Lupine Publishers| Regulatory Inflation in Pharmaceutical Drug Development?

 Lupine Publishers| Journal of Drug Designing & Intellectual Properties

Opinion

During the last decade, and exponentially over the last three years, numerous pharmaceutical manufacturing plants have closed their doors following current Good Manufacturing Practices (cGMP) audits from various agencies, such as FDA, EMA and Health Canada. Regulatory affairs have been evolving and so should be the audits, auditors and regulations. However, the density and interpretations of regulatory requirements have become increasingly stringent, especially with respect to sterile products, making them more difficult to develop and manufacture within reasonable time and cost. A quick search on Google shows numerous press releases from various pharmaceutical organizations reporting critical/ major deficiencies, leading to temporary or permanent closures of manufacturing plants. Furthermore, it seems that this evolving situation has not only impacted drug shortage, but these events have placed the pharmaceutical industry under a permanent state of siege. The negative impacts of regulatory inflation are a center of attention among pharmaceutical professionals.

This article explores three interrelated components of this regulatory inflation phenomenon.

Regulatory Narrative Leading to Global Inadequacy

The Health Canada (HC) website, more precisely the Drug &Health product inspections section [1] is listing 802 pages of cGMP audit results from virtually all Canadian establishment license holders. Even though compliant, the vast majority of them were listed as having inadequate quality systems. Comments such as: The handling of standard operating procedures for good manufacturing practices was inadequate, the written procedures for recalls were inadequate, the education, experience, and/ or oversight of the individual in charge of the quality control department was inadequate, to name but a few, can be read everywhere across the site. Compliant CMOs complain privately that labeling them as inadequate on the public domain, resulted in drops of direct business revenues and a weakening of their competitiveness. Indeed, foreign clients that would like to export their business in Canada are misinformed through HC website and get the impression that Canadian CMOs are problematic. In contrast FDA and EMA do not publish the same kind of data, through detailed documents and audit reports from compliant organizations. At the FDA cGMP audit reports exist and are on the public domain but recently both EMA and FDA have published the first report from the FDA-EMA pilot program for the parallel assessment of qualityby- design elements of marketing applications [2].

Regulatory Inflation: The Emergence and Growth

Originally, regulatory compliance was an integral part of the pharmaceutical industry. Over the last 20 years compliance has evolved to a separate industry, generating multi-billion dollars of revenues. By definition this new autonomous industry must continue to grow, and this growth is mediated via the creation of new, increasingly sophisticated requirements and guidelines. More over, the costs of compliance audits have all been transferred, directly or indirectly, to the industry. Twenty years ago, regulatory auditors were essentially testing and measuring compliance to operating procedures. Today it is the manufacturers who are paying very competent specialists from the compliance industry to piously prepare risk analysis, gap analysis, trending analysis, CAPA etc., on all aspects of operations, and present them to public or private regulatory agencies (e.g. ISO system) as proof of compliance. In parallel with this regulatory requirement inflation, there was an emerging of regulatory consulting firms [3]. In an ideal world, the compliance industry must help the manufacturers it regulates because they generate the economy, the profitability, and the taxes that drive the country. Nowadays, it looks like the compliance industry has developed in less than 25 years everything but a symbiotic relationship. And let.com be clear, there are no villains or conspiracy here: it is a systemic social problem caused by out-ofcontrol human factors: a form of conflict of interest between two groups that should work together.

Generational Turnover of Inspectors and Auditors

As a professor of drug development, I have been training graduate students in scientific and regulatory affairs for two decades. This training attempts to bridge the gap between the theory of a basic research undergraduate training and the reality that will be faced in the industry. Over the years I have noticed that most of the conformity auditors were people with hands-on experience in the past in their field of expertise, meaning that they had the necessary experience to bridge the gap between theory and reality. During the last decade, a younger and ambitious auditor profile, showing a lower hands-on experience level, a more reactive than proactive behavior, and an apparent a lack of sustainability taught by seasoned colleagues, has become the conformity auditing landscape. This new generation of regulatory enforcers are highly knowledgeable in regulatory requirements. However, the lack of “hands-on” expertise makes more difficult for them to bridge the gap between theory and practice. Most of my ex-students work in the industry and all their testimonies are pointing in that sense, even though, as described in Costanza et al. [4] Meta-analysis showed that “generational differences do exist on work-related outcomes, they are relatively small and the inconsistent pat-tern of results does not support the hypothesis of systematic difference.

Effect of Regulatory Inflation on the Next

The gravity of regulatory inflation is only beginning to be measured. It used to be relatively easy for a group of young and ambitious entrepreneurs to build, with a reasonable amount of money, a pharmaceutical CMO. The density of regulations was lower, and the way these regulations were managed were based on audits, or inspections from regulatory agencies sustained by the states. These entrepreneurs form that generation has been raised with these inflationist regulatory constraints.Today, the cost of managing compliance has become so disproportionate that there is no young company pushing behind: No succession. Our opinions on this problem are very visceral: the fact that young graduates cannot practically do the same thing as we are doing because of regulatory inflation should be deeply studies, dug and understood. As a professor andconsultant in product development, I do think that the primary duty of parents is to keep the context of opportunities they have had and transfer it to their children. The Canadian federal government has passed the law that recognizes the problem and provides solutions, “the Red Tape Reduction Act” but this law is not retroactive to heal the harm already done [5]. At the light of these comments, it is difficult to see how the wave can be modified, since it has already started to be painful, by looking at all the companies that have already closed. However, it should be extremely clear that the definition of the word “culture” is the following: Culture is the body of knowledge, know-how, traditions, customs, specific to a human group, to a civilization. It is transmitted socially, from generation to generation and not by genetic inheritance, and largely conditions individual behavior. It means that people, firms and agencies working directly or indirectly in conformity should be advertised in that regards in order to start a paradigm shift and to make the pharmaceutical industry evolving under a progressive way, where all the actors could benefit of it. It is interesting to note that this regulatory inflation does not only affect the pharmaceutical industry, but several other industries, such as the aviation [6] and as the article is mentioning: As the second most geographically vast nation in the world and with a small, open economy, Canada is dependent on air transportation like almost no other country [7].

Conclusion

The author of this article had the chance to be part of the tail of the “golden age” of the pharmaceutical industry. Indeed, I had the chance, regardless of my “specialty” to share, discuss and see how the development was going, from basic research through all the steps that were needed to develop a drug, making myself “hands on” on all the steps that were, and are still needed to file a new drug product successfully. For that reason, I have been raised “holistically” under a “regulated” way of thinking in non-clinical, clinical, CMC, and regulatory affairs so that it was possible for me to understand, to share the same languages than the auditors, whether they were coming from private firms or government agencies. Things have changed (and not evolved) in that regards. For example, if current auditors have never had the chance of being part of a blending operation, it will be very difficult for them to realize if a speed of 10,000rpm would be realistic for a blender impeller. On the other side, they will know better than all of.com the guidelines saying that this or that should be done according to this or that, as written in the page 5 of the FDA/EMA/EP/JP…. Guidelines.

The cost of managing compliance has become such that it has become virtually impossible to start a business without having a lot of money to build large “quality systems” from scratch.

Of course, we do not have proximity expertise in all the other highly regulated field such as commercial aviation to assert anything, but according to what we have seen over the past ten years, the trend is similar, as in other regulated businesses.

As a professor teaching drug development, the next steps could be:

a) To conduct a confidential survey in the industry on the effect of this HC website that is showing relatively clearly this regulatory inflation on the Canadian exportation potential of pharmaceutical product and services.

b) To monitor if there is a correlation between company closures and regulatory affairs and conformity consulting service companies.

Please note that this article strictly represents the point of view of the author based on his expertise and experience.

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Lupine Publishers | Targeting the Immune Checkpoint in Cancer: Is This a Viable Treatment Option for AML?

 Lupine Publishers | Journal of Oncology 

Abbrevations: AML: Acute Myeloidleukaemia; CBF: Core Binding Factor; mAb: Monoclonal Antibody; MDS: Myelodysplastic Syndrome

Editorial

The immune suppressive mechanisms displayed by malignant cells are considered a central process in the pathogenesis of cancer. Research in this area has gained significant momentu mover the past 20 years, with several immune checkpoints identified, including; CTLA-4, CD200/CD200R, Tim-3/Galectin-9 and PD-L1/PD-1 (Figure 1). Whilst characterising the molecular basis of leukaemia for risk stratification remains at the forefront of AML research; this must now extend to understating how the seimmune checkpoint path ways fit into the equation. A good example of why this is important is to consider CD200expression level in AML, which is a negative prognostic indicator [1]. CD200 is an immunosuppressive lig and, that when engaged with its receptor CD200R, has the capacity to attenuate T-cell and NK-cell anti-tumour activity in AML. Interestingly, most cases of CBF AML express high levels of CD200, yet CBF AML performs relatively well clinically. This paradox suggests there is a complex interplay between AML molecular heterogeneity and immune surveillance. Given the recent development and FDA approval of several immune checkpoint therapies, a full understanding of these processes and integration with standard molecular risk stratification is warranted.

