Examples of direct-acting and bioactivation-dependent genotoxic agents
\r\n\tHowever, despite the positive outlook and trends in routing protocol design, there are still several open or unresolved challenges that researchers are still grappling with. Providing adequate responses to those challenges is essential for next-generation networks in order to maintain its reputation and sustain its preponderance in cyber and physical security. Some of the challenges include, but are not limited to, the following:
\r\n\t• Robustness and reliability of routing protocol
\r\n\t• Reduced dependencies on heterogeneous networks
\r\n\t• Security of routing protocols
\r\n\t• Dynamic Adhoc routing Protocols
\r\n\t• Routing in 5G Networks
\r\n\t• Routing IoT enabled networks
\r\n\t• Scalable and dependable routing system architectures
\r\n\t• QoS and QoE Models and Routing Architectures
\r\n\t• Context-Aware Services and Models
\r\n\t• Routing Mobile Edge Computing
\r\n\tThe goal of the book is to present the state of the art in routing protocol and report on new approaches, methods, findings, and technologies developed or being developed by the research community and the industry to address the aforementioned challenges.
\r\n\tThe book will focus on introducing fundamental principles and concepts of key enabling technologies for routing protocol applied for next-generation networks, disseminate recent research and development efforts in this fascinating area, investigate related trends and challenges, and present case studies and examples.
\r\n\tThe book also investigates the advances and future in research and development in Routing Protocols in the context of new generation communication networks.
DNA damage is toxic to the cell, both acutely (perturbing the cell cycle and inducing apoptosis), and in the longer term (accelerating senescence and causing cancer and genetic disease) [1,2]. Therefore it is of great interest for public health to determine the potential of anthropogenic chemicals and other compounds found in the environment to cause DNA damage as likely toxicants, carcinogens and teratogens [3].
This chapter will review methods that use in vivo models (i.e. living organisms and cell lines) for detection of genotoxic damage caused by exposure to chemicals. The reason that living models play such a prominent role in mutagenesis detection is two-fold:
Extremely low frequency of mutation: the mutation frequency induced by exogenous agents is extremely low (in the range of 1 mutation in 106 to 107 nucleotides). The ability of living organisms to amplify these rare events through positive selection is the basis for a number of these model systems.
Modulation by metabolism: metabolism has a dual role for activation (bioactivation) and for detoxification of genotoxic compounds. Therefore, metabolism needs to be taken into account by models of genotoxic exposure. Living organisms incorporate metabolic activity into the equation, although they only approximate human metabolism to various degrees.
In vivo models fall into two broad categories according to how they detect genotoxicity: direct or indirect genotoxicity detection methods. Direct measurement detects alterations in DNA either by sequencing, by the generation of a phenotype linked to specific mutations, or by visualization of the DNA damage such as micronucleus formation, detection of aberrant chromosomes, or an increase in the number of DNA breaks [4-6] (Fig. 1).
Phenotypic detection of DNA damage is based on loss-of-function (forward), or gain-of-function (reverse) reporters. Forward mutation reporters are based on the loss of a phenotypically-detectable trait such as color or sensitivity to a metabolic poison. Therefore they can detect a range of mutations (miss-sense, transcriptional termination, frameshift, indels, etc.) along a sizeable target sequence, which increases the overall frequency of detectable events, allowing in many cases for direct screening. Forward mutation reporters also provide a representation of the range of genotoxic effects induced by the relevant compound, although biased for changes that lead to functional inactivation. Reversion reporters, by contrast, are based on reversion of a specific mutation inactivating a selectable marker. Therefore, reversion markers report very specific mutations at pre-determined sites, which may not be representative of the range of lesions introduced into DNA. Also reversion events are exceedingly rare due to the small size of the target, and can only be identified by positive selection.
Phenotypic detection methods generally produce binary readouts, with the presence of growth on limiting solid or liquid media, or changes in color as primary readouts. This means that the generation of a single data point requires fine-tuning the dose and of the dilution to obtain countable colonies (on solid plates) or a number positive wells that follows a Poisson distribution (in liquid culture) [7].
Genotoxic potential can also be detected by indirect measurement methods, usually based on transcriptional fusion of a reporter gene to a promoter responsive to DNA damage (specific examples are discussed below). Indirect detection methods provide an indication that the cell has sensed genotoxic stress, but the accuracy of each indirect reporting system depends on the range of lesions inducing the relevant transcriptional response and on the specificity of the relevant promoter for DNA damage relative to other types of stress. The reporter can be colorimetric, fluorescent or luminescent. Examples include: lacZ (beta-galactosidase), GFP (green fluorescent protein), luciferase, and phoA (alkaline phosphatase). Some of these markers (GFP and luciferase for example) have a wide dynamic range and are proportional to the amount of damage, greatly facilitating quantification [8,9]. The use of GFP as a reporter, rather than reliance on an enzymatic reaction, produces a measurable response to DNA damage in a shorter time frame.
In general, indirect assays are better suited for high-throughput analysis because they can produce quantitative signals. Surface markers such as CD59 also provide forward mutation reporters that are quantitative, i.e. whose loss in a cell population following chemical exposure is directly proportional to the amount of genotoxic damage induced [10,11]. Quantification of surface markers in large cell populations is made possible by the use of FACS (Fluorescence-Activated Cell Sorting) analysis, which is a high-throughput method that detects the presence or absence of the relevant marker in individual cells. The availability of quantitative reporters for mutagenesis substantially reduces the amount of test sample required. On the other hand, direct mutagenesis detection assays are more labor-intensive but more specific because they detect alterations in DNA.
DNA-damaging chemicals are frequently generated from precursors as reactive metabolic intermediates [12,13]. The precursors are known as procarcinogens even though carcinogenicity has not in all cases been demonstrated. Procarcinogens include most genotoxic natural products and environmental agents since they would be expected to react with other molecules before reaching DNA. Chemotherapeutic drugs and other anthropogenic chemicals or contaminants, on the other hand, are frequently direct-acting. Table 1 provides some examples of direct-acting and of bioactivation-dependent genotoxicants.
Xenobiotic metabolism, which is designed to solubilize lipophilic compounds as a way to facilitate their excretion, contributes prominently to bioactivation [12,13]. The liver is the primary site of metabolic bioactivation, given its large metabolic capacity as well as its anatomical position as the gateway for compounds absorbed in the GI tract. Bioactivation by metabolism also occur in other tissues, including skin, lung, bone marrow, and GI tract. Bioactivation in the GI tract can also result from the action of the intestinal flora, or due to the drastic pH changes that occur as food moves through the tract [12].
Xenobiotic metabolism often involves two reactions, an oxidative one and a conjugative one. Oxygenation is typically carried out by members of the cytochrome P450 family (CYPs). CYPs are membrane-bound heme-proteins that require an effective reductase system to provide electrons [14]. These enzymes tend to exhibit low catalytic efficiency and broad substrate specificity. Humans bear over 50 different CYP genes, which have some overlapping substrate specificities. Conjugation on the other hand transfers N- or O- acetyl groups (acetyl transferases), sulfates (sulfotransferases) or glutathione (glutathione-S transferases) to electrophilic substrates. Metabolism genes (particularly CYPs) are extraordinarily polymorphic, explaining the presence of wide interindividual differences in response to xenobiotics [13]. Liver metabolism can be mimicked in testing paradigms by adding primary hepatocytes, liver slices, or various organ extract fractions to tester cell cultures, or by liver perfusion [15]. The standard fraction is known as S9 fraction, which combines microsomes (containing CYPs) and cytosol (enriched for transferases) from the liver of rodents whose metabolism has been activated through xenobiotic pre-treatment [15,16].
Type of damage | Direct-acting Chemical class | Bioactivation-dependent Chemical class | |
Alkylating | Diazo compounds | Triazenes | |
Nitrosamines | Azoxy compounds | ||
Nitrosoureas | N-alkylnitrosamines | ||
Aziridines | Aromatics | Polyaromatics | |
Halogenated methanes, ethanes | Heteroaromatics | ||
Mustards | Nitroaromatic amines* | ||
Sulfates, sulfonates | Some proximate mustards | ||
Oxidizing | Simple epoxides | Quinones | |
Thiiranes, oxiranes | |||
Simple peroxides |
Examples of direct-acting and bioactivation-dependent genotoxic agents
In the context of drug discovery, in vivo methods are second-line assays performed to support the safety of a compound that is in the pipeline for clinical development [17,18].
