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Clipper microprocessor, which it has been using in its hne of engineering workstations. Intergraph, located here, is a maker of computer-aided design and manufacturing systems. Fairchild has been selling Clipper to Intergraph and a handful of other companies, most of which Fairchild has not named.

Chrysler drives into cehter Consolidation in the computer leasing business continued with two recent acquisitions. Greenwich, Conn. Ulfelder Copy Editors David W.

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In other words, a network that works. For everyone. Or write Sun Microsystems, Garcia Ave. The proposed addition is designated X3. The X3 committee has also announced a review period through Oct. Unmatched installation and implementation program. Inc Masterpiece. CA-Accounts Poyoble. Software superior by design. Changes during the final editing of X3. The standard facilitates the development and utilization of tape peripherals on computers by providing a common logical interface.

Software is no longer a cottage industry. To be a leader, the drive to be inventive must be backed by substantial resources. The way programmers work. The way computer applications are written and managed. The way corporate infomiation is managed.

And the r way future software systems will evolve. Today, ADR continues to lead the industry. And will continue to answer the needs of business. But now in greater diversity than ever before. Unlock the potential. The feature is one of several that the small systems utility firm said it hopes will allow it to compete more effectively with the job scheduling packages offered by Computer Associates International, Inc. Pools systems for scheduling Release 3.

And sessions can be saved on the host. Make contact today with Trax for a free trial! TtaX Trax Softworks, Inc. Tymshare Inc.

International Business Machines. Inc, IBM. Lcslic P. Marcia Feingold — Cap Gemini America m. The company has sold licenses for the product. Macros can be defined in separate files and included with one-line commands in the procedure source code file. It is said to take the place of more expensive mainframe security risk analyses.

Tata Engineering and Locomotive Co. Access Technology, Inc. SQL is key to taking advantage of future technologies. And ADR will fully support the industry standard.

Wliich means choosing a DBMS is now a matter of choosing the system that satisfies your current needs best. Without the fear of being locked out tomorrow. The future may bring something new, but today, businesses like yours depend on computer-based online solutions built by professional programmers.

Only to find that any advantages are lost to an insurmountable learning curve or are offset by an extremely painful performance penalty. That is, until now. You can even utilize existing Cobol copybooks. You get a system that executes real instructions. From the simplest to the most demanding of programs. Call or write today for a free, no obligation trial and complimentary poster. Perfect together. Cincom Systems, Inc. Hessinger said that rating is unofficial; the official one will have to come from the Codd and Date Consulting Group when it decides to make it public.

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Lotus and are registered trademarks of Lotus Development Corporation. This module is integrated with Supertab, the I- Deas finite element modeler. If two users try to simultaneously open the same data set, the product guarantees that all update operations are serialized and protects the overall integrity of the data set.

Enhanced Data Set Integrity operates in a stand-alone or integrated mode. On-Cue generates and submits a batch job request and returns it to the user. A hard copy can be routed to an available printer. Filled-in screens can be saved in a user library, and security for sensitive data is provided. It emulates the deduetive reasoning of human experts and shows how to improve the performance of your system.

In fact, it even gives the rationale for its advice. And can tailor its recommendations to the requirements of your system. It is compatible with other versions of Plantrac.

Computerline, P. Box , 52 School St. A version of the Mass word processing software for Digital Equipment Corp. Mass Version 7-A allows the fonts to be printed in outline form or in various shades from black to white, the vendor said.

Users may change typefaces and point sizes anywhere within a document. Microsystems Engineering, Suite , W. Hassell Road, Hoffman Estates, Ill. Other features include more than component library symbols, editing functions and the abiity to create parts from portions of a drawing. The software also allows definition of a pixel array with a color associated with each pixel.

Raster data from various sources can be merged. Versatec has also announced Veraplot 9. The software outputs raster data and was designed for VAX and Microvax computers. Versatec, Walsh Ave.

The system, called Jcamms, runs on Wang Laboratories, Inc. VS minicomputers. Broadway, Hicksville, N. Version 1. DEC, Maynard, Mass. Louis A. Sharing DASD? Want to Improve Performance? System Devel. Facility Info. You can use a telephone. Reply and it digitizes your voice to be replayed later. So now the company computer is just a phone call away. Teltech, 39 Broadway, New York, N. But since we bought the C Supra from C. Itoh Digital Products, I never have a moment to spare.