Figure 1: Illustrated are immune checkpoint legends expressed on AML blast cells (left) with the cognate T-cell receptors (right), including; CD200/CD200R, PD-L1/PD-1, CTLA-4, CD47 and Galectin-9/Tim-3. Currently clinical trials are exploring the therapeutic potential CD200, PD-1 and CTLA-4 with the mAb’s Samalizumab, Pembrolizumab/Nivolumab and Ipilimumab respectively. CD47 mAb therapy is at a preclinical stage.

The immune checkpoint story is becoming complex for AML, since several studies report that that these immune surveillance pathways function in tandem. For example, the Galectin-9/Tim-3 immune checkpoint has been shown to cooperate with the PDL1/ PD-1 pathway in AML, which is central in driving CD8+ T-cell exhaustion. Thus targeting both Tim-3/Galectin-9 and PD-L1/PD-1 was required to achieve significant cyto reduction and improved survival in pre-clinical models [2]. Another study illustrated that the CD200/CD200R and PD-L1/PD-1 immune checkpoints are also linked in AML. In this instance, activation of CD200R was sufficient to drive the up regulation of PD-1 on memory CD8 T-cells. Further analysis relaveled that targeting both CD200/CD200R and PD-L1/ PD-1 immune checkpoints were required to significantly restore memory CD8 T-cell function [3].

This finding indicates that these immune checkpoints may be important in driving AML relapse. Indeed, this notion is realised in a current phase-II trial (NCT02708641), which is assessing the effects of the PD-L1/PD-1 checkpoint inhibitor ‘Pembrolizumab’ as a post-remission treatment in AML. The potential use of targeting the immune checkpoint in post-remission is also recognised in findings published from a recent phase-IB/II study involving the PD-L1/PD-1 checkpoint inhibitor ‘Nivolumab’. The report shows that when used in combination with azacytidine for relapsed AML, Nivolumab showed an improvement in prognosis and increased numbers of effectors CD8+ T-cells [4]. Given that the PD-L1/ PD-1 checkpoint functions in combination with other immune checkpoints, the question now is to understand whether targeting a combination of these pathways in AML performs well clinically.

To this end, results from a current phase-II trial (NCT02530463) targeting PD-L11/PD-1 with Nivolumab in combination with the CTLA-4 inhibitor ‘Ipilimumab’ in MDS are eagerly awaited. As are the next generation of therapeutic mAb’s such as ‘Samalizumab’ (Alexion Pharmaceuticals), which is designed to target the CD200/ CD200R checkpoint. The potential for immune checkpoint therapy in AML is clearly evident, however the interplay between these pathways needs full appreciation and placed into context with molecular stratification and standard therapy (Figure 1).

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Lupine Publishers | Total Petroleum Hydrocarbon Degradation and BTEX Leaching in Soils after Application of Oil-Base Drilling Mud: Impact of Application Rate, Rainfall Regime, and Time

 Lupine Publishers | Journal of Oceanography and Petrochemical Sciences

Abstract

Increases in oil and gas drilling have resulted in large quantities of oil base "mud" (OBM) to be disposed of. Land application of OBM to agricultural land is a common disposal technique that presents agronomic and environmental challenges since the material is rich in total petroleum hydrocarbons (TPH). Leaching of lower molecular weight hydrocarbons, mainly benzene, toluene, ethylbenzene, and xylene (BTEX), is a concern due to their relatively low octanol: water partition coefficients. The objective of this study was to determine the effect of rainfall regime and TPH loading rate on TPH degradation and BTEX leaching after OBM application. An OBM was characterized for TPH, BTEX, and trace metals. A soil column study was conducted where OBM was applied at five loading rates (0, 22,000, 45,000, 67,000, and 90,000 kg TPH ha^-1) and was subjected to four moisture regimes. OBM samples were taken at day 0, 7, 30, 60, and 91 to monitor TPH degradation. Leachate samples were taken at day 0, 14, 28, 35, 49, 56, 63, 77, and 84 to monitor electrical conductivity (EC), pH, metal concentrations, and BTEX concentrations. After 60 days, a maximum TPH degradation of 35% was measured. Leachate BTEX concentrations increased as TPH application rate increased and was mostly undetectable by day 28. Leachate EC increased over time and with increasing TPH rates. TPH rate had no effect on leachate pH. OBM loading rates had the greatest effect on TPH degradation and BTEX leaching. Under our experimental conditions, little risk of BTEX leaching from land applied OBM was observed.

Abbrevations: OBM: Oil-Base Mud; TPH: Total Petroleum-Based Hydrocarbons; BTEX: Benzene, Toluene, Ethylbenzene, and Xylene; OCC: Oklahoma Corporation Commission (OCC); EC: Electrical Conductivity

Introduction

Currently, the United States is experiencing a boom in oil and gas drilling. In 2013, there were approximately 910,000 and 4,900 onshore and offshore oil and natural gas wells, respectively, that produced nearly 16 million m³ of oil and 665 billion m³ of natural gas [1]. When drilling activity increases, an increase in the production of drilling wastes result, specifically drilling fluids and drill cuttings (i.e. "mud"). A study conducted by the American Petroleum Institute in 1995 estimated that around 150 million barrels of drilling wastes were generated on-shore in the United States alone [2]. In the oil and gas industry, drilling mud is utilized to help cool the drill bit, maintain borehole pressure, and aid in bringing drill cuttings to the surface where the fluids and cuttings can then be separated [3]. Drilling muds are composed of a base liquid (water or diesel fuel) with other potential additives such as bentonite, barium sulfate, cotton seed hulls, and calcium hydroxide, which may be used for specific drilling conditions [4]. When diesel fuel is the base solution for drilling mud, the mud is called "oil base mud" (OBM). OBM is typically utilized when drilling depths exceed 1500 m or during horizontal drilling. OBM is re-used by drillers for as long as possible due to the high cost of production.

Once the OBM is spent and can no longer be used in drilling, it must be properly disposed of. On average, 340 m³ of OBM are produced from a typical southeastern Oklahoma natural gas well at depths ranging from4200-5200 m deep [5]. Some of the products added to the mud may be harmful, and therefore need to be properly handled [6]. Hence, there are two options for mud disposal: land application and burial. Burial of the waste can occur onsite in "reserve pits" or at commercial facilities. In general, onsite reserve pits are only allowed for water-base mud, not OBM. Land application is the most common method of OBM disposal in Oklahoma. The purpose of land applying OBM is to allow soil microorganisms to degrade petroleum hydrocarbons (i.e. "total petroleum hydrocarbons"; TPH). In Oklahoma, regulations for the land application of OBM are controlled by the Oklahoma Corporation Commission (OCC). OBM land application rates are limited based on loading of TPH, chlorides, and solids (Oklahoma administrative code and register, Title 165:10-7-26). Furthermore, the OCC requires that OBM be mixed with a bulking material such as lime or gypsum, at a ratio of 3:1 OBM: bulking material. Although TPH is taken into account when applying OBM, there is still a potential for the over-application of low molecular weight hydrocarbons: benzene, toluene, ethylbenzene, and xylene (BTEX). Benzene is a known human carcinogen and all BTEX components are known to cause neurological effects [7]. BTEX chemicals are prone to leaching due to their relatively low octanol: water partition coefficients [8] and therefore pose a threat to drinking water. In addition to loading limits, there are also several site suitability requirements such as soil texture, depth to groundwater and limiting layers, slope, soil sodium concentrations, and proximity to surface waters. Although thousands of hectares are currently receiving OBM, there has been relatively little research conducted on the degradation of TPH and the leaching of BTEX after land application of OBM.