Lead compounds are typically first prioritized by structure-activity relationship (SAR) analysis. This is a computational method that links specific chemical features of a given compound to individual biological activities, including genotoxicity. Due to its correlative nature, the predictive value of SAR analysis largely depends on how well represented the relevant class of compounds is in the database [19]. Lead compounds that have made this first cut are then tested in vivo by direct mutagenesis detection methods for regulatory compliance. These include at least one prokaryotic phenotypic mutagenesis assay, one eukaryotic cell culture assay, and one animal test visualizing DNA damage [20,21]. The standard test battery includes the Ames Test, the Mouse Lymphoma TK Assay, and the Micronucleus Test, respectively (see below). Transcriptional reporter-based assays can also be used for pre-screening prior to direct detection tests. Finally, the most reliable method to determine the potential carcinogenicity of a compound is testing it in a mammalian animal model (rat or mouse). This is done last, given the high cost of rodent carcinogenicity assays.
Here we discuss different in vivo models reporting on the ability chemicals to induce DNA damage, flagging these compounds as potential hazards to public health. This includes a variety of detection methods in prokaryotic, eukaryotic, tissue culture, whole-animal, and transgenic animal models. We finish by highlighting active areas of technology development and briefly speculate on the impact that next generation sequencing will likely to have in the field.
Prokaryotes are useful for assessing DNA damage because they are haploid, reproduce quickly, and are easily grown in culture. Their use as a model for testing genotoxicity in humans is based on the universal nature of chemical mechanisms of DNA modification, as well as on the strong conservation of mechanisms of DNA repair between bacteria and humans (with the important exception of nucleotide-excision repair) [1]. Genetic alterations are frequently used to enhance the sensitivity of prokaryotic reporter systems to DNA damage. Examples include mutations that increase membrane permeability (rfaE, tolC) and deficiencies in DNA repair (uvrB, uvrA, umuD). Most B- and K-derived laboratory strains of E. coli already exhibit increased permeability to xenobiotics as a result of loss of LPS selected during the long passage of these strains in culture (D. Josephy, personal communication). E. coli tends to be more sensitive to chemical mutagens than Salmonella, particularly to oxidizing mutagens, cross-linking agents and hydrazines [22]. On the other hand, Salmonella facilitates detection of aromatic amines and of nitroaromatic compounds because of substantial endogenous bacterial nitroreductase (NR) and O-acetyltransferase (O-AT) metabolic activity.
Phenotypic reporters in prokaryotes are based on reversion of an auxotrophic marker. The Ames Test was the first of these assays to be developed, revolutionizing the field of genetic toxicology for its low cost and simplicity. This assay is based on reversion of a mutation preventing the biosynthesis of histidine. Reversion is detected by growth of colonies on solid agar in the presence of trace amounts of histidine [23]. Growth on solid agar requires a large amount of test sample (~1 mg) but allows testing of non-water soluble compounds. A set of six strains have been developed to detect a broad range of point mutations and frameshifts [24]. The Ames Test is still by far the most widely-used prokaryotic testing method, in part because it is mandatory for regulatory compliance.
Two variations have been developed to facilitate high-throughput formatting and to reduce the amount of sample needed: Mini-Ames and the Ames Fluctuation Test. Mini-Ames (also known as Mini-Mutagenicity Test) follows the standard Ames Test protocol, except at 1/5 the size. This reduces the amount of sample required to 300 mg of compound for the whole set of 6 reporter strains [25]. Despite these advantages, Mini-Ames is still not widely used. The Ames Fluctuation Test is a variation of the Ames Test that is performed in liquid culture, using a chromophore as a binary indicator of growth [26]. This assay has been adapted to a microtiter format (Ames II Test) [27]. This format can incorporate microsomes, S9 fraction, or hepatocytes for bioactivation. Commercially available, The Ames II Test has comparable accuracy relative to the traditional Ames Test for most compounds (and even higher accuracy for low-potency liquid mixtures) [28], and its use is overtaking that of the traditional Ames Test.
The AraD Test is an alternative assay that detects forward mutations in the arabinose operon. The cells used in this assay have a mutation in the araD gene, which leads to accumulation of a toxic intermediate when arabinose is present. Mutations that inactivate the operon prevent the metabolism of arabinose, allowing cells to grow on arabinose [29,30]. The AraD Test exhibits a different sensitivity profile than Ames, although being a forward mutation assay it has two advantages over Ames: more sensitive to point mutations (larger target for mutagenic action) and producing more accurate spectrum of mutation than the Ames test (since mutations are not limited to a single site). However, in practice this assay does not represent a significant alternative to the Ames Test or other cell-based mutagenesis assays [17].
Transcriptional reporter systems are based on the fusion of reporter genes to promoters of the SOS regulon, which includes a battery of ~40 genes involved in the response to DNA damage [31]. This regulon is under the control of the lexA repressor, which upon genotoxic stress is cleaved by RecA, relieving repression [31]. Two systems enjoy widespread use: the UmuC Test and the SOS Chromotest. Both systems are based on transcriptional fusions of DNA damage-inducible promoters (umuC and sfiA, respectively) to lacZ [32,33].
SfiA detects a broader range of genotoxic damage than umuC. On the other hand, the host for the UmuC Assay is a Salmonella strain (NM3009), making this assay particularly suited for detection of nitroarenes, such as those found in combustion products. The UmuC Test has been adapted to micro-titer plate format. High throughput, fully automated microtiter plate versions are also available for the SOS-Chromotest as well as numerous commercially available kits for testing specific sample types. Thus, the SOS-Chromotest provides easily quantifiable, reproducible and customizable ways to measure genotoxicity in a variety of samples, from wastewater to blood serum [33]. An additional system, based on a fusion between the SOS-inducible gene sulA and the alkaline phosphatase-encoding gene phoA has also been recently described [34].
Eukaryotic systems are also extensively used for detection of genotoxic activity. They have the advantage of having a DNA repair machinery that is even closer to that of humans (with homologous nucleotide excision repair machinery and more translesion synthesis polymerases for example) and of having comparable replication machinery, allowing detection of genotoxicants that interfere with mitosis. Higher eukaryotes also have metabolic systems that are much closer to our own, although even rodents show marked differences in metabolism relative to humans [12,13]. Another advantage is the larger size of the cell nucleus and genome, which facilitates detection of rearrangements and other genomic abnormalities. Disadvantages include higher cost (particularly rodent systems), the presence of efflux pumps that can prevent accumulation of xenobiotics, and a diploid genome, which masks the phenotypic effects of heterozygous recessive mutations. Different strategies for improved detection of recessive mutations have been devised. These include: sporulation (in yeast), heterologous expression of single human chromosomes (in Chinese hamster cells), and selection of X-linked and heterozygous loci as markers (which become dominant or homozygous recessive with only one mutation).
As in prokaryotes, genetic modifications in yeast enhance sensitivity to DNA damage. Examples include deletion of efflux pumps [35], removing mag1 (a N3mA DNA glycosylase), hindering base excision repair [36], and deletion of mre11, preventing both homologous recombination repair and non-homologous end joining pathways [36].
We group eukaryotic models into three sections: 1) phenotypic detection; 2) transcriptional detection; and 3) direct visualization of DNA damage.
Phenotypic detection of genotoxic damage in eukaryotes follows principles of forward and reverse mutation analogous to prokaryotic systems. While some of these systems are as old as the Ames’ test, others are still being actively developed. Below we discuss two yeast mutagenesis reporter systems (the DEL Assay and the Mitotic Gene-Conversion Assay) and four mammalian cell-based ones (HPRT, TK, The Human-Hamster Hybrid (A(L)) and the PigA assay).
This assay detects chemical induction of recombination events by reversion of a his3 locus that has been interrupted by short repeats. Reversion to his+ can be measured by plating [37], or more recently in microtiter plate format, using a colorimetric readout [38,39]. This assay has thus far proven to be very accurate, discriminating between carcinogens and non-carcinogens of the same chemical class, and showing a 92% correlation with two prokaryotic genotoxicity assays (Ames and UmuC) [39].
