The use of penumbrae to define and analyse non-standard fields

Aim A new method of penumbral analysis is implemented which allows an unambiguous determination of field size and penumbra size and quality for small fields and other non-standard fields. Both source occlusion and lateral electronic disequilibrium will affect the size and shape of cross-axis profile penumbrae; each is examined in detail. Method A new method of penumbral analysis is implemented where the square of the derivative of the cross-axis profile is plotted. The resultant graph displays two peaks in the place of the two penumbrae. This allows a strong visualisation of the quality of a field penumbra, as well as a mathematically consistent method of determining field size (distance between the two peak’s maxima), and penumbra (full-widthtenth-maximum of peak). Cross-axis profiles were simulated in a water phantom at a depth of 5 cm using Monte Carlo modelling, for field sizes between 5 and 30 mm. The field size and penumbra size of each field was calculated using the method above, as well as traditional definitions set out in IEC976. The effect of source occlusion and lateral electronic disequilibrium on the penumbrae was isolated by repeating the simulations removing electron transport and using an electron spot size of 0 mm, respectively. Results All field sizes calculated using the traditional and proposed methods agreed within 0.2 mm. The penumbra size measured using the proposed method was systematically 1.8 mm larger than the traditional method at all field sizes. The size of the source had a larger effect on the size of the penumbra than did lateral electronic disequilibrium, particularly at very small field sizes. Conclusion Traditional methods of calculating field size and penumbra are proved to be mathematically adequate for small fields. However, the field size definition proposed in this study would be more robust amongst other nonstandard fields, such as flattening filter free. Source occlusion plays a bigger role than lateral electronic disequilibrium in small field penumbra size.

In pursuit of an architecture realism

The noble idea of studying seminal works to ‘see what we can learn’ has turned in the 1990s into ‘let’s see what we can take’ and in the last decade a more toxic derivative ‘what else can’t we take’. That is my observation as a student of architecture in the 1990s, and as a practitioner in the 2000s. In 2010, the sense that something is ending is clear. The next generation is rising and their gaze has shifted. The idea of classification (as a means of separation) was previously rejected by a generation of Postmodernists; the usefulness of difference declined. It’s there in the presence of plurality in the resulting architecture, a decision to mine history and seize in a willful manner. This is a process of looking back but never forward. It has been a mono-culture of absorption. The mono-culture rejected the pursuit of the realistic. It is a blanket suffocating all practice of architecture in this country from the mercantile to the intellectual. Independent reviews of Australia’s recent contributions to the Venice Architecture Biennales confirm the malaise. The next generation is beginning to reconsider classification as a means of unification. By acknowledging the characteristics of competing forces it is possible to bring them into a state of tension. Seeking a beautiful contrast is a means to a new end. In the political setting, this is described by Noel Pearson as the radical centre[1]. The concept transcends the political and in its most essential form is a cultural phenomenon. It resists the compromised position and suggests that we can look back while looking forward. The radical centre is the only demonstrated opportunity where it is possible to pursue a realistic architecture. A realistic architecture in Australia may be partially resolved by addressing our anxiety of permanence. Farrelly’s built desires[2] and Markham’s ritual demonstrations[3] are two ways into understanding the broader spectrum of permanence. But I think they are downstream of our core problem. Our problem, as architects, is that we are yet to come to terms with this place. Some call it landscape others call it country. Australian cities were laid out on what was mistaken for a blank canvas. On some occasions there was the consideration of the landscape when it presented insurmountable physical obstacles. The architecture since has continued to work on its piece of a constantly blank canvas. Even more ironic is the commercial awards programs that represent a claim within this framework but at best can only establish a dialogue within itself. This is a closed system unable to look forward. It is said that Melbourne is the most European city in the southern hemisphere but what is really being described there is the limitation of a senseless grid. After all, if Dutch landscape informs Dutch architecture why can’t the Australian landscape inform Australian architecture? To do that, we would have to acknowledge our moribund grasp of the meaning of the Australian landscape. Or more precisely what Indigenes call Country[4]. This is a complex notion and there are different ways into it. Country is experienced and understood through the senses and seared into memory. If one begins design at that starting point it is not unreasonable to think we can arrive at an end point that is a counter trajectory to where we have taken ourselves. A recent studio with Masters students confirmed this. Start by finding Country and it would be impossible to end up with a building looking like an Aboriginal man’s face. To date architecture in Australia has overwhelmingly ignored Country on the back of terra nullius. It can’t seem to get past the picturesque. Why is it so hard? The art world came to terms with this challenge, so too did the legal establishment, even the political scene headed into new waters. It would be easy to blame the budgets of commerce or the constraints of program or even the pressure of success. But that is too easy. Those factors are in fact the kind of limitations that opportunities grow out of. The past decade of economic plenty has, for the most part, smothered the idea that our capitals might enable civic settings or an architecture that is able to looks past lot line boundaries in a dignified manner. The denied opportunities of these settings to be prompted by the Country they occupy is criminal. The public realm is arrested in its development because we refuse to accept Country as a spatial condition. What we seem to be able to embrace is literal and symbolic gestures usually taking the form of a trumped up art installations. All talk – no action. To continue to leave the public realm to the stewardship of mercantile interests is like embracing derivative lending after the global financial crisis.Herein rests an argument for why we need a resourced Government Architect’s office operating not as an isolated lobbyist for business but as a steward of the public realm for both the past and the future. New South Wales is the leading model with Queensland close behind. That is not to say both do not have flaws but current calls for their cessation on the grounds of design parity poorly mask commercial self interest. In Queensland, lobbyists are heavily regulated now with an aim to ensure integrity and accountability. In essence, what I am speaking of will not be found in Reconciliation Action Plans that double as business plans, or the mining of Aboriginal culture for the next marketing gimmick, or even discussions around how to make buildings more ‘Aboriginal’. It will come from the next generation who reject the noxious mono-culture of absorption and embrace a counter trajectory to pursue an architecture of realism.