Uncontrolled application rates could lead to soil TPH concentrations that would be detrimental to soil and water quality leading to environmental issues. Penet et al. [9] conducted a study that examined biodegradation of hydrocarbons in the soil and found that microbes degraded the straight chained hydrocarbons faster than the branched chained hydrocarbons. Dou et al. [10] conducted a study focused on anaerobic BTEX degradation under nitrate reducing conditions and determined that BTEX could be biodegraded to undetectable concentrations in 70 days if initial concentrations of BTEX were ≤ 100 mg kg'¹ soil. Very few studies have dealt with TPH degradation and BTEX leaching in soils after land application of OBM. Due to the hazardous risks of TPH, specifically BTEX toxicity to humans and to the environment, there is a need to examine TPH degradation and BTEX leaching in soils after land application of OBM under different scenarios such as multiple loading rates and moisture regimes. Thus, the objective of this study was to determine the impact of rainfall regime and TPH loading rates from OBM application on TPH degradation and BTEX leaching.

Materials and Methods

A soil column study was conducted in Stillwater, Oklahoma in a temperature controlled greenhouse. Soils were contained in 240 aluminum soil columns that were 30.5 cm tall and 7.6 cm in diameter. Columns were filled 15.2 cm with a sandy loam soil from Perkins, Oklahoma. The soil series used in this experiment was Dougherty loamy fine sand (Loamy, mixed, active, thermic Arenic Haplustalfs). Glass wool and aluminum screen with a 7.6 cm hose clamp was placed on the bottom of all columns in order to prevent soil from leaching out. The experimental design was a randomized complete block with factorial structure. There were three replications of each treatment. The OBM sample was characterized for pH, electrical conductivity (EC), total soluble salts (TSS), and total solids content, total and water extractable metals and total chloride. OBM pH and EC were measured using pH and EC probes with a solid: solution ratio of 1:5 and an equilibration time of 45 min. The OBM was analyzed for total P, K, Mg, Ca, Na, Mn, Cu, Fe, Zn, S, Al, Ni, B, As, Cd, Cr, Ba, Pb, and Mo using the EPA 3050 acid digestion method followed by solution analysis with inductively coupled argon plasma analyzer [ICP-AES; Spectro Ciros, Mahwah, NJ]. Water extractable metals and total chloride were extracted with de-ionized (DI) water using a 1:10 solid: solution ratio for 1 hour followed by ICP-AES analysis on the metals and colorimetric flow-injection analysis (Lachat Quick Chem 8000, Loveland, CO) for chloride.

Prior to the application of OBM, BTEX and TPH concentrations were analyzed. Total petroleum hydrocarbons were extracted with hexane at 1:10 solids: solvent ratio, plus addition of 0.5 g Na₂SO₄ for 5 minutes on a reciprocating shaker followed by centrifugation for 10 minutes. Five mL of the resulting supernatant was equilibrated for 2 minutes with 1 g of silica gel in a glass tube for removal of polar organic compounds. The solution was then analyzed for TPH using infrared spectroscopy (ASTM method D 7066) with the Infra Cal TOG/TPH analyzer (model HATR-T2, Wilks Enterprise Inc., East Norwalk, CT). Random samples were duplicated and check samples were utilized in order to assure precise and accurate results. Initial benzene, toluene, ethylbenzene, o-xylene, m, p-xylene and TPH concentrations were 2.65, 23, 35, 64, 94, and 161,558 mg kg^{- 1}. Treatments included five TPH (i.e. OBM) loading rates and four rainfall regimes.

Soil columns were harvested for OBM analysis of TPH at four different times. Oil-base mud was applied onto an aluminum screen which rested on top of the soil that allowed soil to contact the OBM, yet prevented mixing and dilution of the applied OBM TPH with the soil. This allowed for removal of the OBM throughout the incubation in order to test for TPH degradation. Oil-base mud loading rates were applied to achieve a TPH application of 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha-1. Each column was treated with one leaching event per month which consisted of application of 1.5 pore volumes of tap water. In this study, the term "moisture regime" indicates the number of non-leaching wetting events that occurred per month. Moisture regime levels 4, 3, 2, and 1 had 3, 2, 1, and 0 non-leaching wetting events per month, which consisted of 0.5 pore volumes of tap water. These non-leaching wetting events are important because they can move soluble constituents within the column, but not out of the column, as well as provide moisture for microorganisms that may degrade TPH. Collected leachate was analyzed for benzene, toluene, ethylbenzene, and xylene using the EPA 8021B method followed by solution analysis with gas chromatography with a photo ionization detector (GC-PID). In addition, leachate was also analyzed for Na, Ca, Mg, K, SO4, B, P, Fe, Zn, Cu, Mn, Al, Mo, As, Cd, Co, Cr, Pb, and Ba via ICP-AES. OBM was harvested on top of the aluminum screens at 7, 30, 60, and 90 days after application and analyzed for TPH concentrations (mg TPH kg mud^-1) with the Wilks TOG/TPH IR Analyzer. The BTEX concentrations in harvested OBM samples were measured 7 days after application.

Statistics

Analyses of Variance (ANOVA) methods were utilized in PROC GLM [11] to analyze the effects of OBM loading rates and moisture regimes on TPH degradation and BTEX leaching. When the main effects or interactions of OBM loading rates and moisture regimes were significant, treatment means were separated using pair wise comparisons via Duncan's multiple range test. Statistical decisions were made at a=0.05.The data analysis for this paper was computed using SAS software.

Results and Discussion

Background Soil Properties

Table 1: Background chemical analysis of the soils used in the BTEX leaching column study.

The soil utilized in the BTEX leachate study was a sandy loam texture (Table 1) which has great potential for the leaching of soluble constituents. The OCC states in the Oklahoma administrative code and register, Title 165:10-7-26 that OBM must be incorporated into the soil after application; incorporation of the OBM leads to increased mixing (dilution) of the OBM into the soil and faster hydrocarbon degradation. Due to the large hydraulic conductivity of the sandy loam soil and the fact that the OBM was not incorporated made this study a worst-case scenario for land application of OBM with respect to BTEX leaching and hydrocarbon degradation. The background soil had N-NO3-, P, and K concentrations of 8, 6, and 147 kg ha^-1, respectively. Soil pH was 6.8 and was in the optimal range for microbial degradation and limiting metal migration in the soil [12].

Background Oil-Base Mud Properties

Table 2: Characterization of the raw (solids plus liquid) and the water extractable portion of the oil-base mud (OBM) used in the BTEX leaching column study. All water extraction results were obtained by using a 1:10 solids to DI water ratio unless otherwise noted.

The initial chemical analysis of the raw OBM and water extractable portion are listed in Table 2. The raw OBM had an initial TPH concentration of 161,558 mg TPH kg'¹ and consisted of 74% solids. The raw OBM had a benzene concentration of 2.65 mg kg^-1 which was higher than the inhalation limit of 0.8 mg kg^-1 established by the U.S. EPA [13] and for risk to groundwater by leaching (0.03 mg kg^-1; [14]). The water-soluble benzene concentration (0.015 mg L^-1) was higher than the groundwater limit of 0.005 mg L^-1 set by the Oklahoma Guardian [15]. Calcium was the dominant cation in both the raw solid and water extractable portion of the OBM. Chloride and sulfate were the two most abundant anions in the water extractable portion of the OBM. All heavy metal concentrations (Zn, Cu, Ni, As, Cd, Cr, and Pb) measured in the raw OBM were below EPA 503 thresholds for "exceptional quality" bio solids, indicating that there is only slight risk of metals contamination from land application of this OBM sample [16]. In fact, heavy metal concentrations in the OBM were in the normal range typically found in soils [17].

Degradation of total petroleum-based hydrocarbons with oil-base mud application

The main effects of TPH rate, moisture regime, sampling day (i.e. time), and the two-way interaction of rate*day were significant at α = 0.05 for TPH concentration (mg kg^-1 OBM). An ANOVA table with the complete list of main effects and interactions for TPH concentration (mg kg^-1 OBM) are listed in Table 3.The main effect of TPH application rate (kg TPH ha^-1) on overall TPH concentration (mg TPH kg’¹ OBM) was significant (P ≤ 0.05) and is shown in more detail in Table 4 (averaged across all sampling times and moisture regimes). TPH application rate 1 (22,000 kg TPH ha^-1) had a significantly lower TPH concentration than all other rates and was closely followed by application rate 2 (45,000 kg TPH ha^-1) which was also significantly different than all other application rates. Application rate 3 (67,000 kg TPH ha^-1) and rate 4 (90,000 kg TPH ha^-1) had the highest TPH concentrations but were not significantly different than each other. The decreased TPH degradation displayed by application rates 3 and 4 were likely due to reduced contact between OBM and the soil surface (i.e. lower OBM: soil contact area), resulted in less TPH degradation [18,19].