The Mitotic Gene-Conversion Assay uses a combination of heteroallelic (ade2-40/ade2-119 and trp5-12/trp5-27) and homoallelic (ilv1-92/ilv1-92) gene loci to detect induction of mitotic crossing over, mitotic gene conversion and reverse mutation [40]. The original heteroallelic condition ade2-40/ade2-119 forms white colonies. Mitotic crossing over can be detected visually as pink and red twin sectored colonies due to the formation of homozygous cells of the genotype ade240/ade240 (deep red) and ade-2-119/ade2-119 (pink). Mitotic gene conversion can be detected by the loss of auxotrophy for adenine (ade2 locus) or tryptophan (trp5 locus). Mutation induction can be followed by the appearance of isoleucine non-requiring colonies on selective media. Detecting both reversions and repair-associated recombination events is a unique feature of this assay that increases the sensitivity to genotoxicity. This assay is widely used and included in the Code of Federal regulations of the United States of America. However, the need to assess mitotic cross-over by screening for changes of color makes full automation of this assay very difficult.
This assay measures inactivating mutations at the hprt locus, which encodes the salvage-pathway enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT). HPRT catalyzes the formation of inosine or guanosine monophosphate from hypoxanthine or guanine, respectively. Treatment with 6-thioguanine generates 6-thioguanine monophosphate (6-TGM), which is highly cytotoxic to wild-type cells [41]. Inactivating mutations in the hprt gene are dominant because this gene is carried on the X chromosome and is subject to X-inactivation [42-44]. The standard cells for use in this assay are CHO (Chinese hamster ovary) cells, V79 (Chinese hamster lung cells), G12 or G10 cells (V79-derived cells). A variation on this assay is the expression of bacterial gpt gene (the functional homolog of HPRT) in an HPRT- background [42].
The cells used for the assay are mouse lymphoma cells L5178Y, which are heterozygous at the thymidine kinase locus (tk1) on chromosome 11. Inactivating the WT allele induces trifluorothymidine (TFT) resistance, and tk−/− mutants can be selected for in a background of tk+/− non-mutant cells [45-47]. Colony size is an indicator of the type of mutation involved: large colonies typically correspond to small TK-inactivating mutations, while small colonies often indicate clastogenic damage. This test (which is mandatory for regulatory compliance) is the most favored of the cell-line based assays because of its sensitivity to mutagens [48,49]. However, this assay is also very susceptible to false positives [48,49].
Two tests use surface proteins as forward mutation markers, the Human-Hamster Hybrid (A(L)) Cell Mutagenesis System and the PigA Assay. Surface markers offer several advantages over drug-dependent readouts. Results are quantitative, producing not only a binary (yes/no) result but an indication of the potency of the chemical tested. In addition, with these assays cells do not need to be lysed for analysis, which enables tracking of the phenotype over time, as well as testing multiple or constant low-level exposures.
Human-hamster hybrid (A(L)) cells were generated containing a single human chromosome 11 in addition to a standard set of CHO chromosomes. This human chromosome expresses CD59, CD44 and CD 90 surface antigens. The presence of CD59 on the cells’ surface makes them sensitive to binding by a polyclonal antibody known as E7. Upon binding of the E7 antibody, incubation with serum stimulates the complement cascade, which lyses the cells. The yield of CD59- mutants can also be detected by immunofluorescence and quantified using flow cytometry, providing a quantitative readout for mutagenesis [50,51]. Detection of CD59- mutants exhibited a linear correlation with clastogen (gamma-radiation) and point mutagen (MNNG) dose, confirming the quantitative nature of the assay [50].
The phosphatidylinositol glycan complementation group A (Pig-A) gene encoded on the X-chromosome is essential for attaching GPI-anchored proteins to the cell surface. The PigA assay detects the loss of CD59 (incidentally the same marker used in the Human-hamster hybrid (A(L)) assay described above) in red blood cells as and indicator of loss-of-function mutations at the endogenous Pig-A locus. Anti-CD59-PE is used to stain blood cells, and individual cell fluorescence is monitored by FACS analysis [10,52]. Thiazole orange is used to differentiate between mature erythrocytes, reticulocytes (RETs), and leukocytes; and anti-CD61 to resolve platelets [10]. The assay has been adapted for monkeys, mice, rats and humans (11). In rats, phenotypes can be detected earlier in reticulocytes than in erythrocytes (2 weeks versus 2 months following exposure, respectively).
As in the case of prokaryotes, eukaryotic transcription reporter systems are transcriptional fusions to genes that are specifically induced in response to DNA damage.
In yeast, one of the promoters of choice is that of ribonucleotide reductase 3 (rnr3), which encodes a form of the large subunit of ribonucleotide reductase. This gene is transcribed in response to low levels of damage, discriminates between DNA damage and other forms of stress, and its expression reaches higher levels than other DNA damage-responsive genes [53]. The rnr3 promoter is therefore ideal as a reporter. An assay was developed with rnr3 driving lacZ expression (rnr3-lacZ) [35], and has had a modest impact following its initial description (10 PubMed citations, and 260 Google Scholar hits). A promising variation was developed that uses secreted Cypridina luciferase as a reporter (rnr3-luciferase) in a DNA repair-deficient yeast strain [54,55]. Secretion of luciferase into the culture medium facilitates sequential measurements of DNA damage because cells don’t need to be collected. This allows the detection of chronic effects, i.e. accumulated damage due to chronic low-level exposue over an extended period of time. It is easy to envision a fully automated adaptation of this assay, which would be cheap, and would not require specialized technicians.
Another promoter that has been used in yeast is that of HUG1 (Hydroxyurea- UV- and Gamma radiation-induced). The HUG1 promoter is used to drive expression of GFP [56]. While the specific function of HUG1 is unknown, it is a part of the Mec1p kinase pathway, a signal transduction cascade that has a pivotal role in DNA damage-sensing in yeast. The sensitivity of the initial strain was enhanced by two deletions: that of mag1 and that of mre11. These changes increased the sensitivity of the assay to alkylating agents and to inducers of strand-breaks, but did not change the sensitivity to other forms of DNA damage [36]. However, in order for this system to have a clear advantage over other luminescence-based reporters, the sensitivity still needs to improve considerably.
In human cell lines, the promoter of choice is that of the Growth Arrest and DNA Damage 45 (GADD45) gene, which is a sensor for genotoxic stress in mammalian cells. GADD45 is induced upon exposure to clastogens, aneugens, and mutagens. The GreenScreen Assay, which uses a transcriptional fusion with GFP transformed into human lymphoblastic TK6 primary cells as a reporter, showed high specificity for carcinogens that do not require metabolic activation (100% accuracy with 75 chemicals tested) [57], as well as for procarcinogens (91% accuracy with 23 chemicals tested) [58]. This assay has since undergone extensive validation with more than 8,000 compounds. The overall specificity to genotoxins has remained quite high at 95% [59]. The GreenScreen Assay has been commercialized by the company Gentronix, including a 96-well plate version, and is becoming increasingly popular.
A sensitive way to visualize DNA damage in eukaryotic cells is the COMET assay. This assay detects DNA fragmentation, which can result from a wide range of lesions including double strand breaks (DSBs), single strand breaks (SSBs), alkali labile (abasic) sites, oxidative DNA base damage, and DNA-DNA/DNA-protein/DNA-drug crosslinking. Cells are embedded in a thin layer of agarose, which is mounted on a microscope slide. The slide is immersed in an ionic running buffer (usually TBE or TAE) and the cells are electrophoresed through the agarose. DNA fragments will travel faster than the intact parts of the nucleus, and will run in front of the nucleus. When the DNA is stained and observed with a microscope, the fragments form what looks like a comet’s tail, and the nucleus forms the comet’s head [17,18] (Fig1. direct visualization). The COMET assay does not test for a specific end-point and can therefore be used to monitor both the genotoxic effects of chemical exposure and the kinetics of DNA repair. The use of the COMET assay as a readout for genotoxicity is increasing. Full automation has recently been achieved [60,61], which will greatly facilitate standardization and use of the assay as a screening tool. In addition, the sensitivity of this assay is being improved through combinations with other visualization methods, such as FISH [6,62].