I’m living life in the fast lane. It manages continuous forms, labels, letterhead and up to 6-part invoices with its rear or bottom feed paper paths. Sound investment The finance department says the Supra is a great investment since C. Itoh Digital Products, Inc. It prints high volume data processing output, like invoices and spreadsheets, at speeds up to characters per second cps.

And for word processing, the Supra prints sharp, clear, high-speed letter quality at cps. And they were right. Forms expert Our executives are really impressed with the Whether it’s high volume spreadsheets and multi-part invoices or letter quality business letters and presentations, the Supra is fast and reliable.

MS-DOS-based systems. Software Research, Third St. Francisco, Calif. According to the vendor. Version 2. Updata, Holmdel Road, Holmdel, N. The Tapesaver Utility backs up and restores data by volume or by file. No system generation is required for installation. The utility can be run by an operator in interactive menu prompt mode or unattended under batch control.

And offers software designers a CASE system that works the way they do. A commitment that has made ADR the leader. Up to 16 watch points can also be set. Program statements can be traced as they are executed. Glenstone, Springfield, Mo. The system lets engineers and managers focus their efforts on software development, quality, and productivity, without having to supervise a complex computer facility.

A composite material made of graphite epoxy is ideal for use in space because it is stronger than steel yet lighter than aluminum. Unlike metal, it does not expand from exposure to heat or cold, and its reduced weight translates into lower costs and larger payloads. For example, saving just one pound in a space vehicle means a reduced launch cost of several thousand dollars or added fuel for longer operations.

Until now, however, graphite composites have proved difficult to mold to shapes more complex than a simple cylinder. But research and development by Hughes has opened the way for the fabrication of a variety of new forms, including tubes with integrated end fittings in a one-piece design, support beams, and ring structures up to seven feet in diameter.

Air Force FE dual role fighters. Unlike previous systems requiring software check-out after the completion of hardware, the Hughes Digital Software Integration Station DSIS can test and de-bug software while the hardware is being built, resulting in substantial development cost and schedule savings. It has ten times the software and six times as many test targets as its predecessor, the APG radar. The signal is then relayed to a Japanese ground station north of Tokyo and fed into the local NHK studio.

The daily broadcasts include segments of major US. An ultramodern facility spanning 1. S3, El Segundo, CA Ada is a registered trademark of the U S. Government Ada Joint Program Office. For more information write to: P. Development tools Cadre Technologies, Inc. Cadre Technologies, Richmond St. Smalltalk DE Version 2. Continued on paged? Postscript has clearly emerged as a standard, and Palo Alto, Calif.

The Continued on paged? How do you plan to penetrate that market? Users report dramatic productivity improvements and more. All these and more to improve productivity and produce quality applications. For the most efficient development of either your PC or mainframe programs, call us now. The company also unveiled a Holiday Clipart Library that users can incorporate into holiday correspondence, newsletters and other types of publications, according to a company spokesman.

They are compatible with Adobe Systems, Inc. Data integrity is key for such an application. Another reason for Follet to go with Baler was purely economic. The plan eventually calls for 60 copies of the model to be in place. According to Butler, compiling a spreadsheet with Baler was easy.

At up to 1. SCO Xenix has proved to be a reliable operating system. It offers an excellent low-cost opportunity to get back up to speed on the current state of Unix. Xenix vs. Even a little experience with the two systems is enough to show that both will have their place in corporate use. SCO Xenix is clearly the operating more professional, unified look.

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LaserJet Plus is a a-gislemd trademark of Hewlett-Bickard. Inc, Infomuition Systems Division system of choice when more traditional, multiuser, multiterminal configurations are desired. Control-C Software, Inc. We also have regional marketing people that are also focused exclusively on the Fortune Why should MIS directors buy Tandy equipment?

What are your goals for selling to MIS in large corporations? Our market share is small — in the few- percent range. We would be very pleased to double that in the next year. I think every new piece of hardware that comes into the market, regardless of the manufacturer, has features that the whole industry reviews and has to determine the importance of for the long term.