Table 3: Mean total petroleum hydrocarbon (TPH) concentrations (mg kg^-1 OBM) in the surface applied OBM averaged across moisture regime and sampling day for each TPH application rate. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha^-1. The treatments were subjected to four different moisture regimes. OBM was sampled at 0, 7, 30, 60, and 90 days after application. Uppercase letters represent mean separation of TPH concentration (mg TPH kg^-1 mud) between TPH rates. Statistical decisions were mad at P = 0.05.

Table 4: Mean total petroleum hydrocarbon (TPH) concentration (mg TPH kg^-1 OBM) at each sample day averaged over moisture regime and TPH application rate. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha^-1. The treatments were subjected to four different moisture regimes. OBM was sampled at 0, 7, 30, 60, and 91 days after application. Uppercase letters represent mean separation of TPH degradation (mg TPH kg^-1 OBM) between all sample days. Statistical decisions were made at P = 0.05.

Table 5: Mean total petroleum hydrocarbon (TPH) concentration (mg TPH kg^-1 OBM) averaged across moisture regime and compared between sample day and TPH application rate. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha^-1. The treatments were subjected to four different moisture regimes. OBM was sampled at 0, 7, 30, 60, and 91 days after application. Uppercase letters represent mean separation of TPH concentration between sampling days at each TPH application rate. Lowercase letters represent mean separation of TPH concentration between TPH application rates at each sampling day. Statistical decisions were made at P = 0.05.

The main effect of sampling day (time) on overall TPH concentration was significant (P ≤ 0.05) and is shown in further detail in Table 5 (averaged across all application rates and moisture regimes). As time increases, a significant decrease in TPH concentration was observed until day 60. Day 60 and 91 had a significantly lower TPH concentration than all previous sampling days; however there was no significant difference between day 60 and 91. Figure 1 and Table 6 illustrate the insignificant degradation between day 60 and 91 for each application rate. There was a large decrease in TPH concentration for all TPH rates up until day 60. This plateau effect in degradation is likely due to the consumption of microbial nutrients, probably nitrogen, which inhibited further biodegradation of hydrocarbons. There were no significant differences in TPH concentrations between TPH application rates at day 0 or 7. Significant difference between TPH rates occur at day 30 and continue through day 91. TPH application rate 1 had the lowest TPH concentration followed by rate 2 and rate 3, while rate 4 is not significantly higher than rate 3. The TPH application rates 1 and 2 possess a higher proportion of OBM in contact with the soil surface, which may have improved degradation. Not only do TPH rates 3 and 4 have lower OBM to soil contact ratios, which limited microbial degradation of hydrocarbons. TPH concentrations for all biodegradation of TPH, but the excessive loading rates could have application rates at day 90 were higher than the Oklahoma Guardian impeded oxygen flow into the soil which may have further restricted thresholds established for non-sensitive soils (46,000 mg kg^-1; [5]).

Table 6: Mean total petroleum hydrocarbon (TPH) concentration (mg TPH kg^-1 OBM) averaged across moisture regime and compared between sample day and TPH application rate. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha^-1. The treatments were subjected to four different moisture regimes. OBM was sampled at 0, 7, 30, 60, and 91 days after application. Uppercase letters represent mean separation of TPH concentration between sampling days at each TPH application rate. Lowercase letters represent mean separation of TPH concentration between TPH application rates at each sampling day. Statistical decisions were made at P = 0.05.

Figure 1: Mean remaining total petroleum hydrocarbon (TPH) concentrations in the OBM in mg kg-1 OBM. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha-1. The treatments were subjected to four different moisture regimes. OBM was sampled at 0, 7, 30, 60, and 91 days after application. TPH values are for each sampling day and TPH application rate averaged over moisture regime.

Changes in BTEX concentrations in the oil-base mud

The main effect of sampling day on OBM BTEX concentration was significant at α = 0.05. The main effect of TPH rate and the two-way interaction of rate*day was also significant at α = 0.05 and is shown in Table 7, which provides a complete list of ANOVA results for the main effects and interactions. Table 8 shows a significant decrease in BTEX concentration (mg kg^-1) for all BTEX constituents between day 0 and 7. These decreases in BTEX concentrations over for inhalation and groundwater risks.

Table 7: ANOVA results for oil-base mud (OBM) benzene, ethylbenzene, toluene, o-xylene, and m, p-xylene (BTEX) concentrations in mg kg^-1 OBM for the BTEX leaching column study. Results are significant when (Pr ≤ 0.05).

Table 8: Mean benzene, ethylbenzene, toluene, o-xylene, and m, p-xylene (BTEX) concentrations (mg kg^-1 OBM) averaged across moisture regime and total petroleum hydrocarbon (TPH) application rate and compared between each sampling day. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha^-1. The treatments were subjected to four different moisture regimes. OBM BTEX was sampled at 0, and 7 days after application. Lowercase letters represent mean separation for BTEX degradation (mg kg^-1 OBM) between each sampling day. Statistical decisions were made at P = 0.05.

The main effect of TPH application rate (kg TPH ha^-1) was significant (Pr ≤ 0.05) for OBM BTEX concentration (mg kg’¹) for every BTEX constituent except for benzene (Table 9), when averaging over the two sampling days. TPH application rate 1 had significantly lower concentrations of ethylbenzene, toluene, o-xylene, and m, p-xylene than all other TPH application rates. The TPH application rate 2 had the next lowest concentration values, rates. TPH application rates 3 and 4 had the highest concentrations of BTEX and were both significantly higher than TPH rates 1 and 2, although not significantly different from each other. Similar trends were noted regarding TPH concentrations (Table 4). Higher BTEX concentrations (i.e. lower degradation) at the highest application rates (3 and 4) likely occurred for the same reasons as previously discussed for TPH degradation.

Table 9: Mean benzene, ethylbenzene, toluene, o-xylene, and m, p-xylene (BTEX) concentrations(mg kg^-1 OBM) at each total petroleum hydrocarbon (TPH) application rate for the BTEX leaching column study. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha^-1. The treatments were subjected to four different moisture regimes. OBM BTEX was sampled at 0, and 7 days after application. Lowercase letters represent mean separation for BTEX concentration (mg kg^-1 OBM) between each TPH rate. Statistical decisions were made at P = 0.05.

Concentrations and loads of BTEX leached from applied oil-base mud

The main effects of TPH rate, moisture regime, leaching event, and the interactions between each are shown in Table 10.The main effect of leaching event was significant (P ≤ 0.05) for BTEX leachate concentrations (μg L^-1) and is shown in added detail in Table 11, averaged over TPH application rate and moisture regime. Significantly higher concentrations of BTEX were measured at leaching event 1 when compared to leaching events 2 and 3. For every BTEX constituent except for o-xylene, leaching event 1 was the only leaching event in which detectable levels of BTEX were measured in leachate. All BTEX concentrations at leaching event 1 were low (< 5 ng L^-1) and below the threshold limits for drinking water established by EPA 816F regulations. It is noteworthy to mention that each leaching event is an average of three leachate sampling days; a higher leaching event number (e.g. leaching event 1, 2, and 3) also indicates a greater amount of time that has occurred since application of OBM. No BTEX was detected in leachate from leaching events 2 and 3 because it was either mostly volatized, degraded, or sorbed to soil surfaces.

Table 10: ANOVA results for benzene, ethylbenzene, toluene, o-xylene, and m, p-xylene (BTEX) leachate concentrations in (μg L^-1) for the BTEX leaching column study. Results significant when (Pr≤ 0.05). LE = "leaching event".

Table 11: Mean benzene, ethylbenzene, toluene, o-xylene, and m, p-xylene (BTEX) leachate concentrations (μg L^-1) averaged over total petroleum hydrocarbon (TPH) application rate and moisture regimes and compared between leaching events. For the BTEX leaching column study. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha^-1. The treatments were subjected to four different moisture regimes which had one leaching event per month. Lowercase letters represent mean separation between leaching events for each BTEX constituent concentration (μg L^-1). Statistical decisions were made at P = 0.05. LE = "leaching event".