The Sister Chromatid Exchange (SCE) Assay detects reciprocal exchanges between two sister chromatids of a replicating chromosome, apparently involving homologous loci [63]. The DNA is labeled for two cell cycles (for example with bromodeoxyuridine) and visualized by fluorescence microscopy. It can be performed on a variety of cells, including cells from sentinel species like mussels and fish, which makes this assay extremely useful for environmental monitoring [64]. This assay has also been used in humans as a marker for genotoxic exposure [65]. While this assay does not detect DNA damage per se, SCE is an indication of ongoing DNA repair and therefore a genuine indicator of genotoxicity.
Two other visualization methods (the Micronucleus Test and the Chromosomal Aberration Test) are largely aimed at the detection of clastogens (agents that produce alterations affecting more than a few contiguous bases) and of aneugens (agents that alter the number of chromosomes). Prokaryotic systems have poor sensitivity for clastogens and aneugens because prokaryotes do not have multiple chromosomes, and their replication shares little mechanistic homology with mitosis. In addition, the larger size of the genome and of the nucleus in eukaryotes greatly facilitates the direct visualization of large aberrations. Therefore, these two assays complement prokaryotic reporter systems and are required for regulatory compliance.
Micronuclei (MN) are broken fragments of daughter chromosomes that did not make it into the nucleus during mitosis. MN formation is therefore diagnostic for chromosomal DNA damage. It is detected by staining for DNA, cell membrane and nuclear membranes, followed by observation of individual cells with microscopy. The approved method for scoring micronucleus induction is to image stained cells and count those with MN. Cells can be harvested from a live animal or from tissue culture. The presence of MN is best visualized in erythrocytes (because they are anucleate) but it can also be used with other cell types. The success of this test relies on proper cell harvesting and culturing techniques, as the integrity of the cell and nuclear membrane are vital. It also depends on careful scoring of cells, since the nucleus must be clearly defined in order to determine the occlusion of MN from the nucleus [5,66]. Flow cytometry can be used to quantify cells with MN induction [67], although careful microscopy controls are recommended. Recently, micronuclei induction in TK6 cells by a battery of reference compounds was determined using both microscopy and flow cytometry [68]. This study produced a good correlation between the two readouts, suggesting that MN assay by flow cytometry may become one of the methods of choice for routine genotoxicity testing in the near future, particularly in the pharmaceutical industry.
The Chromosomal Aberration Assay detects large-scale damage of chromosomes, including structural aberrations (fragmentation or intercalations) and numerical aberrations (aneuploidy and polyploidy). Numerical aberrations are most frequently the result of unequal segregation of homologous chromosomes during cell division, which can be caused by interference with cohesion during mitosis [69]. The test is most commonly carried out in vitro by exposing cell cultures to the test substance, and then treating the cells with a compound that stops mitosis in metaphase (colcemid). Following staining, the chromosomes are analyzed microscopically for aberrations. FISH-staining techniques have been used to increase the sensitivity of CA, allowing each chromosome to be differentially stained to reveal chromosomal rearrangements not detectable with conventional staining techniques [70,71].
Transgenic animals represent one of the pillars of toxicological analysis, because they combine exposure in a whole organism with efficient detection in microbial systems. Every cell of the transgenic animal carries a chromosomally-integrated vector-reporter fusion gene that is not expressed and is therefore free to accumulate mutations. The vector is either a bacteriophage or a bacterial plasmid. Following exposure of live animals to a test chemical, transgenes are recovered from the genomic DNA and placed in the appropriate bacteria for readout of mutational frequency. Mutants are identified through the use of phenotypic reporters and their mutational spectrum can be determined by sequencing [72]. Transgene models are ideal for study of the effects of chronic and repeated exposure, given the genetic neutrality of the transgenic reporter in the live animal. When the goal is to obtain mutation spectrum information, prolonged and/or repeated genotoxic exposure maximizes the number of independent mutational events obtained.
The Muta™Mouse was the first transgenic rodent system to be introduced [73]. In this system, the transgenic mice have, on their third chromosome, the g10 bacteriophage vector linked to a single lacZ. Following treatment, the genomic DNA is extracted from the tissues of interest, packaged into a lambda vector and transfected into lacZ-\n\t\t\t\t\t\tE. coli. Mutations result in while plaques in the presence of X-gal. This system is not nearly as popular as the LacZ Plasmid Mouse and the Big ® Blue Mouse because of poorer yield of transgenic DNA [72].
Another bacteriophage-based assay is the Big ® Blue Assay, which exists in both mouse and rat backgrounds [74,75], and is available from several different companies [72]. The original mouse version uses LacI, the lac repressor, as the reporter that is linked to the LIZ phage vector. Multiple copies of the transgene (40 for the mouse model and 30 for the rat) are integrated in the chromosome, arranged head-to-tail. Transformation of recovered vector into E. coli followed by plating on X-gal medium allows the identification of blue plaques (with inactive mutant lacI) on a background of white plaques. The Big Blue system was greatly improved by the use of the cII gene as a reporter. The cII gene is responsible for transition from the lytic to the lysogenic phase at low temperatures, inducing expression of the CI repressor. Inactivating mutations sustained at the cII locus confer phages with the ability to form plaques, making detection of mutations a simple positive selection [76,77].
The LacZ Plasmid Mouse has 20 copies of the pUR288 plasmid per haploid genome (a total of 40 copies) integrated into multiple chromosomes [78]. Genomic DNA is recovered, and digested by the HindIII restriction enzyme, releasing single copies of linearized plasmid. Magnetic beads coated in Lac repressor protein are used to isolate plasmid DNA from the digest, and the isolated vector is then recircularized into individual plasmids. These plasmids are transformed in E. coli and mutant frequency can be determined by scoring white colonies in the presence of X-gal. Compared with bacteriophage-based transgenic systems, plasmids can be isolated more efficiently and are more tolerant of deletions (both internal and involving flanking sequence) [72]. A significant improvement to the test was the introduction of P-gal (which generates a toxic product when broken down by -gal) as a positive selection for -galactosidase loss-of- function [79].
Mutagenesis detection in vivo is key for testing the genotoxic potential of anthropogenic chemicals produced for industrial or medical applications as well as of products present in our environment. Both prokaryotic and eukaryotic models are useful, and complement each other. Prokaryotic models are simple, inexpensive, and frequently amenable to high-throughput formatting but detection is largely restricted to mutagens that induce point mutations and frameshifts. Eukaryotic models, by contrast, are more labor-intensive and time-consuming but are more sensitive to clastogenic and aneugenic activity and facilitate visualization of DNA damage (nicks, breaks, abasic sites, etc.). Indirect methods are cost-effective and easily amenable to automation, while visual or phenotypic detection is more specific because it reports DNA damage or genetic alterations caused by DNA damage but is generally more expensive and labor-intensive.
Accurate reproduction of human metabolism in model systems of genotoxicity remains one of the most urgent challenges in the field. As mentioned in the introduction, bacterial strains used for genotoxicity testing exhibit some metabolic activities. However, they lack cytochrome p450 activity completely, making them poor models for human bioactivation. Individual CYP proteins have been expressed in E. coli [22]. However, expressing active CYP proteins in E. coli is not trivial, as it requires special media and co-expression of a reductase system as electron donor. More importantly, only a few CYP alleles can be expressed at a time, so it will be extremely difficult to reproduce the complex patterns of CYP expression occurring in liver cells. In the classic Ames Test, mammalian xenobiotic metabolism is mimicked through the addition of post-mitochondrial hepatic rodent extract (S9 fractions). While this in vitro metabolic model allows detection of a range of pro-carcinogens, it misses short-lived metabolites that fail to cross the bacterial cell wall and suffers from low reproducibility because of the variable composition of the extracts (15% inter-laboratory variability) [48].