Of course, customers themselves have an important vote as well. In fact, VGA is an option on our based machines today. The real significance of that is that all manufacturers now have the ability to bring some real innovations to hardware design as long as the operating environment is compatible with it and the software is compatible with it.

Does it matter? The rumor is that it needs an exceptionally large amount of memory to handle all these extended functions. So, if you believe their literature, it would appear to run on all other machines as well. Anyone who focuses on it is the ultimate victim of fear, uncertainty and doubt. How badly were you harmed by that decision? We were anything but a hardware clone.

But our sales have been very robust. What do you hope to accomplish during the next 10? In the microcomputer area, our No. One of the more interesting things that we did next was our barnstorming campaign in and We also made significant inroads in the education market. We gave free computer-literacy training to , school teachers. The next 10 years will probably be more interesting than the last With all the advances being made in hardware and software, the end user is going to be the big beneficiary.

BASIS is designed to keep pace with your world of information, and, without the constraint of hardware dependence. Fast, efficient information retrieval is possible in even the largest databases.

Novice and casual users may retrieve information and generate reports using menus and simplified command statements. In , the firm shipped 3. Once an IBM-only shop. Saavedra said Wells Fargo was drawn to Tandy because of its ability to provide on-site service.

GE makes the switch General Electric Co. And, that makes sense. New files and record fields may be added or changed without reloading data.

BASIS is accurate, efficient, and secure. DM is the first relational DBMS with full-text handling capabilities integrated with complete database management facilities. If you need to know who, what, where, when, or why.. Let DPS be your Guide. Digital is and will continue to be the dominant factor! Or call your local sales office.

The Powermate includes a processing unit with IM byte of random-access memory, a 1. It can accommodate five 5V4-in. Based on the Intel Corp. CPT, P. Box , Mitchell Road, Minneapolis, Minn.

The Acer bit system runs at 16 MHz. No host changes required. Aspen Research NE. Does the vendor offer a true distributed matrix switch versus an electronic patch panel?

Are there any documented problems with the control software, resulting in inability to control the switch? Can references be contacted, with sites visited?

Is performance monitoring integrated in the distributed matrix switch? I Does the switch provide V. And, we know that no competitor within our markets can match the service and support we offer. Prove it to yourself. The Ivy portables are said to run the Unix operating system. The Model 40 features a 1. The Model 80 features an 80M-byte hard drive, and the Model features a M-byte hard drive instead of the 40M-byte drive.

Ivy Microcomputer, 15 Ararat St. Software applications packages An entry-level computer-aided drafting and design program called Cub has been announced by Innovative Computer Aided Technology, Inc. Macintosh has been introduced. Users can select record sizes of 1,, 2, or 4, char. Vectras and compatibles. Box , Cumberland Ave. Lafayette, Ind. Response, an integrated contingency planning system for data processing and corporate disaster recovery planning, has been announced by Mosaic Computer Security, Inc.

Mosaic, Massachusetts Ave. You can correct or bypass the error right away —without wading through transaction dumps—and then resume testing without losing valuable time.

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It all adds up to greater productivity. For specs on our full line, call your local Amdahl representative. The Hobbs Group, P. Box , S. Techpro, P. Box , Springfield, Va. Bridgeware operates as a stand-alone application.

MS-DOS 2. Other features include a rewritten source-entry utility and an 8-million-record limit. California Software, N. A code-generating graphics editor called Drawbridge has been introduced by Courseware Applications, Inc. Drawbridge automatically generates the source code required to create graphics displays. Graphics objects available include arcs, boxes, circles, lines and polygons. They may be in color and can be either outlined or painted. A built-in text editor allows the addition of text to graphics displays.

It automates new or modified application testing, from simple program tests to the most complicated stress testing. The automated logging function permanently stores the screen dialogues on a file. You can then browse and customize your test stream dialogues with a variety of powerful on-line edit and utility functions.

VERIFY is then ready to retest any portion of your system, giving you the flexibility to control the application mix, input values and arrival rate of the transactions to be re-executed on CICS.

Through an on-line menu display, you can see the exact differences VERIFY discovers during its interactive comparison. And respond immediately with two full menus of mismatch processing options. It helps you get it right the first time.