The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals : consequences for occupational and environmental medicine

The importance of the isoform CYP2E1 of the human cytochrome P-450 superfamily of enzymes for occupational and environmental medicine is derived from its unique substrate spectrum that includes a number of highly important high-production chemicals, such as aliphatic and aromatic hydrocarbons, solvents and industrial monomers (i.a. alkanes, alkenes, aromatic and halogenated hydrocarbons). Many polymorphic genes, such as CYP2E1, show considerable differences in allelic distribution between different human populations. The polymorphic nature of the human CYP2E1 gene is significant for inter-individual differences in toxicity of its substrates. Since the substrate spectrum of CYP2E1 includes many compounds of basic relevance to industrial toxicology, a rationale for metabolic interactions of different CYP2E1 substrates is provided. In-depth research into the inter-individual phenotypic differences of human CYP2E1 enzyme activities was enabled by the recognition that the 6-hydroxylation of the drug chlorzoxazone is mediated by CYP2E1. Studies on CYP2E1 phenotyping have pointed to inter-individual variations in enzyme activities. There are consistent ethnic differences in CYP2E1 enzyme expression, mostly demonstrated between European and Japanese populations, which point to a major impact of genetic factors. The most frequently studied genetic polymorphisms are the restriction fragment length polymorphisms PstI/RsaI (mutant allele: CYP2E1*5B) located in the 5′-flanking region of the gene, as well as the DraI polymorphism (mutant allele: CYP2E1*6) located in intron 6. These polymorphisms are partly related, as they form the common allele designated CYP2E1*5A. Striking inter-ethnic differences between Europeans and Asians appear with respect to the frequencies of the CYP2E1*5A allele (only approximately 5% of Europeans are heterozygous, but 37% of Asians are, whilst 6% of Asians are homozygous). Available studies indicate a wide variation in human CYP2E1 expression, which are very likely based on complex gene-environment interactions. Major inter-ethnic differences are apparent on the genotyping and the phenotyping levels. Selected cases are presented where inter-ethnic variations of CYP2E1 may provide likely explanations for unexplained findings concerning industrial chemicals that are CYP2E1 substrates. Possible consequences of differential inter-individual and inter-ethnic susceptibilities are related to individual expressions of clinical symptoms of chemical toxicity, to results of biological monitoring of exposed workers, and to the interpretation of results of epidemiological or molecular-epidemiological studies.

Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology

Although cytosolic glutathione S-transferase (GST) enzymes occupy a key position in biological detoxification processes, two of the most relevant human isoenzymes, GSTT1-1 and GSTM1-1, are genetically deleted (non-functional alleles GSTT1*0 and GSTM1*0) in a high percentage of the human population, with major ethnic differences. The structures of the GSTT and GSTM gene areas explain the underlying genetic processes. GSTT1-1 is highly conserved during evolution and plays a major role in phase-II biotransformation of a number of drugs and industrial chemicals, e.g. cytostatic drugs, hydrocarbons and halogenated hydrocarbons. GSTM1-1 is particularly relevant in the deactivation of carcinogenic intermediates of polycyclic aromatic hydrocarbons. Several lines of evidence suggest that hGSTT1-1 and/or hGSTM1-1 play a role in the deactivation of reactive oxygen species that are likely to be involved in cellular processes of inflammation, ageing and degenerative diseases. There is cumulating evidence that combinations of the GSTM1*0 state with other genetic traits affecting the metabolism of carcinogens (CYP1A1, GSTP1) may predispose the aero-digestive tract and lung, especially in smokers, to a higher risk of cancer. The GSTM1*0 status appears also associated with a modest increase in the risk of bladder cancer, consistent with a GSTM1 interaction with carcinogenic tobacco smoke constituents. Both human GST deletions, although largely counterbalanced by overlapping substrate affinities within the GST superfamily, have consequences when the organism comes into contact with distinct man-made chemicals. This appears relevant in industrial toxicology and in drug metabolism.