Whole-animal models are still the most sensitive systems available for detection of procarcinogens. Fish were proposed as a model organism early on due to their enhanced liver metabolism relative to humans and to the easy exposure to xenobiotics in the water or in the trophic chain [80]. Transgenic reporters analogous to the ones created in mice were developed in fish [80,81], although their use is not yet widespread, possibly due to the need for specialized labor and facilities. Drosophila melanogaster is also likely to become more prominent in the future as a model for genotoxicity because it complements in many ways bacteria or yeast-based models. It is a whole organism, but extremely cheap and easy to maintain. Like fish, Drosophila produce large numbers of testable offspring (high n), and have metabolic and DNA repair systems that are highly homologous to human systems. Assays for genetic damage in germ cells, mostly in males (Sex-Linked Recessive Lethal Test (SLRLT), and Reciprocal Recombination Test) were the initially developed [82]. Recombination assays were later devised in somatic cells for improved sensitivity [82]. These assays rely on endogenous forward mutation markers, with visible developmental abnormalities in wings, eye morphology, or bristle shape as readouts. Flies can be exposed to test chemicals in early stages of development (larvae), further increasing the sensitivity of the assay. Larvae are very actively metabolically and have been shown to be sensitive to teratogenic effects of pro-carcinogens [83]. The large number of endogenous targets, the suitability for early exposure, and its active metabolism make Drosophila possibly the most sensitive phenotypic detection model available and a very promising model for detection of genotoxic and teratogenic effects [83].
New molecular technologies are likely to enhance our ability to detect the presence of mutations at very low frequencies, as illustrated by the Random Mutation Capture Assay [84]. This technique detects the loss of a specific restriction site in chromosomal or mitochondrial genomes using multiplex PCR amplification [65,84] and has enabled establishing spontaneous mutation rates in tumors [85], and in a mouse model of aging [86]. Importantly, by limiting dilution of the template, this technique has the ability to detect mutations from single DNA molecules templates, identifying non-clonal mutations in a heterogeneous population [85].
High-throughput sequencing technology will also likely allow the determination of genotoxic effects in the near future with an unprecedented level of resolution. Next-generation sequencing is based on massive, parallel amplification of templates [87]. While DNA amplification is PCR-based, and therefore susceptible to the error-rate of the polymerase, mutations present in the template can still be detected through redundant coverage (typically in the 30-fold range). The accuracy of coverage information can be ensured through adequate design of bar-coded primers for amplification. Because, given the structure of the human genome, most random mutations in a cell are expected to be neutral, they should occur randomly and increase the genetic diversity in exposed the population over a period of time. In the absence of positive selection, sequencing of clonal mutations (i.e. mutations that are present in a significant fraction of the population) would miss this underlying genetic diversity [88]. Therefore, obtaining an adequate representation of chemically-induced mutations would require sequencing DNA from individual cells.
As these new models and molecular tools become established in the field of genetic toxicity, they will need to be incorporated into the regulatory process for approval of new chemicals or for reassessment of chemicals currently in use.
The authors would like to thank a Special Research Grant from the UCSC Academic Senate for support for this work and Dr. Jason Bielas (Fred Hutchinson Cancer Center) for his input on this manuscript.
Urban design is the only multidimensional and multidisciplinary approach aiming to establish functional, esthetic, and safe urban public spaces for the societies. It is one of the planning strategies such as spatial planning, strategic planning, cultural planning, regional development, and economic strategies. Rather than replacing the other planning approaches and implementations, it can be seen to move together with them and consider the subjects from the third dimension [1]. It can be stated that the planning decisions must incorporate the “design” aspect because of this step, in which the spatial theme of the planning decisions at the upper scale comes to the forefront [2]. From this aspect, the design aspect has been defined as making 3D designs or design policies at the local and city scale when putting the planning decisions into practice [3, 4]. Hence, it is necessary to focus on the urban design criteria in order to discuss the quality of urban space. The criterion here refers to the criteria determining the success of the design reflecting on the urban space. The main condition for constructing livable and sustainable urban spaces is for the urban design processes to play an active role in planning processes. The main subjects of urban design are to revive social and economic life, using natural sources, esthetic sensitivity, and the pleasure derived from the space. Qualified urban design implementations might contribute to creating livable places with a rich and different character. The integration of urban design and urban planning is very important from this aspect. Considering the case of Turkey, there are very important problems in this integration. The main starting point of this study is to discuss the formation of urban space, which is caused by these problems, in terms of specific criteria.
The main objective in the present study is to evaluate the “urban design” quality (the level of success) of the Turkish cities which have been shaped within the scope of urban plans since the proclamation of the republic, over the relevant and effective actors playing a role in the urban design and planning processes. This assessment was performed using a fuzzy multi-criteria decision-making (MCDM) method incorporating the processes emphasized in the flowchart (Figure 1). The results of the present study allow a general discussion about the urban design quality of Turkish cities. The insufficient and negative conditions influencing the urban design aspect were re-discussed over the current state analysis, and infrastructure to guide all the relevant actors was established.
Methodological diagram of the study.
The planning can be described as the process of preparing systematic action plans in order to achieve the desired goals. The plan is defined over two components constituting it. These components are:
The target to be achieved, which refers to the project.
The regulations needed for achieving this target, which refer to the instruments.
In planning, which refers to systematically implementing the theoretical knowledge, it is necessary to determine both the target of the plan and the ways to follow in order to achieve the target. Within its widest meaning, the planning has three characteristics:
It should be a design for the future.
It should be made for achieving specific targets/objectives.
It should be a systematic action series.
The planning is to systematically implement theoretical knowledge. It is a process extending from the current time to the future. The main sub-processes are as follows: preparing the research, planning, implementing, monitoring, and assessing [5, 6].
Urban planning is defined as a science, art, and discipline aiming to shape the physical development of the cities by considering the social and economic necessities. Besides that, it is also considered to be a way of directing the change of urban areas [7].
The construction and design of the urban built environment are performed with a systematic approach in countries having a national planning system. The urban design should be a part of this system. The core of the planning system is the urban plans prepared at specific levels. Accordingly, the urban plans offer a framework for directing all the construction activities in the cities. The success of the framework offered by these plans depends on their relationship with the urban design in terms of the spatial dimension of the plans. The position of urban design in the planning system of Turkey is controversial. Urban design could not be positioned in Turkey’s planning system in the form specified in the literature, being nothing but a technical implementation carried out because of the legal obligations. For this reason, it would be very useful to discuss the concept of planning.
Urban design is a comprehensive and multidimensional concept. In general, it reveals the ways of creating ideas and putting them into practice. All the long-run social, economic, administrative, and spatial change factors related to the use of sources in the habitat are considered within the scope of planning.
In urban science, planning is discussed at four levels: the city, the environmental, the regional, and the national. As for the topic of urban spaces, it can be defined as the process of determining the land use, transportation, and physical structure within a mutual interaction with the social relationship, including the investigation of the positions of cities in the region [8]. Urban planning is a comprehensive process with economic, social, and esthetical dimensions, as well as the directing of the physical formation developments. The steps of this complex process are as follows:
Defining the problem
Determining the objectives ad targets
Collecting and constructing the knowledge
Assessment, synthesis
Designing the options (suitable plans)
Assessment
Feedback and control
Projecting
Since the outcomes of the urban planning processes were different, various assessments were developed. Especially in keeping with the understanding that the city is a multidimensional and complex case, urban planning has shown advancement towards becoming an interdisciplinary and inter-specialty field of implementation. Urban design has an important role in urban planning’s process of gaining an identity, and, as one of the peoples’ activities of organizing the environment in which they live, it cannot be separated from the planning [10, 11, 12]. From this aspect, different actors also play a role together with the components of the planning system in this process. The urban spaces, which are constructed by the sociopolitical dimension, are the spaces in which the discussions and reconciliations between the actors having different interests and expectations occur. The area in which the process occurs defines the participation styles, effects, and activity forms of the actors.
From the aspect of planning and urban design, the main reason for the problems observed in Turkey is the “zoning approach and practice” [13]. Being the main guideline of the legal foundation of the Turkish planning system, Zoning Law Nr.3194 can be summarized as follows: the zoning plans can be defined as the “master plan” and the “implementary development plan”; the “master plan” is the plans prepared in order to lay the foundation of the preparation of the implementary development plans and to show subjects such as general usage types, main region types, future population densities, building density (when necessary), size and principles of the development of various residential areas, transportation systems, and solutions for the problems on the existing maps prepared in accordance with the regional or environmental plans. The “implementary development plan” is, however, drawn up based on the principles of the master plan drawn on the existing maps showing the cadastral statuses, and these plans show the building blocks, the intensity and order of these blocks and roads, and all the implementation steps and information to form the basis of the development implementation programs in detail.
As can be seen here, the zoning planning aiming to achieve a legal document generally defines how a building can be constructed on a parcel, but it falls short as a regulation instrument shaping the physical environment. Even though the land-use plan (physical plan) is an important input for managing the quality of the environment, the land-use plan alone without comprehensive urban design plan/project may not ensure and maintain a high-quality environment [10, 14].
