 4-in2 area of a sterile glass Petri dish. Steel carriers consisted of brushed stainless steel discs of 1 cm in diameter. The serum matrix consisted of undiluted FBS, while the medium matrix consisted of RPMI medium containing 5% NCS for PV-1 and DMEM medium containing 5% FBS for Ad5.
\nVirus was spread onto the glass carriers (0.4 mL virus suspension) or steel carriers (0.05 mL virus suspension) and allowed to dry at room temperature (20–21°C) per ASTM International (ASTM) standard E1053 [15]. For liquid inactivation, 0.2 mL of virus suspension was added to 1.8 mL of serum or medium in glass tubes per ASTM standard E1052 [16].
\nCarriers containing virus were placed into a hot-air oven (Isotemp™ General Purpose, Fisher Scientific Catalog No. 151030509) set at one of three test temperatures (46, 56 and 65°C) for 5, 20, or 60 min. The relative humidity of the oven was not measured.
\nGlass tubes containing virus/medium or virus/serum solutions prepared as described earlier were placed into a hot air oven set at one of three test temperatures (46, 56 and 65°C) for 5, 20, or 60 min. The relative humidity of the oven was not measured.
\nFollowing the heating times, 4 mL of neutralizer (FBS) was added to the virus film on the glass or steel carriers and used to remove the film from the surface with cell scrapers. The liquid heat inactivation conditions were neutralized following heating by addition of 2 mL of cold neutralizer.
\nPost-neutralization samples were serially diluted and selected dilutions were inoculated onto the proper host cells for each virus (8-wells per dilution in 96-well plates). A virus recovery control (VRC) was included to determine the relative loss in virus infectivity as a result of drying and neutralization. Virus was applied to the carriers (glass or steel) or added to liquids (serum or medium) and held at room temperature (20 ± 1°C) for the longest contact time evaluated (60 min). The resulting TCID50/mL titer results for the VRC were then compared to heat-treated titers for the corresponding carrier/matrix type to calculate the reduction in infectivity caused by heat treatment. The various 96-well plates were incubated at 36 ± 2°C with 5 ± 1% CO2 for 6–9 days (PV-1) or 11–14 days (Ad5). Following incubation, the plates were scored for CPE. The 50% tissue culture infective dose per mL (TCID50/mL) was calculated using the Spearman-Kärber formula [17].
\nDecimal reduction (D) values were estimated from the most linear portions of the inactivation versus time curves for the various set temperatures (not shown). The plots included both replicate values for any given temperature and time point, therefore represent an analysis of the pooled replicate data, with a single D value being generated. Rapid deviation from linearity in these plots was noted as complete inactivation of virus occurred rapidly at the higher temperatures. We acknowledge that a certain degree of error is associated with the D value estimation process. Such errors do not detract from the validity of the comparisons to be made between carrier and liquid inactivation results, since comparison of the raw inactivation versus time results obtained leads to similar conclusions.
\nThe z value (°C per log10 change in D) for a given data set was obtained from plots of log10D versus temperature (not shown), evaluated using the linear regression function of Excel. The z value is obtained as 1/slope (m) from the linear fit equation (Eq. (1)):
\nwhere y = log10D, x = temperature, m = slope and b = y-axis intercept.
\nPlots of D versus temperature were evaluated using the power function of Excel to obtain the line fit equation (Eq. (2)):
\nwhere y = D, x = temperature and a and b are constants unique to each line fit equation. This equation allows one to extrapolate the D value at any given inactivation temperature and can also be rearranged to solve for temperature, as shown in (Eq. (3)).
\nallowing one to estimate the inactivation temperature required to achieve a desired D value [18] (see also discussion later).
\nReplicate results for heat inactivation of PV-1 on carriers or in solutions are displayed in Table 1. Three exposure times (5, 20 and 60 min) and three temperatures (46, 56 and 65°C) were evaluated.