Occurrence of urinary tract tumors in miners highly exposed to dinitrotoluene

Between 1984 and 1997, six cases of urothelial cancer and 14 cases of renal cell cancer occurred in a group of 500 underground mining workers in the copper-mining industry of the former German Democratic Republic, with high exposures to explosives containing technical dinitrotoluene. Exposure durations ranged from 7 to 37 years, and latency periods ranged from 21 to 46 years. The incidences of both urothelial and renal cell tumors in this group were much higher than anticipated on the basis of the cancer registers of the German Democratic Republic by factors of 4.5 and 14.3, respectively. The cancer cases and a representative group of 183 formerly dinitrotoluene- exposed miners of this local industry were interviewed for their working history and grouped into four exposure categories. This categorization of the 14 renal cell tumor cases revealed no dose-dependency concerning explosives in any of the four exposure categories and was similar to that of the representative group of employees, whereas the urothelial tumor cases were predominantly confined to the high-exposure categories. Furthermore, all identified tumor patients were genotyped by polymerase chain reaction, using lymphocyte DNA, regarding their genetic status of the polymorphic xenobiotic metabolizing enzymes, including the N-acetyltransferase 2 and the glutathione-S-transferases M1 and T1. This genotyping revealed remarkable distributions only for the urothelial tumor cases, who were exclusively identified as 'slow acetylators.' This points to the possibility of human carcinogenicity of dinitrotoluene, with regard to the urothelium as the target tissue.

Nephrotoxicity and nephrocarcinogenicity of dinitrotoluene : new aspects to be considered

Technical dinitrotoluene (DNT) is a mixture of 2,4- and 2,6-DNT. In humans, industrial or environmental exposure can occur orally, by inhalation, or by skin contact. The classification of DNT as an 'animal carcinogen' is based on the formation of malignant tumors in kidneys, liver, and mammary glands of rats and mice. Clear signs of toxic nephropathy were found in rats dosed with DNT, and the concept was derived of an interrelation between renal toxicity and carcinogenicity. Recent data point to the carcinogenicity of DNT on the urinary tract of exposed humans. Between 1984 and 1997, 6 cases of urothelial cancer and 14 cases of renal cell cancer were diagnosed in a group of 500 underground mining workers in the copper mining industry of the former GDR and having high exposures to explosives containing technical DNT. The incidences of both urothelial and renal cell tumors in this group were 4.5 and 14.3 times higher, respectively, than anticipated on the basis of the cancer registers of the GDR. The genotyping of all identified tumor patients for the polymorphic enzymes NAT2, GSTM1, and GSTT1 identified the urothelial tumor cases as exclusively 'slow acetylates'. A group of 161 miners highly exposed to DNT was investigated for signs of subclinical renal damage. The exposures were categorized semi-quantitatively into 'low', 'medium', 'high', and 'very high'. A straight dose-dependence of the excretion of urinary biomarker proteins with the ranking of exposure was seen. Biomarker excretion (alpha1-microglobulin, glutathione S-transferases alpha and pi) indicated that DNT-induced damage was directed toward the tubular system. New data on DNT-exposed humans appear consistent with the concept of cancer initiation by DNT isomers and the subsequent promotion of renal carcinogenesis by selective damage to the proximal tubule. The differential pathways of metabolic activation of DNT appear to apply to the proximal tubule of the kidney and to the urothelium of the renal pelvis and lower urinary tract as target tissues of carcinogenicity.

Pathological excretion patterns of urinary proteins in miners highly exposed to dinitrotoluene

A cohort of 161 underground miners who had been highly exposed to dinitrotoluene (DNT) in the copper-mining industry of the former German Democratic Republic was reinvestigated for signs of subclinical renal damage. The study included a screening of urinary proteins excreted by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and quantitations of the specific urinary proteins α 1-microglobulin and glutathione-S-transferase α (GST α) as biomarkers for damage of the proximal tubule and glutathione-S-transferase π (GST π) for damage of the distal tubule. The exposures were categorized semiquantitatively (low, medium, high, and very high), according to the type and duration of professional contact with DNT. A straight dose-dependence of pathological protein excretion patterns with the semiquantitative ranking of DNT exposure was seen. Most of the previously reported cancer cases of the urinary tract, especially those in the higher exposed groups, were confined to pathological urinary protein excretion patterns. The damage from DNT was directed toward the tubular system. In many cases, the appearance of Tamm-Horsfall protein, a 105-kD protein marker, was noted. Data on the biomarkers α 1-microglobulin, GST α, and GST π consistently demonstrated a dose-dependent increase in tubular damage, which confirmed the results of screening by SDS-PAGE and clearly indicated a nephrotoxic effect of DNT under the given conditions of exposure. Within the cluster of cancer patients observed among the DNT-exposed workers, only in exceptional cases were normal biomarker excretions found.