From this aspect, the framework offered by the zoning approach and practice is a regulatory system based on high-level accuracy and offering uniformity at the national level. The zoning plan, which is the expression of this framework, is to create and audit the urban built environment qualitatively. In this process, the main auditing subject of the zoning plans is the parcel [15]. This structure, not including the urban design processes but offering a strict frame, may fall short in providing a qualified urban space. Urban planning and urban design are two important phenomena complementing each other. For this reason, excluding the urban design from the planning process prevents the plans from achieving their targets. Hence, urban design should be involved in the entire planning process.
The spatial quality of urban spaces in developed countries is better than other countries. The main reason for this is thought to be that the planning system starting from the upper scales moves together with the urban design approaches to the lower scales. Thus, everything in the city that people have contact with is provided using various instruments developed together with the plans. These instruments, playing an important role in shaping the urban space, also show similarity from the aspect of urban design.
For instance, in England, the design codes, design briefs, design guidelines, and development briefs named as supplementary planning guidance are prepared for this purpose. In the USA, however, this process is generally named as design review, and the design auditing instruments such as urban design guideline are prepared. In France, the urban plans (Schéma Directeur master plan) and the “land-use plans” (Plan d’occupationdessols-POS) are not alone considered sufficient for managing the change in the urban space, and therefore the instruments such as “planning zone” (ZAC-Zoned’AménagementConcerte) and “zoning plan” (PAZ-Plan d’Aménagement de Zone) are used [15].
In the different planning approaches and legal regulations worldwide, both the central and local administrations use urban planning and urban design together in ensuring urban quality. Even though the framework offered by the zoning plans in Turkey seems enough from the quantitative aspect, the plans are not sufficient in the process controlling and directing the urban design in different countries, and the urban design instruments are used together with the plans. This is the hint for creating high-quality spaces and a successful outcome [16, 17, 18].
Since the nineteenth century, the concept of urban design has been considered in different contexts and scopes within urban planning. In this process, practitioners and theoreticians such as Kevin Lynch, David Mackay, Francis Tibbalds, etc. have offered different definitions. In parallel with the works and discussions of the theoreticians and practitioners, urban design has been conceptualized in an organized fashion (Figure 2).
Conceptualization of the idea of urban design [18].
In this conceptualization, urban design is close to urban planning at a high scale. Besides that, considering urban design as the design of small urban spaces at a low scale, it is close to the esthetic and spatial points of interest of the architecture and arts. Moreover, urban design is interested in the interaction between public and private development and its effect on the form of the city, the relationships between people and locations, movement and urban form, nature, building structure, and the processes providing successful cities and towns [1, 2, 19].
In this form, one of the most important objectives of urban design is to ensure and maintain quality and character, to integrate the old and new; to protect the natural characteristics of the city, providing new and multidimensional areas; to improve the security, health, and comfort of the city, etc. The environmental quality includes many components such as “esthetic,” identity, assessing the vista and natural exposition points and corridors, human scale, comfort in pedestrian transportation, ability of keeping away from the traffic noise, providing public spaces to rest-commune, developing the consciousness of heritage, and re-evaluating culture and historical heritage [19].
Summarizing the theoretical frame might significantly contribute to the urban design approach and the organization of the city. In the cities that are in the development process, many of the human scales disappear, the memories of the cities weaken or disappear, and the connections between the city and people rupture. The process of reconciling humans and the city in which they live incorporates a series of tasks starting with planning works, continuing with urban design practices, taking place in the third dimension. From this aspect, the best way of constructing successful and sustainable cities is to think about urban design from the very beginning of the planning and development process.
The physical environment is formed as a result of urban planning and the urban design process. The components of this formation are the appearance of buildings, the relationships between these structures, their locations, densities, spatial sense, landscapes, and pedestrian and vehicle movements. The components of the physical environment are gathered under nine groups: spatial, morphologic, contextual, visual, perceptual, functionality, sustainability, and the design/planning process [8, 20]. This process, designed as multidimensional, is constructed by the actors having different expectations and objectives. In order to understand or perceive the built environment, it is necessary to define key actors, the objectives and targets of these actors, the expectations of them in designing the built environment, and the relationships between the actors [21]. The roles and positions of the actors in urban design may always vary depending on the progression of the process. Although the actors may vary between the parts of the built environment, they continue existing.
It is difficult to define and to clearly describe the actors of urban design. Despite this difficulty arising from diversity and multidimensionality, there also is a consensus on some of the main actors. From this aspect, the actors deciding in the formation of built environment in urban design are divided into four groups: private sector, public sector, public-private cooperation, and society [22]. In other words, they can be described as professionals (urban designers, planners, architects, landscaping architects, etc.), politicians, municipalities (those working at local administration), non-governmental organizations (NGOs), universities, users-society-urbanites, sponsors, and entrepreneurs/investors. These actors have different specialties and financial and political effects depending on their professional, administrative, capacities, etc. The professional identities in these fields have an interdisciplinary character related to planning, architecture, and landscape architecture. The specific character and professional capabilities of each of the relevant design professions are reflected in the urban design [23]. Besides these professional characters, the other professional groups supporting the process and playing a binding role are the social scientists, lawyers, economists, environmental scientists, and engineers [1].
Within the scope of this study, the evaluations of the most effective actors directly influencing the urban places in the design and implementation phases are discussed. In other words, an analysis was made of the actors having a fundamental professional identity in the urban design. These are the professionals working in the private sector, public sector, and NGOs. The common character of these professionals is that they have an effective and specialized structure in the field of urban design. From this aspect, the professional titles of these actors were selected to be an urban planner, architect, and landscape architect. Seventy-three professionals following the urban design processes in Turkey and involved in many processes were involved in the analyses. Among these actors, there are 30 urban planners, 27 architects, and 16 landscape architects (Table 1).
Actors selected for the analysis.
Among the selected actors related to the field of urban design, the urban planners are interested in the quality of the built and visual environment, examine the design-related subjects from theoretical and political aspects, and ensure that they are reflected in the practice. They prepare the projects, which will meet the necessities of future objectives and provide solutions for the problems at different scales. Within the scope of plans, the architects make use of their creativity and implement their original and independent designs. They play a role in the entire project design and implementation process. The landscape architects, however, integrate the physical content, nature, and nature’s components with the design by making use of their experience in using the dependence to location/ground and time as an important design element [24]. The decision-makers in this process may significantly vary in terms of person and institution. The effects of powers such as politicians, entrepreneurs, financial institutions, investors, etc. have always been effective on the actors. However, the present study does not involve these powers. It focuses on the evaluations of the main actors about the reflection of design processes on the space.
Determining the “urban design” quality of the Turkish cities which have been designed using urban plans is very important for future urban design approaches. In the following sections of this study, the success level will be determined by making use of the evaluations of the relevant and effective actors. In this analysis to be performed using the fuzzy logic method, the urban design criteria specified in the literature will be taken as a basis. The results of the evaluations will be used in analyzing the Turkish cities which come to the forefront with their planned development, in terms of the urban design criteria, and a general evaluation will be made.
Developed by Zadeh in 1965, fuzzy logic is a method for defining and solving the problems having no exact limits [25]. Besides that, it is generally accepted as a way of thinking and deciding in the way closest to the human’s way of thinking. In the study of Yager, McNeill and Thro [26], this method was reported to have various positive characteristics such as simplicity, easiness, robustness, and the use of linguistic variables similar to the human’s way of thinking. The multi-criteria decision-making methods are used for defining and solving decision-making problems with multiple criteria and repetitive decision-making processes.
The criteria involved in assessing urban design have different complex relationships. Since the urban design criteria are multifactorial and have various sizes and the criteria could not be expressed in a common way, the analysis of the cities in the present study can be formulated as multi-criteria decision-making [27]. In MCDM methods, the opinions of the main actors are requested, and these opinions are directly utilized. Since the specialists make net evaluations while making a decision, useful results may sometimes not be achieved when comparing complex criteria. For this reason, the fuzzy MCDM allowing an analysis of an interval and presenting the evaluations of the specialists within a range was used in the present study.