\nMode | \nInactivation matrix | \nInactivation time (min) | \nLog10 reduction at inactivation temperature | \n||
---|---|---|---|---|---|
46°C | \n56°C | \n65°C | \n|||
Carrier inactivation | \n\n | \n | \n | \n | \n |
\n | Glass | \n5 | \n−0.25a | \n0.00 | \n0.25 | \n
5 | \n−0.50 | \n1.50 | \n0.50 | \n||
20 | \n−0.25 | \n≥ 4.86 | \n5.21 | \n||
20 | \n0.00 | \n≥ 5.72 | \n≥ 5.10 | \n||
60 | \n4.26 | \n≥ 4.85 | \n≥ 4.97 | \n||
60 | \n4.71 | \n≥ 5.72 | \n≥ 5.10 | \n||
\n | \n | \n | \n | \n | |
Steel | \n5 | \n−0.25 | \n0.25 | \n0.25 | \n|
5 | \n0.37 | \n0.87 | \n0.50 | \n||
20 | \n1.63 | \n≥ 4.97 | \n≥ 4.72 | \n||
20 | \n1.37 | \n≥ 5.22 | \n≥ 4.85 | \n||
60 | \n≥ 4.35 | \n≥ 4.97 | \n≥ 4.72 | \n||
60 | \n≥ 4.22 | \n≥ 5.22 | \n≥ 4.85 | \n||
Liquid inactivation | \n\n | \n | \n | \n | \n |
\n | Medium | \n5 | \n0.00 | \n0.00 | \n0.12 | \n
5 | \n0.00 | \n−0.13 | \n0.75 | \n||
20 | \n0.13 | \n2.25 | \n≥ 5.22 | \n||
20 | \n0.13 | \n2.12 | \n≥ 5.60 | \n||
60 | \n1.13 | \n≥ 5.10 | \n≥ 5.22 | \n||
60 | \n0.88 | \n≥ 4.22 | \n≥ 5.60 | \n||
\n | \n | \n | \n | \n | |
Serum | \n5 | \n−0.25 | \n0.37 | \n0.00 | \n|
5 | \n0.13 | \n0.00 | \n0.50 | \n||
20 | \n0.00 | \n2.12 | \n≥ 5.22 | \n||
20 | \n−0.12 | \n2.00 | \n5.38 | \n||
60 | \n1.38 | \n≥ 4.97 | \n≥ 5.22 | \n||
60 | \n1.50 | \n≥ 4.35 | \n≥ 5.47 | \n
Heat inactivation data for PV-1.
The values indicate the log10 reduction (log10 titer heated – log10 titer for VRC) for two replicates per time point. Values shown as “≥” indicate complete inactivation.
The results of a virus recovery control for the virus stock have been subtracted from the log10 reduction values displayed in this table. This corrects for any loss of infectivity associated with drying of the virus stock and recovery after a 1-h hold at room temperature. A striking difference in carrier versus liquid inactivation was noted for the 46°C study. The PV-1 heated on steel carriers was completely inactivated (≥4.2 log10) in 60 min.
\nOn glass carriers, 4.3–4.7 log10 PV-1 inactivation occurred in 60 min. During this time frame, less than 1.5 log10 inactivation of PV-1 occurred when liquid heating was compared. In the 56°C study, greater inactivation occurred on carriers by 20 min, compared to virus heated in solution. In the 65°C study, similar inactivation occurred for virus heated on carriers or in solution, regardless of the inactivation time.
\nIn order to reduce the heat inactivation data for PV-1 to a form usable for comparisons between viruses and between matrices/carriers, D values (minutes required for 1 log10 titer reduction) were estimated from the most linear portions of the inactivation versus time curves for the various set temperatures. The D values, displayed in Table 2, were then used to generate log10D versus temperature curves from which z values (°C per log10 change in D) were obtained. Plots of D versus temperature (Figure 1) depict a surface along which the D required for 1 log10 inactivation at any given heating temperature is displayed.
\nTemperature | \nD values (min) | \n|||
---|---|---|---|---|
Glass | \nSteel | \nMedium | \nSerum | \n|
46°C | \n15.2 | \n14.0 | \n64.1 | \n47.4 | \n
56°C | \n3.9 | \n4.1 | \n12.5 | \n10.1 | \n
65°C | \n4.0 | \n4.4 | \n3.9 | \n9.3 | \n
\n | \n | \n | \n | \n |
\n | z values (°C per log10 change in D) | \n|||
\n | 32 | \n37 | \n16 | \n27 | \n
\n | \n | |||
\n | Power function coefficients | \n|||
a | \n6 × 107 | \n8 × 106 | \n2 × 1015 | \n5 × 109 | \n
b | \n4.02 | \n3.50 | \n8.11 | \n4.87 | \n
Estimated D, z and power function values for PV-1.