The main effect of moisture regime was significant (P ≤ 0.05) for BTEX leachate concentrations (μg L^-1) and is presented in further detail in Table 12. Moisture regime 1 (0 wetting events per month) showed significantly higher BTEX concentrations than all other moisture regimes that received non-leaching wetting events. The leachate concentrations of each BTEX constituent at moisture regime 2, 3, and 4 were statistically the same. However, the highest concentrations of BTEX observed in the leachate for moisture was averaged over the first sampling day of each month (day 0, 35, and 63). Specifically, moisture regime 1 was sampled (i.e. leached) on day 0, 35, and 63 and only had BTEX concentrations above 0 ng L^-1 on day 0, which were the highest for the entire study. The highest BTEX leachate concentrations from day 0 thus caused moisture regime 1 to be significantly higher than the other moisture regimes. Again, this shows the importance of time on BTEX degradation, volatilization, and sorption to the soil.

Table 12: Mean ethylbenzene and toluene leachate concentrations (μg L^-1) averaged over total petroleum hydrocarbon (TPH) application rate and leaching events and compared between moisture regimes. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha^-1. The treatments were subjected to four different moisture regimes which had one leaching event per month. Uppercase letters represent mean separation for ethylbenzene and toluene between moisture regimes. Statistical decisions were made at P = 0.05.

Table 13: Mean benzene and toluene leachate concentrations (μg L^-1) at moisture regime one comparing total petroleum hydrocarbon (TPH) application rates and leaching events for the BTEX leaching column study. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha^-1. The treatments were subjected to four different moisture regimes which had one leaching event per month. Uppercase letters represent mean separation of benzene and toluene leachate concentrations between TPH application rates at each leaching event within moisture regime one. Lowercase letters represent mean separation of benzene and toluene leachate concentrations between leaching events at each TPH application rate within moisture regime one. Statistical decisions were made at P = 0.05.

The three-way interaction of TPH rate by moisture regime by leaching event was significant (P ≤ 0.05) for benzene and toluene leachate concentrations (ng L^-1; Table 13). Moisture regime 1 is the only regime shown in Table 13 because this was the only moisture regime that had significant amounts of BTEX in the leachate (Table 12). A general trend of increasing concentrations of benzene and toluene in leachate was observed as the rate of TPH application increased, for leaching event 1. Leaching events 2 and 3 have no detectable concentrations of benzene or toluene in the leachate. By the time leaching events 2 and 3 occurred, all amounts of benzene and toluene were lost via microbial degradation, volatilization, and sorption to the soil, or through leachate. The main effects of TPH application rate, moisture regime, and leaching event on BTEX leachate loads and the interactions between variables are shown in Table 14. The three-way interaction of TPH rate by moisture regime by leaching event was significant (P ≤ 0.05) for all constituents of BTEX except for o-xylene and is shown in further detail in Table 15. Moisture regime 1 is the only moisture regime listed due to the fact that this was the only moisture regime that contained detectable concentrations in leachate (Table 12). For leaching event 1, a general trend of increasing BTEX loads is evident with greater TPH application rates.

Table 14: ANOVA results for benzene, ethylbenzene, toluene, o-xylene, and m, p-xylene (BTEX) leachate loads (μg) for the BTEX leaching study. Results were significant when (Pr ≤ 0.05). LE = "leaching event".

Table 15: Mean benzene, ethylbenzene, toluene, o-xylene, and m, p-xylene (BTEX) leachate loads at moisture regime one, comparing TPH application rates and leaching events. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha^-1. The treatments were subjected to four different moisture regimes which had one leaching event per month. "┼-"- o-xylene was not significant at P = 0.05. Uppercase letters represent mean separation of BTEX loads (μg) between TPH application rates at each leaching event, for moisture regime one. Lowercase letters represent mean separation of BTEX loads (^g) between leaching events at each TPH rate, for moisture regime one. Statistical decisions were made at P = 0.05.

Leachate electrical conductivity and pH

The main effects of TPH application rate, moisture regime, and leaching event on leachate EC, and interactions between variables are shown in Table 16. The two-way interaction of TPH rate by leaching event was significant (P ≤ 0.05) for leachate EC (mS cm^-1) and is shown in greater detail in Table 17. A significant increase in leachate EC is observed with increasing TPH application rates for each leaching event. As TPH rate increased, the total amount of salts applied from the OBM (Table 2) was greater, which led to higher leachate EC values as the salts dissolved with the leaching water? A general trend of increasing leachate EC with leaching event was observed for each TPH application rate except for the control which received no amendment. The leachate EC can serve as an indicator of the mobility of soluble species in the solution and can be used to indicate the leaching front for soluble species. Due to the fact that leachate EC continues to increase at each leaching event while BTEX concentrations do not (Table 11), this confirms that the BTEX has either degraded or sorbed to the soil or was lost via volatilization (Figure 2).

Figure 2: Mean remaining total petroleum hydrocarbon (TPH) concentrations in oil-base mud (mg kg-1 OBM) for the BTEX leaching study. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha-1. The treatments were subjected to four different moisture regimes. OBM was sampled at 0, 7, 30, 60, and 91 days after application. Remaining TPH concentrations are shown for each TPH application rate, and sampling time, and are averaged over moisture regime.

Table 16: ANOVA results for leachate electrical conductivity (EC; mS cm^-1) and pH for the BTEX leaching column study. Results were significant when (Pr ≤ 0.05). LE = "leaching event".

Table 17: Mean leachate electrical conductivity (EC; mS cm^-1) averaged across moisture regime comparing total petroleum hydrocarbon (TPH) application rates and leaching events (LE). OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha^-1. The treatments were subjected to four different moisture regimes which had one leaching event per month. Uppercase letters represent mean separation of leachate EC (mS cm^-1) between leaching events at each TPH application rate. Lowercase letters represent mean separation between TPH application rates at each leaching event. Statistical decisions were made at P = 0.05.

The main effects of moisture regime and leaching events, and the interactions of TPH rate*leaching event and moisture regimes*leaching events were significant at a = 0.05 for the pH of the leachate. Table 16 provides a complete list of ANOVA results for all main effects and interactions for leachate pH. The main effect of leaching event was significant (P ≤ 0.05) for leachate pH and is shown in more detail in Figure 3. There were significant increases in leachate pH with each additional leaching event. However, TPH application rate had no effect on leachate pH because the pH of the control leachate also had significant increases in pH with each additional leaching event (Figure 4). The increase in leachate pH across the leaching events was likely due to the alkaline pH (8.23) of the water that was used to leach the soil columns. As time progressed throughout leaching events, the leachate pH approached the higher pH values of the water that was used to leach the soil columns(Table 18).

Figure 3: Mean leachate pH comparing each leaching event for the BTEX leaching column study. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha-1. The treatments were subjected to four different moisture regimes which had one leaching event per month. Leachate pH values are averaged over total petroleum hydrocarbon (TPH) rate and moisture regimes. Uppercase letters represent mean separation of leachate pH between leaching events. Statistical decisions were made at P = 0.05.

Figure 4: Mean leachate pH of the control (no OBM) comparing each leaching event for the BTEX leachate column study. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha-1. The treatments were subjected to four different moisture regimes which had one leaching event per month. Leachate pH was averaged over moisture regimes. Uppercase letters represent mean separation of leachate pH between leaching events. Statistical decisions were made at P = 0.05.

Table 18: Mean leachate pH values averaged over total petroleum hydrocarbon (TPH) rate, comparing moisture regimes and leaching events. OBM loading rates were applied at 90,000, 67,000, 45,000, 22,000, and 0 (control) kg TPH ha^-1. The treatments were subjected to four different moisture regimes which had one leaching event per month. Uppercase letters represent mean separation of leachate pH between moisture regimes at each leaching event. Lowercase letters represent mean separation of leachate pH between leaching events at each moisture regime. Statistical decisions were made at P = 0.05.

Summary and Implications

The OBM was applied in this study at rates much greater than what is allowed by current OCC regulations, and were not incorporated in order to examine the worst-case scenario regarding environmental impact. The OBM used in this soil column leachate study did not possess heavy metal concentrations beyond normal soil concentrations. Benzene concentrations in the raw OBM (2.65 mg kg^-1) were higher than the EPA threshold limits established for inhalation (0.8 mg kg^-1) and leaching to groundwater (0.03 mg kg ^-1). Regardless, by day 7, the BTEX concentration in the mud had decreased by 88% and benzene only leached out during the first leaching event which produced benzene concentrations that were acceptable according to USEPA drinking water standards. This was surprising due to the high benzene content in the OBM, which greatly exceeded USEPA risk levels for groundwater leaching, the short column length, and high hydraulic conductivity of the soil utilized. An explanation for this is found in closer examination of the assumptions made in creation of the USEPA concentration thresholds for leaching to groundwater i.e. the assumption that there is no degradation of benzene and that the entire soil profile contains benzene from the surface to the groundwater interface. As expected, increased OBM application rates resulted in higher leachate benzene concentrations.