The common characteristics of qualified/successful urban spaces are to offer livable, dynamic, and different spaces having character and (most importantly) satisfying the people living there. Nowadays, the first step of constructing these qualified/successful urban spaces is to determine and implement the principles of urban design. The urban design criteria are abstract on their own. However, when they are concretized within the process of development, they have significant effects on the city and consequently on the people because they gain an environment for contacting all the senses of people after the concretization.
The most effective part of these urban spaces is the urban public spaces. Urban public spaces cover all the built or natural environments easily accessed by the public and used free of charge. It covers all the streets, squares, roads, residential areas, parks incorporating commercial or public usage areas for the citizens, open areas, and the public or private properties where the society can freely visit at least in the daytime. The urban spaces should be freely accessible for every person and provide the highest urban quality to the urbanites. The most important necessities in public spaces are comfort, relaxation, active/passive participation, exploration, and human needs [28].
Certain urban design criteria are utilized in order to keep the urban space quality at the highest level. These criteria cannot become clear because of the different perspectives of researches and the spatial conditions in different periods. However, there are also certain common points.
According to the analyses made in the literature by various researchers, the criteria constituting the components of high-quality urban spaces are classified in different ways. The physical needs and the need for security, belonging, respect, and existing in a space are the fundamental needs [24, 29]. Another perspective is about the relationship and continuity of the patterns. The integrity and continuity of spatial relationships are crucial. From this aspect, many principles influencing the quality of urban life have been determined [30]. Another approach is that of Kevin Lynch. The criteria he put forward as design criteria are vitality, identity, adaptation, access, diversity, freedom, and domination [31]. In the criteria discussed by Nasar [32], there are common points besides the differences from the other theoreticians. These criteria were classified as compliance with nature, order, definitiveness, identity, and cleanliness. Similarly, discussing the importance of human scale and the pedestrian- and cyclist-oriented urban design for ensuring the urban quality and the destructive effect of vehicles, Gehl designed the criteria for the livability of urban spaces. These criteria are security, vitality, density, perceptibility, accessibility, and control [33]. From the same perspective, considering that the importance of the urban design criteria arises from livable cities, Llewelyn Davies Yeang also designed certain criteria. These criteria are noise, sound, crowdedness, the material quality of space, presence, function of open and public area, presence of pedestrians, accessibility, service diversity and quality, mass transportation, and security [34].
The criteria selected here are based on the literature review and the participation of a specialist group, which consists of actors playing an effective role in urban design decisions, in Turkey. This group consists of 73 specialist actors (urban planners, architects, and landscape architects). In this approach, the quantitative weight method is used in defining the relative importance of the criteria following the vision of specialists.
Considering the specific conditions of Turkish cities in terms of urban design, the specialists defined the criteria. In the next phase, these criteria were weighted and prioritized.
The “urban design success criteria,” which were defined using the literature review, were asked to every specialist separately in the form of survey. Four main criteria and 13 sub-criteria accepted by all the specialists were accepted in the present study. In the next step, the specialists were asked to prioritize the criteria, and the weights of selected criteria representing their importance in the success level of urban design were determined. In the third step, the design and current status of Turkish cities were analyzed in terms of the selected criteria.
Four main criteria and 13 sub-criteria presented in Tables 2 and 3 were used in analyzing the success level of urban design in Turkey within the scope of this manuscript.
Evaluation percentages of assessment criteria and sub-criteria pairs.
Weights of the sub-criteria.
In this parallel, the urban design assessment criteria were defined based on the relevant literature. These criteria are as follows:
Urban design quality
Character and identity
Diversity
Readability and definitiveness
Continuity, closeness, coverage, and guidance
Flexibility
Environmental quality
Urban built environment’s compliance with nature
Level of noise
Appearance and level of cleanliness
Functional quality
Pedestrian and non-motorized vehicle access
Mass transportation opportunities
Urban services
Security
Pedestrian security
Balance of daytime-nighttime usage
This can be defined as the “location” and its identity. The character is the quality consisting of the combination of topography, building type, geology, traditional structures, urban texture, and borders. In other words, it can be defined as improving the townscape and landscape character by supporting and answering the distinguishing/featured texture of the development and culture locally. The positive characteristics and habitats of a location are important for gaining that place a character and a meaningful identity. The landscaping, building types and materials, the structure of local life, and the other characteristics distinguishing the place from the others are the components of that place’s character.
It can be defined as the mixture of appropriate developments and development of options and differences between the usages in order to create livable places answering local needs. The usages offering diversity indicate how well a place is used, and it supports the economic and social activities in that place. The urban design criteria specified above are meaningful only when concretized. From this aspect, the design policy is an intermediary design instrument between the urban design criteria and the design instruments allowing the implementation of these criteria. The effective design policies do/should focus on how the urban design criteria can be achieved within a specific scope/context.
It can be defined as assisting the people in finding their way by making use of the definable roads and crossroads. The readability is always neglected; thus, it is very important to strengthen it because, in the design process, it is necessary to consider that not all the people are literate, and they do not get pleasure out of a place in the same way. Women and men, children and adults, visitors and inhabitants, old and young persons, and persons from different cultures perceive and interpret the same location in different ways. For this reason, a frame addressing all the perception styles is important.
It can be defined as improving the continuity of the street fronts and closeness of “places” via the advancements clearly defining the public and private places. The successful urban space is a field closed and defined by structures, buildings, and landscape components. Both relationships between the structures on a street and between street and structures are an indicator of it. The buildings following the general structure lines define the street and strengthen the effect of the street. The advancements following the borders of street fronts might contribute to clearly distinguishing the public and private spaces.
It can be defined as creating advancements answering to the social, technologic, and economic conditions changing in the course of time. The urban spaces should be adaptable for usage at different scales. The most successful spaces are those capable of changing under different conditions. From this aspect, the cities should be able to adapt themselves to the rise and collapse of industries and the change from residential to commercial areas, and the structures and infrastructures should show the same adaptation. Moreover, the spaces should allow diversity in usage under different conditions and in different seasons.
The compliance and integrity of built physical environment with the natural environment are very important for the value added to the quality of life. Rather than ignoring the natural formations, it is necessary to move together with them if possible, and the urban spaces should be created with this integrity. It is the basic objective of sustainability. The quality of the public space depends on its compliance with the local climatic conditions, material, vegetation, lighting, instructions, signs, street furniture, functions, and esthetic qualities.
It is one of the important factors of environmental quality in urban spaces. Motor vehicles are among the parameters determining the quality of space because of the production activities of various intensities (such as pedestrian or vehicle).
From the aspect of cleanliness, the rate of use of the urban spaces compatible with the health conditions will always be high. From this aspect, it is a necessity to take measures preventing the dirtiness of urban spaces. It is important to adapt the design processes to space in this context.
Given the physical environment and the relationship with others, the easiest and most appropriate way of movement is seen to be moving as a “pedestrian.” For this reason, the pedestrian movement should be well-organized in order to maintain the urban space life based on the healthy human-human relationship. It is a fundamental necessity to gather the pedestrian movements and flows in an appropriate and meaningful manner and to canalize it to the activities.
Walking is the most frequently used method for accessing to the mass transportation vehicles and is one of the traveling modes used by the people between a departure and a destination. In the present study, the walking distance to mass transportation vehicles (busses, taxis, rail-system stops, etc.) was a maximum of 800 m, which is recommended for such studies.
One of the most important reasons for the existence of humans in the cities is the services. The presence and quality of administrative, social, educative, recreational, access, etc. services indicate the success level of that city in terms of urban services.
It can be defined as developing attractive, safe, non-complex, and effectively functioning roads and public spaces by considering elderly people, children, pregnant women, etc. Besides that, the crime factors are also evaluated within the security. This parameter, which is very important from this aspect, indicates that the presence of a pedestrian in the city depends on the elements of security.
The cities and especially the city centers should not be designed only for daytime usage. In light of the safety factors, the balance should be established between the daytime and nighttime usages. Especially the city centers isolated from the residential areas turn into desolate and insecure spaces at night. From this aspect, it is important to establish the conditions of safe nighttime usage.
The criteria and sub-criteria were selected by the specialists, and then the experienced actors evaluated Turkey before and after the urban planning-implementation processes. The relevant assessment data were obtained. These data include all the information related to the selected criteria and spatial physical environment.