D vs. temperature relationships for heat inactivation of PV-1 on Steel (\n\n\n) or Glass (\n\n\n) carriers and Medium (\n\n\n) or Serum (\n\n\n) liquid matrices. All points along the fit lines represent 1 log10 inactivation of PV-1.
Replicate results for heat inactivation of Ad5 on carriers and in solutions are shown in Table 3. These studies involved the same temperatures and exposure times used for the PV-1 studies described earlier. The log10 reduction values have again been corrected for the virus recovery control. In the case of Ad5, differences in susceptibility to heat inactivation on glass carriers, relative to steel carriers, were noted at each temperature, with greater inactivation at any exposure time being observed on steel carriers. In general, heat inactivation on carriers was found to be similar to that observed in solutions, with no clear differences noted between temperature dependence and time kinetics.
\nMode | \nInactivation matrix | \nInactivation time (min) | \nLog10 reduction at inactivation temperature | \n||
---|---|---|---|---|---|
46°C | \n56°C | \n65°C | \n|||
Carrier inactivation | \n\n | \n | \n | \n | |
\n | Glass | \n5 | \n1.12a | \n1.25 | \n1.63 | \n
5 | \n0.50 | \n1.00 | \n2.00 | \n||
20 | \n2.00 | \n1.63 | \n2.88 | \n||
20 | \n0.88 | \n1.00 | \n2.75 | \n||
60 | \n2.37 | \n4.85 | \n≥4.10 | \n||
60 | \n1.13 | \n4.47 | \n≥4.10 | \n||
\n | \n | \n | \n | \n | |
Steel | \n5 | \n0.62 | \n−0.25 | \n0.75 | \n|
5 | \n0.88 | \n−0.13 | \n−0.37 | \n||
20 | \n2.25 | \n3.20 | \n3.85 | \n||
20 | \n1.63 | \n3.12 | \n3.10 | \n||
60 | \n3.10 | \n≥ 3.97 | \n≥ 3.85 | \n||
60 | \n2.86 | \n≥ 4.22 | \n≥ 3.10 | \n||
Liquid inactivation | \n\n | \n | \n | \n | |
\n | Medium | \n5 | \n0.25 | \n−0.12 | \n0.63 | \n
5 | \n0.38 | \n−0.25 | \n−0.25 | \n||
20 | \n0.37 | \n1.13 | \n4.10 | \n||
20 | \n0.63 | \n1.75 | \n3.35 | \n||
60 | \n1.37 | \n4.10 | \n≥ 4.10 | \n||
60 | \n1.75 | \n4.10 | \n≥ 3.35 | \n||
\n | \n | \n | \n | \n | |
Serum | \n5 | \n0.50 | \n−0.37 | \n0.62 | \n|
5 | \n0.63 | \n0.25 | \n0.25 | \n||
20 | \n0.38 | \n2.25 | \n4.22 | \n||
20 | \n1.00 | \n1.25 | \n3.85 | \n||
60 | \n2.63 | \n4.10 | \n≥ 4.22 | \n||
60 | \n3.25 | \n4.35 | \n≥ 4.85 | \n
Heat inactivation data for Ad5.
The values indicate the log10 reduction (log10 titer heated – log10 titer for VRC) for two replicates per time point. Values shown as “≥” indicate complete inactivation.
This conclusion may also be reached through examination of the calculated D and z values (Table 4) and the power function curves displaying the relationship between D and temperature (Figure 2). In no case was complete inactivation of the virus observed in exposure times under 60 min and with the exception of heating on steel carriers, complete inactivation was not observed at temperatures under 65°C.
\nTemperature | \nD values (min) | \n|||
---|---|---|---|---|
Glass | \nSteel | \nMedium | \nSerum | \n|
46°C | \n29.2 | \n18.2 | \n38.3 | \n20.8 | \n
56°C | \n12.9 | \n6.8 | \n14.7 | \n14.0 | \n
65°C | \n6.5 | \n6.0 | \n5.6 | \n5.1 | \n
\n | \n | \n | \n | \n |
\n | z values (°C per log10 change in D) | \n|||
\n | 29 | \n39 | \n23 | \n32 | \n
\n | \n | |||
\n | Power function coefficients | \n|||
a | \n5 × 108 | \n5 × 106 | \n6 × 1010 | \n8 × 107 | \n
b | \n4.34 | \n3.28 | \n5.51 | \n3.95 | \n
Estimated D, z and power function values for Ad5.