Psychological effects upon exposure to polyhalogenated dibenzodioxins and dibenzofurans

Thirty workers who had been exposed to combustion products for several years due to testing of flame retarding qualities of building materials and 30 controls from the same facility were investigated. Concentrations found in samples taken from different places of the facility were up to 14,660 μg/kg for polybrominated dibenzofurans and up to 67.1 μg/kg for polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs). Physical examination, routine laboratory parameters, and blood fat concentrations of PCDDs and PCDFs revealed normal findings. Neurotoxic symptoms showed a weak tendency of overrepresentation among the exposed workers. The frequency of neurobehavioural symptoms increased significantly with trait anxiety independent of exposure to combustion products. (C) 2000 Elsevier Science Ltd.

Interactions of ingested food, beverage, and tobacco components involving human cytochrome P4501A2, 2A6, 2E1, and 3A4 enzymes

Human cytochrome P450 (P450) enzymes are involved in the oxidation of natural products found in foods, beverages, and tobacco products and their catalytic activities can also be modulated by components of the materials. The microsomal activation of aflatoxin B1 to the exo-3,9-epoxide is stimulated by flavone and 7,8-benzoflavone, and attenuated by the flavonoid naringenin, a major component of grapefruit. P4502E1 has been demonstrated to play a potentially major role in the activation of a number of very low-molecular weight cancer suspects, including ethyl carbamate (urethan), which is present in alcoholic beverages and particularly stone brandies. The enzyme (P4502E1) is also known to be inducible by ethanol. Tobacco contains a large number of potential carcinogens. In human liver microsomes a significant role for P4501A2 can be demonstrated in the activation of cigarette smoke condensate. Some of the genotoxicity may be due to arylamines. P4501A2 is also inhibited by components of crude cigarette smoke condensate. The tobacco-specific nitrosamines are activated by a number of P450 enzymes. Of those known to be present in human liver, P4501A2, 2A6, and 2E1 can activate these nitrosamines to genotoxic products.

Hydrolysis of genotoxic methyl-substituted oxiranes : Experimental kinetic and semiempirical studies

The kinetics of acid-catalyzed hydrolysis of seven methylated aliphatic epoxides - R1R2C(O)CR3R4 (A: R1=R2=R3=R4=H; B: R1=R2=R3=H, R4=Me; C: R1=R2=H, R3=R4=Me; D: R1=R3=H, R2=R4=Me(trans); E: R1=R3=H, R2=R4=Me(cis); F: R1=R3=R4=Me, R2=H; G: R1=R2=R3=R4=Me) - has been studied at 36 ± 1.5°C. Compounds with two methyl groups at the same carbon atom of the oxirane ring exhibit highest rate constants (k(eff) in reciprocal molar concentration per second: 11.0 ± 1.3 for C, 10.7 ± 2.1 for F, and 8.7 ± 0.7 for G as opposed to 0.124 ± 0.003 for B, 0.305 ± 0.003 for D, and 0.635 ± 0.036 for E). Ethylene oxide (A) displays the lowest rate of hydrolysis (0.027 M-1 s-1). The results are consistent with literature data available for compounds A, B, and C. To model the reactivities we have employed quantum chemical calculations (MNDO, AM1, PM3, and MINDO/3) of the main reaction species. There is a correlation of the logarithm k(eff) with the total energy of epoxide ring opening. The best correlation coefficients (r) were obtained using the AM1 and MNDO methods (0.966 and 0.957, respectively). However, unlike MNDO, AM1 predicts approximately zero energy barriers for the oxirane ring opening of compounds B, C, E and G, which is not consistent with published kinetic data. Thus, the MNDO method provides a preferential means of modeling the acidic hydrolysis of the series of methylated oxiranes. The general ranking of mutagenicity in vitro, A > B > C, is in line with the concept that this sequence also gradually leaves the expoxide reactivity optimal for genotoxicity toward reactivities leading to higher biological detoxifications.

Influence of cytochrome P-450 inhibitors on the inhalative uptake of methyl chloride and methylene chloride in male B6C3F1 mice

Dichloromethane (DCM) is thought to be metabolized in vivo by two independent pathways: a glutathione (GSH) dependent pathway that yields CO2 and a cytochrome P-450 mediated one that yields both CO and CO2 (Gargas et al 1986). With a physiologically based pharmacokinetic (PB-PK) model, Andersen et al (1987) calculate the quantitative parameters for both metabolic pathways. Using the kinetic parameters thus obtained and the results of two carcinogenicity studies with rodents (Serota et al 1986; NTP 1985), the authors then estimate the tumour risk for humans.