All leachate BTEX concentrations were below drinking water thresholds. No trace metals were detected in leachate. Part of the reason for non-detectable BTEX concentrations in leachate after the initial leaching event on day 0, was due to 88% degradation of BTEX in the applied OBM by day 7. Based on the results of this study, there is little risk of BTEX leaching to ground water through land application of OBM. However, it is unknown if this lack of BTEX movement was due to extreme soil sorption, degradation, or volatilization. The main effect of TPH application rate had the greatest effect on TPH degradation, BTEX concentrations in the OBM, leachate BTEX concentrations and loads, and leachate EC. As the rate of TPH increased, a decrease in hydrocarbon degradation was observed due to the higher OBM to soil ratio that limited oxygen inflow and microbial degradation. A plateau effect on biodegradation of TPH was seen at day 60 and continued throughout day 91. At that point, we hypothesize that the microorganisms had likely consumed all of the nutrients and could no longer biodegrade the TPH.

Therefore, applying a source of fertilizer and increasing the surface area to volume ratio of the OBM via disking or using a bulking agent is important when considering microbial degradation of TPH. During the study, the maximum TPH degradation that occurred was 35%, which occurred from the lowest TPH application rate. Leachate EC increased as TPH rate increased due to higher loads of soluble salts. Leachate EC also increased at each leaching event as opposed to the decreasing BTEX concentrations with additional leaching event, which confirmed that the BTEX had volatilized, sorbed to the soil, or degraded. The main effect of TPH rate had no effect on leachate pH. Further studies should be conducted in order to quantify BTEX volatilization that may occur with land application of OBM, and deter mine if there is any possible human health risks associated with any potential volatilization.

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Lupine Publishers | Towards a Corpus of The Inscriptions of Ottoman Buildings in Greece

 Lupine Publishers | Journal of Anthropological and Archaeological Sciences

Abstract

The amount of surviving inscriptions from the Ottoman Times in Greece is astonished. This paper is the first ever study announces these inscriptions throughout Greece in a quantitative approach. Through statistical methods, this research surveys the building inscriptions, proper to each region or in Greece as a whole. This article surveyed 684 inscriptions belong to 343 Ottoman buildings all-over Greece. Considering the language and the content of these 684 inscriptions, they comprise 1788 different texts. It shows with the help of two tables along with their charts with type, building function and region indexes the criteria of classification of these inscriptions considering the most common approaches comprising language, function, content, patron, stylistic features and region. It is also analyzing the surviving inscriptions of the Ottoman buildings in Greece considering these criteria with statistic evidences. The paper concludes with a suggested methodology in cataloguing the corpus of the inscriptions of Ottoman buildings in Greece.

Keywords: Inscription; Ottoman; Balkan; Greece; Epigraphy; Corpus

Introduction

The Ottoman existence in the present-day Greece began in 1361 AD, when the Ottomans took possession of Didymoteichon. The Ottomans ruled the present-day Greek territories for periods almost ranging between three and five centuries as the case in Thrace, Macedonia and Thessaly. During that period thousands of buildings were constructed under the Ottomans’ patronage throughout Greece. Though a large number of Ottoman architectural heritage in Greece has been demolished, due to different factors, still the extant Ottoman buildings in Greece represent, as a whole, one of the biggest well-preserved and varied collection of Ottoman architecture in the Balkans [1].

One of the most characteristics of Islamic art and architecture is the extensive use of lettering. The Ottoman art and architecture were no exception. Though, a large number of Ottoman inscriptions in Greece were lost, still the preserved ones represent, as a whole, one of the biggest well-preserved and varied collection of Ottoman inscriptions in the Balkans.

Inscriptions related to Ottoman presence in Greece could be classified into three main categories:

a) Building inscriptions.

b) Tombstones

c) Artifacts and numismatics inscriptions.

The latter group is very interesting and did not gain the deserved attention of the scholars yet. It basically presented via the objects including jewellery, swords, furniture, tools and coins that are found either exhibited or stored in the museums throughout Greece with special reference to the Numismatics and Benaki Museums at Athens, Museum at Arslan Pasha Mosque (Figure 1) of Ioannina, the Historical Museum (Figure 2) at Iraklion (Crete) and the Archaeological Museum (Figure 3) at Drama (Northern Greece).

Ottoman tombstones in Greece forming one of the most plenteous collections in the Balkans. Many historic cemeteries of hundreds tombstones are found in Greece especially in Komotini, Xanthi, Crete, Rhodes, Kos and Chios. Some collections are well documented as the case of Komotini [2], Rethymno (Crete) [3], but the others are still unknown. Some groups of tombstones are gathered in a dangerous way which may destroy them as in Iraklion (Figure 4).

Figure 1: A group of Ottoman swords exhibited in the museum inside the Arslan Pasha Mosque of Ioannina (@ Ahmed Ameen 2008).

Figure 2: Ottoman numismatics exhibited in the Historical Museum at Iraklion (@ Ahmed Ameen 2016).

Figure 3: Ottoman numismatics exhibited in the Historical Museum at Drama (@ Ahmed Ameen 2008).

Figure 4: A group of Ottoman tombstones in Iraklion (@ Ahmed Ameen 2016).

This research compiles only the inscriptions of the first category i.e. building inscriptions. This study counted 684 inscriptions related to 343 buildings throughout Greece. Considering the language and the content of these 684 inscriptions, they comprise 1788 different texts. For example, one inscription may include two or three different texts: a qur’anic quotation, and/or an invocation, and foundation text. Also, some inscriptions are bilingual or trilingual [4].

This paper provides a statistic inventory of the extant inscriptions of the ottoman buildings in Greece. Moreover, notes some considerations on this epigraphic material discussing their importance, numbers, categories and the different supposed ways of classification.

Classification of Inscriptions

Generally, Islamic inscriptions are classified according to multiple inputs, including language, historical period, calligraphy features, raw material where the inscription executed on, methods of execution, framework or general design of inscriptions, content, etc. The most common approaches of classification are language, function, content, patron, stylistic features and region.

Language

The language(s) of the inscriptions on Ottoman architecture in Greece came in Arabic, Ottoman Turkish (in Arabic alphabet), Modern Turkish (in Latin), Persian, and Greek.

Most of the inscriptions came, of course, in Arabic and Ottoman Turkish. Three surviving inscriptions in Persian, as far as I know, one is preserved in the Historical Museum of Iraklion, Crete, one of the türbe of Sheikh Hortaci (St. George Church, Rotunda) at Thessaloniki, while the third is inside the Arslan Pasha Mosque at Ioannina (Figure 5). These Persian texts refer to the presence of Sufi orders within Ottoman communities in Greece in particular, and in the Balkans as a whole.

Figure 5: The Arabic-Persian inscription of the central medallion of the interior of the dome of Arslan Pasha Mosque in oannina (First publishing, @ Ahmed Ameen 2008).

Some inscriptions are also written in Greek, French and Italian, as well as in Modern Turkish; characterizing the last stage of Ottoman presence in Greece, and continued somewhat after the end of the ottoman rule of Greece, especially in Thrace.

Arabic was the main and official language of Ottoman foundation and historic inscriptions in Greece and the Balkans during the early ottoman period, which extended from the beginning until the early 16th century [5, 6]. The language of the inscriptions became significantly Ottoman Turkish, especially since the mid-16th century, by the end of this century it became the official language of the inscriptions as well as all aspects of culture and art in the Ottoman Empire. Numbers of the existing foundation inscriptions, classified in terms of language and date, clearly reflect this hypothesis.

Complete foundation, restoration or renovation inscription consists of five main elements [7]:

a) The basmala or qur’anic quotation or invocation to God.

b) A verb representing what was done.

c) The object of the work.

d) The patron’s name (and sometimes his titles).

e) The date of construction/restoration.

If an inscription bears the date of the foundation or restoration but missed one or more of these elements, I will name it as a short foundation inscription.

There are 367 foundation/restoration inscriptions, either full or short, of the Ottoman buildings in Greece comprising 54 in Arabic, 210 in Ottoman Turkish, 60 inscriptions in Greek, 4 inscriptions in Byzantine, 3 inscriptions in modern Turkish, two inscriptions in French, 9 inscriptions representing dates recorded in numbers only, and 25 inscriptions-some represent foundation inscriptions, others are informal personal inscriptions-written in more than one language, will be studied in detail in the second part of this research, bilingual and trilingual inscriptions.