D vs. temperature relationships for heat inactivation of Ad5 on Steel (\n\n\n) or Glass (\n\n\n) carriers and Medium (\n\n\n) or Serum (\n\n\n) liquid matrices. All points along the fit lines represent 1 log10 inactivation of Ad5.
A recent paradigm shift in virology has been the recognition of the important role of fomites (environmental porous and nonporous surfaces) in disseminating infectious virus (reviewed in [19, 20]). With this recognition has come a movement toward the conduct of carrier studies (in lieu of solution inactivation studies) to evaluate survival of viruses on typical fomite surfaces (glass, stainless steel, plastic, Formica, etc.) and to determine the efficacy of inactivation approaches for disinfection of contaminated fomites. This is not to say that carrier studies were not performed previously (e.g., [21]), but the literature for carrier inactivation of viruses was relatively sparse prior to the turn of the century. Arguments for and methodologies for conduct of carrier studies have become more common within the past two decades (e.g., [22, 23]) and a literature data base for viral inactivation on carriers is now accumulating. As mentioned within the introduction, however, side-by-side comparisons of inactivation efficacy in solutions versus on carriers are lacking. This is true in particular for thermal inactivation.
\nOn the basis of the prevailing opinion [7, 9, 10, 11, 12], our assumption going into these comparison studies was that we would confirm the expected increased resistance of viruses to dry heat inactivation as compared to heating in solutions. Although the humidity associated with carrier heating was not measured in our studies, this was expected to be low for a dry heat oven. This condition was predicted, on the basis of previous work [7, 11], to further reduce the effectiveness of the carrier heating approach, relative to liquid heating. Our side-by-side studies clearly did not confirm these expectations. For instance, PV-1 exhibited markedly reduced D values when subjected to dry heating at the relatively low temperature of 46°C, indicating increased susceptibility of this enterovirus, relative to liquid heating. This difference is not attributed to experimental artifact, since our liquid heating results compare reasonably well with previous results obtained for hepatitis A virus (another enterovirus from the Picornavirus family) inactivation in culture medium [24] and food homogenates [25, 26] (Figure 3; see also review by Bozkurt et al. [27]).
\nD vs. temperature relationships for heat inactivation of PV-1 in Medium (\n\n\n) or Serum (\n\n\n) liquid matrices; comparison to hepatitis A virus inactivation in culture medium (×, Ref. [24]) or in homogenates of mussels (o; Ref. [25]) and (□; Ref. [26]).
Our carrier results indicate a much greater sensitivity of PV-1 to dry heat than was determined by Sauerbrei and Wutzler [9]. These authors observed 4.3 log10 inactivation after 60 min at 75°C, providing an approximate D value of 13 min at this temperature. The differences may be due to methodology, as these authors also reported much different results for Ad5 relative to our results (see below). The impact of organic load on heat inactivation of PV-1 in our study was minimal, as shown by the similarity in D values and D versus temperature curves for liquid inactivation in culture medium vs. bovine serum. This is in marked contrast to our findings [6] for the flaviviruses Zika virus, bovine viral diarrhea virus and West Nile virus, where dry heating at 56°C was much more effective in the absence compared to the presence of a high organic load.
\nThere have been few reports on heat inactivation of adenovirus. Maheswari et al. [28] evaluated liquid heat inactivation and observed over a 7.5 log10 reduction in titer following 10 min heating at 70°C. This corresponds to a D of ~1.3 min at this temperature. Tuladhar et al. [29] examined liquid heating of Ad5 in the presence of organic load (1% stool) and in culture medium. The D values at 73°C were 0.53 and 0.40 min, respectively [29]. This indicated a minor impact of organic load on heat inactivation, as we found in the present study. Comparisons between carrier and liquid heat inactivation for adenoviruses have not been reported. Sauerbrei and Wutzler [9] found Ad5 to be relatively resistant to dry heating. Their data indicate a D value of 67 min at 75°C [9]. This is very discrepant from our carrier results for Ad5. The reason is not clear, although the time kinetics for inactivation were not studied in detail in the previous study (time points included 60 and 120 min only). In our study, clear differences between liquid heating and dry (carrier) heating were observed primarily at 46°C, as the time kinetics were relatively similar for the higher temperatures evaluated.