In the next step, fuzzy logic was used, and MCA was developed for preparing and analyzing all the criteria and sub-criteria by using the fuzzy logic method. Since the values obtained from the criteria are expressed in different qualitative and quantitative scales, it was necessary to normalize the data in order to be able to make a comparison. The linear normalization, which is a common approach used in process, MCA, and decision-making problems, was used together with fuzzy logic. The fuzzy theory is based on a fuzziness level (probability) varying between 0.0 and 1.0 and showing a constant increase. The calculation was made using the sigmoidal function specified below:
The next step was to determine the importance of the urban design criteria and sub-criteria. The analytical hierarchy process was used for assigning the weights given by 73 specialists (Tables 2–4). The pairwise comparison matrix was used in translating the opinions of specialists into values. As shown in Tables 2–4, the weights of criteria and sub-criteria were calculated using different combination pairs.
Weights of the main criteria.
The last step of this process is the involvement of weights given by the specialist actors to the sub-criteria and criteria. The method used here was the weighted linear combination (WLC) because it is an analytical approach that can be used in multi-featured decision-making. In the WLC, the combination enabled the application of the weights obtained from the binary combination to the conditions provided by Turkey’s urban design approach. The conditions provided by the country were ordered based on the priority number and calculated by summing up the results of every criterion. The higher the score is, the better the relevant criterion is reflected in the urban spaces. The WLC enables an exact balance between various criteria. In other words, even though a criterion has a very bad score, a balance can be established by a higher score from another criterion. WLC was used with GIS and calculated using Eqs. (2) and (3):
where j = 1,2,…,9;
T(xi) is the evaluation of all criteria for the element k.
The results obtained for Turkey in terms of the criteria examined for the urban planning and design approach by considering 4 main criteria and 13 sub-criteria are presented in Table 5. All the criteria were scored between 0.000 and 1.000. For all the criteria, the scores closer to 1.000 indicate the high level of success for the criterion, whereas the scores closer to 0.000 indicate failure. In this section, the evaluations are made based on the scores of criteria.
Scores by the main criteria and sub-criteria.
In this criterion aiming to measure the urban design quality of Turkish cities in terms of the physical design, there are five sub-criteria. Constituting the main principles of the physical design in general, the highest score among the five criteria was 0.35, whereas the lowest one was 0.15. Since it has a score of 0.35, “diversity” is the criterion with the highest score, but it is much lower than the intermediate level (0.50). Moreover, the mean score of these five criteria was found to be 0.21. From this aspect, the score of the main criteria is 0.19. Given these values, it can be understood that urban design quality is not at a good level in Turkey. All the scores were found to be below 0.35. There are many problems to solve before Turkish cities can come to the forefront with their planned development. It is an inevitable necessity to reconsider the integrity of planning and design in both planning and designing processes. It is understood from these results that, without considering the identities and characters of the cities, they were either damaged or neglected and not included in the planning and design processes. Rather than emphasizing or enhancing the diversity, an inclination towards stereotyping and monotony has been exhibited. Rather than making the cities more readable and defined, the complexity and irregularity have become the dominant approach. The physical and functional continuity has been destructed by the point regulations. There are many undefined areas. The effects of guidance, coverage, and closeness have decreased. Rather than flexible regulations meeting the current necessities, strict and old-school implementations have become prominent.
In this criterion, taking the environmental quality as a basis, there are three sub-criteria. None of these sub-criteria could exceed the score of 0.30 (appearance and cleanliness). The lowest score was that of “the compliance of the urban built environment with the natural environment” (0.15). Thus, the score of the main criteria is 0.27. These results indicate that the compliance between Turkish cities’ physical environment with their natural environment is at very low levels. Nature has been neglected and deteriorated via urban interventions. But, the results of planning and design procedures integrated with nature are more successful and more important for sustainability. Besides that, as a result of the urban spaces left to the production of motorized vehicles and industrial production, noise pollution is one of the most negative situations. Although it has a higher score than the other sub-criteria, the level of appearance and cleanliness in Turkish cities is much lower than the intermediate level.
Examining the functional quality of Turkish cities, this criterion has three sub-criteria. The highest score belongs to the mass transportation opportunity (0.25), whereas the lowest score belongs to pedestrian and non-motorized vehicle access (0.10). The score of the main criterion is 0.25. Hence as in the other criteria, the level of success is very low in this criterion. In particular, the score of the criterion “pedestrian and non-motorized vehicle access” is a result of a desperate situation. Turkish cities have been designed for the motorized vehicles, and all the planning-designing processes strengthen this resignation. The pedestrians and non-motorized vehicles are given second priority in the cities. The priority is given to motorized vehicles. It is gradually becoming more difficult to be a pedestrian in the cities. In this parallel, the mass transportation opportunities are limited, and there is a lack of alternatives. In some of the cities, the buses are used only at specific hours. The alternatives (metro, light rail system, sea transportation, train, etc.) do not seem to be a dominant approach yet. The urban services start to fall apart from the city centers. They are relegated to the borders, access to which is difficult. This is one of the reasons why the functional quality of the city centers has decreased.
This criterion examining the security in the cities has two sub-criteria. The scores of these two sub-criteria are very low (0.10 and 0.15). The security here is not limited to the statistical values related to crime. The secure presence of pedestrians in the cities was especially taken into consideration. If all the pedestrian groups such as elderly people, children, patients, pregnant women, etc. can securely reach the locations they want, then that city is a secure city. At this point, the other risk factors such as continuity of the road and confliction with the motorized vehicles were evaluated. Besides that, the transformation of cities into insecure and unsafe places after certain hours was considered within the scope of this main criterion. For this reason, the balance between daytime-nighttime usages is important. The urban services supporting the cities and the planning-designing approach separating the housing from city centers disrupt the balance between daytime-nighttime usages. The cities become deserted and unsafe at night.
Analyzing the “urban design quality” of countries in terms of various criteria is very difficult because of the depth and multidimensionality of the subject. Within the scope of fuzzy logic used in the present study, a multi-criteria method was used. Thirteen sub-criteria and four main criteria were selected, and they were weighted according to the opinions of 73 specialists. All the values were normalized in order to obtain the final order.
The results showed that the urban design quality of the Turkish cities is very low. In these cities coming to the forefront with their planned development from past to present, the negative results have various reasons. However, one of the most important reasons is the lack of an urban design approach that will guide spatial decisions. The urban design approaches do not comply with urban plans. For this reason, the upper scale plans fall short in shaping the spaces or shape them in an unqualified manner.
Within the scope of this study, a general evaluation was made on the urban design approach of Turkey. However, it is believed that similar results would be achieved even if the cities are separately examined. These results indicate that the “urban design” approach shaping the spatial decisions has not been integrated into the planning approach of Turkey. The upper-scale plan approach that does not deal with the urban space has served only for the motorized vehicles, taken the design aspect away from the cities, and reduced the design to a mechanical process.
The present study is important for an understanding of the urban design approach of Turkish cities. The results obtained here can be used in order to define the current problems and to suggest solutions. After determining the problematic criteria, it might contribute to supporting the urban planning decisions aiming to improve the urban design approaches. The problems detected have arisen from the fact that the planning policies giving low importance to the design and implementation processes are still in effect. However, the urban design has become more important from various aspects in the modern planning approaches, and it becomes active together with the planning processes.
In any field, quality is related to a product’s ability to solve the targeted problems and meeting the physical, social, and other needs. The quality of the urban design is directly proportional to its ability to meet the vital needs in urban spaces and ensuring urban comfort. Since the concept of quality is a multidimensional concept, the urban design quality should be considered together not only with the functional characteristics of the urban spaces but also with their descriptive characteristics. Urban quality can be achieved with the right urban space design. Increasing, ensuring, or maintaining the quality of spaces, in which humans live and their lives are shaped, affect all the life segments including the culture, economic status, and physical aspects as the components of urban quality. The more perceptible and readable the urban space is and the more complementary the urban components are, the more satisfactory it is for the spatial quality of life and urban quality. In order to increase urban quality, the actors related to urban design should support all the interventions to be made on the urban space with social and economic sustainability. Urban design quality can be achieved with the cooperation of all the actors who play a role in urban design in creating urban space focusing on the targeted design objectives.
IntechOpen's Authorship Policy is based on ICMJE criteria for authorship. An Author, one must:
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