This group of Arabic foundation inscriptions (54) composes a considerable number, especially if compared to any other country in the Balkans. The content of these inscriptions provides a wealth of data concerning their contemporaneous Ottoman community.

Worth mentioning, that 50 inscriptions from the 60 Greek ones belong to fountains ‘çeşme’ were found on the island of Lesbos ‘Mytilene’ [8]. The rest 10 Greek inscriptions belong to fountains and residential buildings distributed in the towns and villages of Komotini, Xanthi, Rhodes and Crete. Though, most of the patrons of the structures that bear Greek inscriptions were Greeks and not Ottomans, but these buildings were built during the Ottoman rule influenced by the Ottoman culture; characterizing late Ottoman period in Greece. The biggest bulk of the extant non-religious inscriptions of the Ottoman buildings in Greece is surely came in Ottoman Turkish language.

Function

Studying the building inscriptions in terms of function is a common approach. The inscriptions of each category of buildings are often alike in their content. Regarding the inscriptions of Ottoman buildings in Greece, as far as concerned, are divided according to function (Table 1, Chart 1) as follows: 117 inscriptions belong to Mosques, 118 to water works (109 fountains ‘çeşme’ and ‘şâdırvân’, 2 water reservoir, 3 springs, 2 baths ‘hammams’, 1 aqueduct and 1 bridge ‘Köprü’), 20 belong to educational buildings (17 to mektep, medrese, idâdî and rüşdiye, and 3 to libraries ‘kütüphane’), 17 inscriptions belong to tekke, imaret, and zawiya, 15 inscriptions belong to fortifications, 14 inscriptions belong to mausoleums ‘türbes’, 17 inscriptions belong to houses, 7 inscriptions belong to clock-towers ‘saat kulesi’, 4 inscriptions belong to commercial building (2 khans and 2 shops), 2 inscriptions belong to courts, in addition to one inscription belongs to a prison, and one to a customs building ‘gümrük’.

Studying the inscriptions in this regard helps to detect the change in the building function and the different names of the building of almost same function over centuries. This approach is useful especially if the research covering a long period as our case study. The various names of the educational institutions on the ottoman inscriptions comprising: mektep, medrese, idâdî, rüşdiye, dârülfünun, etc. show a good example.

Generally, text follows function; thus the content of the inscriptions of the buildings belong to the same function is somewhat alike. As the case of the educational buildings, the texts usually concentrated on the highest value of learning and teaching in Islam, the prestigious position of the professors ‘müderris’ and the texts that encourage the students to learn.

Content

The epigraphic content is the most important data to study the history of any building, and its historic context. Analyzing the content of the inscriptions is a most popular approach in epigraphic studies. The content of the epigraphic material of the buildings could be studied in many ways. Considering the extant inscriptions of the Ottoman buildings in Greece, there are six different approaches available to present the content of those inscriptions as follows:

1) Foundation/restoration (or dedicatory) inscriptions

2) Religious inscriptions

a. Qur’anic inscriptions

b. Non-Qur’anic inscriptions

3) Endowment text

4) Funerary text

5) Signatures

6) Graffiti

The above groups are not exclusive but often overlap, as the case of a foundation inscription which may also contain a qur’anic quotation and/or the signature of a craftsman.

All previous studies almost tackled only the foundation/ restoration inscriptions, following the traditional western approach that focuses on historic inscriptions underscores the history of the building and its patron(s). This approach slights religious inscriptions, though the latter form the biggest group of inscriptions, 350, existed in Greece. These 350 religious inscriptions can shed light on the meaning and function of the building; even most religious inscriptions are repeated in stereotyped formulas.

There is only one example belong to each category of endowment and funerary inscriptions. The endowment inscription is placed on the wall of Mahmoud Ağa Mosque (Figure 6) which also known as ‘Yenice Mahalle Camii’, while the funerary one is found inside the mosque of Karaca Ahmed (Figure 7) which built in 1450 and renewed in 1950 in the village of Shaheen in Xanthi.

Figure 6: An endowment “Waqffiye” inscription of Mahmud Agha Mosque at Komotini (@ Ahmed Ameen 2008).

Signature inscriptions come in both cases:

a) as a single inscription as the case of the Yeni Mosque at Thessaloniki (Figure 8), of the Italian architect Vitaliano Poselli [4], and

b) included in a foundation inscription with two distinguished examples.

The first is the subordinate Arabic foundation inscription of Sultan Mehmed Çelebi Mosque at Didymoteicho, providing the name of the famous Turkish Architect Haci İwaz “ ʿawaḍ” (Figure 9) [5]. The second is the Greek inscription of the Sultan Abdülhamid II çeşme (1301/1884) in Kalami village at Chania, Crete. It provides the name of its Greek architect Georgaraki (Figure 10) [4].

Figure 7: A funerary inscription inside the mosque of Karaca Ahmed in the village of Shaheen in Xanthi (@ Ahmed Ameen 2008).

Figure 8: A signature inscriptions of the architect of the Yeni Mosque at Thessaloniki (@ Ahmed Ameen 2009).

Figure 9: the second Arabic foundation inscription of Sultan Mehmed Çelebi Mosque at Didymoteicho (@ Ahmed Ameen 2009).

Figure 10: Both Ottoman and Greek inscriptions of the Sultan Abdülhamid II çeşme of the Kalami village at Chania (@ Ahmed Ameen 2016).

Graffiti inscriptions are incised handwritings on stone or marble that adorned many Ottoman buildings throughout Greece. They are represent the travellers’ writings and express one’s impressions and thoughts. Graffiti inscriptions come usually on the frames of the doors and windows of the buildings as the case of Fethiye Mosque at Athens, and Ishak Paşa Mosque at Thessaloniki and Ibrahim Pasha Mosque in Rhodes, and sometimes on the shafts of the colmuns of the portico as the case of Arslan Pasha Mosque at Ioannina and Sultan Süleyman Mosque in Rhodes.

Graffiti inscripions repesnet usually religious writings comprising qur’anic quotations, hadith or sayings of the Prophet Muhammad, invocations, poems, and may also recorded the name and/or the nickname of the scriber and sometime scribed a date. Graffiti inscriptions sometime are very useful and in some cases it helps to date the structure on which they are found as the case of the Fethiye Mosque at Athens [9].

Patron(s) and Craftsman

One of the most specific approaches in studying inscriptions is the patron(s) either as a person, family, position or rank, sex; to whom such inscriptions are belong. Thus we found studies entitled the inscriptions of the Sultan(s), women, architect, calligrapher, etc.

The inscriptions of the Ottoman buildings in Greece, as far as concerned, represent various patrons including Ottoman sultans themselves (Bayezid I, Mehmed Çelebi, Murad II, Bayezid II, Süleyman the Magnificent, Mustafa III and Sultan Abdülhamid II), the high ranking class (Includes the Sultans’ relatives, the Grand Vezirs, Vezirs and commanders, such as Mehmed Bey Mosque at Serres, a foundation of son of Grand Vezir Ahmad Paşa and husband of Princess Selçuk Hatun, daughter of Sultan Bayazid II) [10]. Also there are some inscriptions provides the women as patrons of Ottoman architecture, and in some cases buildings were built by husbands dedicated to their wives as the case of many fountains.

The studied inscriptions present a shifting in the patronage of the construction of mosques and medreses replacing single funded patronage of the Sultans or grand commanders or officials or wealthy individuals with the Muslim community i.e. the Muslims of a district or a village as a patron of building mosques as in the Ierapetra Mosque [11] at Crete, and the Alankuyu Mosque and the Kir Mahalle Medrese at Komotini.

Noteworthy, that wealthy Christian Greeks has also participated in constructing secular welfare buildings in late ottoman period, as the case of the Clock-tower of Naousa ‘Ağustos’ which was built by industrialist George Anastasiou Kergi in 1895 as cited in its still extant bilingual inscription (Figure 11) [4].

Figure 11: The bilingual foundation inscription of the Clock-tower of Naousa (@ https://odosell.blogspot.com/2014/04/ blog-post_9961.html [Accessed on 25 June 2018]).

Stylistic Features

Figure 12: A Kufic inscription above the lateral niche eastern the main entrance of Sultan Mehmed Çelebi Mosque at Didymoteicho (@ Ahmed Ameen 2008).

Studying the inscriptions of the Ottoman buildings in Greece in terms of style tackles their visual characteristics. Thus, it deals with the placement, height, dimensions, material on which is executed, colors, the shape of inscription as a whole, the way that the inscription is divided in, the shape of the letters and methods of execution of the inscriptions. The inscriptions of the Ottoman buildings in Greece, as far as concerned, still in lack of such this study.