\nQuestions regarding the impact of organic load and carrier versus liquid heating on the efficacy of thermal inactivation of enteroviruses spread by the fecal-oral route are relevant in achieving adequate disinfection of surfaces in healthcare settings where such viruses might be present in organic-containing physiological substrates (blood, sputum, feces, etc.). It has been shown that transfer of infectious virus from contaminated fomites to humans can result in acquisition of disease [30, 31]. It is important therefore to collect information on the utility of different inactivation approaches, whether these are chemical or physical that might be used to disinfect contaminated fomites. Our results with two enteroviruses from different nonenveloped families suggest that the efficacy of heat inactivation assessed in a liquid versus carrier test format varies according to the virus under evaluation. If extent of heat inactivation is dependent more on the protein composition of the virus than the presence or absence of a lipid envelope, perhaps the differences observed for these two enteroviruses are not unexpected. The variability observed, even among these two nonenveloped viruses, suggests that extrapolation of carrier versus liquid inactivation efficacy should not be made across virus families. As a result, we are now conducting similar studies with a wider range of viruses to more fully characterize the requirements for heat inactivation under these varied conditions.
\nHistorically, the relationship between D and temperature has been displayed in plots of log10D versus temperature (e.g., Figure 4). The slope of the (typically) linear relationship thus generated is equivalent to −1/z. The z value so obtained can then be used to predict D values at other (nonmeasured) temperatures, using the rather cumbersome formula shown in Eq. (4):
\nwhere Tpredicted is the temperature at which D is to be predicted and Tref is the temperature at which Dref was actually measured [32]. On the other hand, the plotting of D versus temperature is much more straightforward and intuitive and is occasionally seen in the inactivation literature (e.g., [29]).
\nA plot of log10D vs. temperature for heat inactivation of the OPN strain of the Picornavirus foot and mouth disease virus (Figure from [18], data are from reference [33]).
The utility of the plot of D versus temperature is greatly enhanced when the power function line fit is added to the plots, as has been done in Figures 1, 2, 3. The resulting fit lines may be viewed as surfaces along which any temperature and D-value pair is associated with 1 log10 inactivation. The extrapolation of D to nonempirical temperatures that requires some effort using the z values therefore becomes quite easy and straightforward using the D vs. temperature power curve plots.
\nThe nonlinear relationship displayed in the D versus temperature plot (Figures 1, 2, 3), with the steep portion of the curve at relatively lower temperatures followed by a flattening out at higher temperatures, is more informative also from a mechanism of inactivation point of view than the log10D versus temperature plot. If heat inactivation is attributed to capsid opening followed by nuclease destruction of genomic material [2, 3], then the steep portion of the curve may represent reaching a threshold temperature required for capsid opening. Once this threshold temperature has been reached, relatively small incremental increases in temperature result in dramatic decreases in the time required for 1 log10 inactivation. Differences between carrier and liquid heat inactivation observed at the lower end of the D versus temperature plot might then correspond to differences in extent or kinetics of heat exchange or other factors to be described below.
\nThere are frequent errors associated with calculation of D values and our own results are not immune to this, as we acknowledged in the methods section earlier. Some might argue that the concept behind the D value for heat inactivation is not always correct. The implication behind D values is that heat inactivation at a given temperature is first order with respect to time, such that a constant log10 inactivation occurs within a given unit of time. In reality, the time frames over which linear behavior is observed experimentally are very short at high temperatures and are limited by the titers of the virus stocks being inactivated. At lower temperatures, extended contact times are required to obtain several log10 of inactivation, so again the determinations of D values can be challenging. In addition, there is always a degree of error associated with the measurement of virus titers before and after heat treatment. D values at three or more different temperatures are required for calculation of power function coefficients and for determining z values, so thoroughly characterizing heat inactivation efficacy in this manner is a rather complicated endeavor.
\nIn general, experimental error associated with calculation of D values translates to poorer linear line fits (i.e., lower coefficients of determination or R2 values) in the log10D versus temperature curves. Since the D versus temperature relationship is merely a transformation of the log10D versus temperature relationship, we have routinely noted that deviations from linearity for the log10D versus temperature plots (such as those shown in Figure 4) are associated with poorer power function fits for the D versus temperature curves generated from the same inactivation results. In Figure 4, the R2 value for the line fit to all six points is 0.82, while the R2 value for the line fit only to the higher five points is 0.90. The corresponding R2 values for the power function fits are 0.89 (for all six points) and 0.94 (for the highest five points). The two constants (a and b) from the power function equation (Eq. (2)) are derived from the y-intercept and slope, respectively, from the linear line equation (Eq. (1)) of the corresponding log10D versus temperature plots.