It is worth noting that each one of the aforementioned items of stylistic features may be used as a clue of dating other comparable undated inscriptions. The monumental inscriptions of Sultan Mehmed Çelebi Mosque at Didymoteicho represent a very interesting example of early Ottoman inscriptions. They are executed in thuluth and Kufic (Figure 12) scripts; characterizing the transitional stage of execution the monumental inscriptions in early Ottoman period. The majority of the inscriptions of the Ottoman buildings in Greece are executed in thuluth script (jali; Turkish celi).

Region

Studying Islamic inscriptions on a geographical basis, by country, region, island or city, is a typical approach. Since the geographically norm is the standard way of documenting of inscriptions; it is also adopted here in the suggested cataloguing method for the inscriptions of the Ottoman buildings in Greece.

Figure 13: A map shows the regional units of Greece (@ https://en.wikipedia.org/wiki/Geographic_regions_of_Greece [Accessed on 16 June 2019]) [12].

Administratively, there are thirteen regional units (prefectures or peripheries) form the present-day Greece (Figure 13), comprising:

1) Attica.

2) Central Greece.

3) Central Macedonia.

4) Crete.

5) Eastern Macedonia and Thrace.

6) Epirus.

7) Ionian Islands.

8) North Aegean.

9) Peloponnese.

10) South Aegean.

11) Thessaly.

12) Western Greece.

13) Western Macedonia.

Considering the extant inscriptions of the Ottoman buildings in Greece, the focus of this research, we can divide the Greek territories geographically into five main groups (Table 1, 2; Charts 1, 2):

Table 1: Geographical proportion of inscriptions of Ottoman buildings in Greece considering their content (@ Ahmed Ameen 2019).

Chart 1: Geographical proportion of inscriptions of Ottoman buildings in Greece considering their content (@ Ahmed Ameen 2019).

Table 2: Geographical proportion of inscriptions of Ottoman buildings in Greece considering their function (@ Ahmed Ameen 2019).

Chart 2: Geographical proportion of inscriptions of Ottoman buildings in Greece considering their function (@ Ahmed Ameen 2019).

1) Thrace.

2) Macedonia.

3) Aegean Islands.

4) Crete.

5) Epirus, Thessaly, Central Greece, Attica and Peloponnese.

And there are no extant Ottoman inscriptions in Ionian Islands.

Analyzing the statistics of the inscriptions of Ottoman buildings in Greece geographically concludes that the numbers of the extant inscriptions correspond to those of the surviving ottoman architectural heritage in the same regions. The largest amount of surviving Ottoman inscriptions is found in the Aegean Islands (224 inscriptions), Thrace (211 inscriptions), Crete (101 inscriptions), Macedonia (70 inscriptions), and finally the last group (78 inscriptions) in Epirus, Thessaly, Central Greece, Attica and Peloponnese.

The highest number of surviving Ottoman inscriptions in the Aegean Islands and Crete is obviously thanks to the large number of well-maintained fountains ‘çeşme’. Thus the highest number of foundation and short foundation inscriptions is found in the Aegean Islands and Crete. But the largest amount of religious inscriptions, including both qur’anic and non- qur’anic, are found in Thrace; in which the largest amount of Mosques that still function, where the Greek Muslim minority live. Thus, the regions that still have Muslim minorities in Greece and those located near present-day Turkey have the highest numbers of existing Ottoman inscriptions. Neighbourly relationships and consequent economic relations played a role in preserving the Ottoman architectural heritage including inscriptions in these regions. The limited number of existing Ottoman inscriptions in Central Greece, Peloponnese and Thessaly is due to the liberation of these regions being earlier than those of other Greek regions, as well as their early revolutionary wars against the Ottomans. There is an inverse geographical relationship between the cultural aversion against ‘Turkish’ objects and the number of existing Ottoman inscriptions. This number is decreased from East to West.

The city of Ioannina ‘Yanya’ is an exception in Epirus, northwestern Greece, with a remarkable and well preserved surviving Ottoman epigraphic heritage. This obviously reflects Ioannina’s own historical contexts, which were different from other Greek regions either during the Ottoman rule or after the incorporation into the Greek State in 1913.

A Suggested Methodology in Cataloguing the Corpus of Inscriptions

Inscriptions of the Ottoman buildings in Greece, in our projected corpus, will be catalogued following the aforementioned regional approach, dealing with each structure separately. It provides, as possible, for each given inscription a recent photo(s), the deciphering, an English translation, and a commentary concluding with a list of its significant literature.

Since it is not possible to tackle with each one among the 684 surveyed inscriptions in a detailed study; thus it basically catalogues the raw material and makes it available for scholarly community. A group of inscriptions were erased, as many fountains in Lesvos and the Clock tower of Preveza, or covered with later inscriptions as the inscription above the door of left room of Ghazi Evrenos Imaret at Komotini, or damaged as the foundation inscription of the Ottoman Medrese at Athens, and some inscriptions of the Ierapetra Mosque. These inscriptions require using advanced technological tools and materials of cleaning and photographing to be readable. These tools are not available to me; thus such inscriptions will included without full or partially deciphering, or English translation.

This paper suggests a new codification for the inscriptions of the Ottoman buildings in Greece; facilitating the upcoming research and digitizing these inscriptions. Each inscription will acquire this new codification ID. This ID will refer to the analysing of the inscription as the following example “0001Did01Ar”; hence this ID is composed of four parts as shown in the next table: (Table 3)

Table 3.

So that, the first four-digits number refers to a serial number consequence in the whole corpus of Ottoman buildings inscriptions in Greece, then a three-letters abbreviation referring the main regional unit (city) where the inscription belongs, thereafter a twodigits number states the number of this inscription among those of the same regional unit, and finally the abbreviation of the main language of the inscription, whereas the A=Arabic, O=Ottoman, P=Persian, G=Greek, I=Italian, F=French, TR=Modern Turkish, B=Bilingual, and T=Trilingual. This code will be mentioned as a Corpus ID.

So, each given inscription in this estimated corpus will be catalogued, as possible, through eight main items comprising: 1) Corpus ID: Caption of the inscription, 2) Regional Unit Name, 3) Basic Data, 4) Photo(s), 5) Reading “Text,” 6) Translation(s), 7) Commentary and 8) Bibliography as shown in the following example: Inscription (X)

Corpus ID: Caption of the inscription

Is the codification ID of the inscription –as noted earlier in this paper-followed by a caption describes the inscription. e.g. 0001Did01A: Main foundation inscription of Sultan Mehmed Çelebi Mosque at Didymoteicho

I. Regional Unit Name

This item states the first-level administrative entity with the corresponded ottoman names, to which the inscription belongs, then the second-level unit, afterward the location/Site of the inscription and its current condition.

This summary table provides the basic data of the inscription including: column 1: the type of the building, column 2: indicates the type of the inscription, column 3: divided into three subcolumns, provides the date in the three calendars cited in ottoman inscriptions; the Rumi date characterizes late Ottoman inscriptions, and will be stated only if cited in the given inscription, then column 4: shows the material on which was the inscription executed, and column 5: shows its language as explained in the corpus ID.

Table 4.

III. Photo(s)

Recent photo(s) if available is provided, either a reproduction of an old photo. For those mentioned by Evliya Çelebi but disappeared now, and there is no preserved old photo, will give the related parts of his manuscript.

IV. Deciphering “Text”

The text of the inscription is reproduced as original in its own language. If it is previously published, I will only refer to the related reference.

V. Translation(s)

As possible, English translation of the inscription is provided, but if it is previously published in whichever language, we will just refer to the corresponded reference.

VI. Commentary

Commentary comprises remarks, if required, on the building to which the inscription belongs, the content of the inscription and the previous significant studies.

VII. Bibliography

In bibliography citing where the inscription was previously published, described and/or studied.

Conclusion

The immense amount of the surviving inscriptions of the ottoman buildings in Greece which are not known to most scholars in Islamic epigraphy is the main motive of writing this article. These inscriptions comprise a rich material to study the Ottoman heritage in Greece over almost five centuries. The 684 inscriptions surveyed in this paper and analysed in quantitative method show their exceptional value taking into account their language and content. These inscriptions belong to 343 Ottoman buildings allover Greece and compose 1788 different texts. This paper is a part of a postdoctoral research on the same topic will be published soon as a corpus of Islamic inscriptions in Greece.

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