\nIn sum, regardless of the method used for the analysis of heat inactivation results, it is the D value itself that is the source of most error. However, the conclusions made above regarding efficacy of heat inactivation applied to viruses in solution versus viruses dried on carriers, or the impact of organic load on heat inactivation, can be made directly by evaluation of the raw inactivation data itself. Therefore, the difficulties associated with the appropriateness or accuracy of the D value concept do not detract from our overall conclusions regarding heat inactivation of these two enteroviruses.
\n\n
Virus inactivation by chemical and physical means may be evaluated either in liquid studies or in carrier studies.
Liquid inactivation studies are relevant to a barrier or clearance process intended to reduce the viral titer of a solution, while carrier inactivation studies are relevant for surface disinfection approaches.
A greater volume of virus inactivation data exists in the literature for liquid, relative to carrier, inactivation. Very few studies have compared liquid and carrier inactivation in a side-by-side design.
Prevailing opinion has been that viruses are less susceptible to heat inactivation in the carrier format relative to the liquid format. Our studies have not confirmed this.
We found that PV-1 was much more susceptible to inactivation at 46°C on carriers than in liquids, while the susceptibility to inactivation at 65°C was similar for both test formats.
We found that Ad5 was only slightly more susceptible to inactivation at 46°C on carriers than in liquids, while the susceptibility to 65°C was similar for both test formats.
Regardless of study format (liquid or carrier) complete inactivation of PV-1 occurred within 20 min at 65°C, while 1 h was required at this temperature to completely inactivate Ad5.
The presence or absence of increased organic load in the liquid inactivation matrix did not impact heat inactivation efficacy for either PV-1 or Ad5.
The decimal reduction value (D) versus temperature relationship is described well by a power function line fit and the resulting line fit equation may be used in a straightforward manner to extrapolate log10 reduction in virus titer from empirically tested temperatures to other temperatures of interest.
Inactivation studies performed in solutions have been useful in providing comparative efficacy data for different physical and chemical inactivation approaches targeting a given virus or for comparing the intra- and inter-family susceptibilities of different viruses to a given inactivation approach. The current rankings of viruses in terms of susceptibilities to such approaches (e.g., [34, 35]) have largely been derived from liquid inactivation studies. The results of liquid inactivation studies should not be extrapolated to inactivation of viruses on surfaces, however. This is because differences in presentation of the virus to the active, in diffusion of the active through the liquid or virus film (for chemical approaches) or in penetrability of radiation to the viruses or in kinetics of heat exchange (for physical approaches), almost certainly exist. Such differences may favor inactivation in one or the other of the liquid or carrier formats. Generalizations on the relative sensitivities of viruses to inactivation on carriers versus in liquids should not be made in the absence of data. Side-by-side carrier and liquid inactivation studies such as the ones described in this chapter are needed to elucidate the possible differences in efficacy for the various chemical and physical inactivation approaches. This aspect of the inactivation literature is in its infancy, but with time it is expected that the database will continue to grow.
\nAs more sophisticated thinking about the relationship between our environmental microbiome and public health has been evolving, arguments have been made that the current approach to surface disinfection should change. In other words, there is a viewpoint that advocates replacement of the current “sterilization approach’ with the use of “smart” antimicrobial agents that target the pathogens while sparing the nonpathogenic population [36]. Heat is, in some regards, capable of serving as a targeted inactivation approach. This is due to the rather striking differences in heat inactivation sensitivity of various viruses or, indeed, various microorganisms in general. At least for the moment though, and especially where viruses are concerned, it would appear that our current “sterilization” approach to heat inactivation will prevail, as we are not overly concerned about the possibility of nonpathogenic viruses competing with pathogenic ones.
\nIntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Chapters",metaDescription:"IN TECH aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.\n\nWhen submitting a manuscript the Corresponding Author is required to accept the terms and conditions set forth in our Publication Agreement as follows:",metaKeywords:null,canonicalURL:"/page/publication-agreement-chapters",contentRaw:'[{"type":"htmlEditorComponent","content":"The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\\n\\n1. DEFINITIONS
\\n\\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\\n\\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\\n\\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\\n\\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\\n\\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\\n\\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\\n\\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\\n\\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\\n\\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\\n\\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\\n\\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\\n\\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
\\n\\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\\n\\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\\n\\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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