The V 2 -in. Emerald Systems, Mo- rena Blvd. Nth Group, P. Box , West Hills, Calif. Information Storage, Inc. Features include self-loading and self-threading. M4 Data, Building 14, N. A series of internal hard disk drives for Apple Computer, Inc. Macintosh computers has been announced by the Rodime, Inc. Peripheral System Division. Both offer average seek times of 28 msec, and both have embedded SCSI controllers.

Rodime, Suite , Chagrin Blvd. You can take the Macintosh SE for a test drive. Or experience the blazing speed of the Macintosh H. Based on the processor, the newest Macintosh has color for vivid graphics, and open architecture for maximum expandability of memory to handle the biggest jobs. Most importantly, youll find out about the new connection between IBM and Apple! About DOS compatibility cards and the new option of emulation.

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Businessland is an authorized Apple dealer. Text editing is done on the composed page in a what-you-see-is- what-you-get format. Canon U. A in. The monitor has a 0. Tatung, El Presidio St. The device can scan both halftone photographs and line-art drawings in one pass. Interfacing the Apple Computer, Inc.

Microtek Labs, S. Western Ave. Three models are available. All feature two full-length, eight-bit IBM Personal Computer slots, two plug-in expansion adapters, K bytes of random-access I memory, four asynchronous serial shar- j ing ports, one serial printer port and one parallel pinter port.

Model 2, with a 1. Page Reader supports the formats of such word processing programs as Micro- pro International Corp. Page Reader has a built-in sheet feeder that enables it to read stacks of up to five typewritten pages. While the scanner is operating, users can continue to use the personal computer for other tasks.

Saba Technologies, S. Gemini Drive, Beaverton, Ore. Cornerstone, A E. Tasman Drive, Sanjose, Calif. Board-level devices General Computer Corp. It automatically detects and repairs system abends and loops on-line. And since diagnostic data is available on-line or in a complete, concise report, you reduce the need to wade through large portions of lengthy system dumps.

Get the only CICS stabilizer around. Because PowerHouse supports these vendors’ relational databases as well as their dominant file systems, many of the problems associated with adopting a relational DBMS are solved.

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CSS Laboratories, S. Ritchey St. Safe Power Systems, W. Clary, W. Clary Ave. Tilt and swivel base. An easier set-up mode. Our dual resolution mode lets you retain full VT compatibility and shift from DEC resolution to hi res.

When it comes to quality and value in terminals, we wrote the book. Tferminal Census. CW CHART ing from security breaches has mounted with the proliferation of effective network analysis tools that let outsiders tap in and monitor data on the network, Russell said. Vista-Gate was co-developed with Communications Solutions, Inc.

Direct access to Profs will be announced within the next six months, according to a Data- point spokesman. Virtually every new computer supports C, and portable programs created with the mainframe compiler under OS or CMS will run on any other machine with a C compiler.

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Thefast, flexible applications development system. Bridge said. Somehow, a little programming change can take on monstrous proportions if you’re not careful. And an undetected error can make a program look like a different animal altogether. TRAPS captures keystrokes and screens and provides consistent, repeatable playback of test scripts. And since TRAPS runs on a personal computer, you conserve host resources and bypass the installation and scheduling roadblocks of mainframe testing tools.

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See you at the user conference. A comprehensive guide designed to make the mainframe software selection process much easier for you. By design. There are two basic approaches to this; contention and assignment. In a contention-based system, there is a pool of sessions available on a first come, first served basis. In an assignment system, sessions are dedicated to specific users. The latter is important for printers and terminals that will run production jobs. Some products support both approaches.

Your batch jobs will always have the files they need for processing without operator intervention. Netec International, Inc. How easy will it be to add another controller? Are there lines to run back to the host? Will there be ports available when you get there? These are questions you should ask. A related issue is how much user support the gateway provides.

How much does the system tell you about what is going on? Can you see exactly which logical units are in use? The absence of this kind of data, which is essential for diagnostics and monitoring, can be good reason to avoid an otherwise excellent product. But be careful. You should ensure that users on one network can establish sessions on a host connected to a gateway on another network. Otherwise you will have to put a gateway in every LAN.

Alternate strategies include using a redundant piece of hardware for backup, a second line or a standby dial-up connection.

One or more of these is a good investment. Different factors come into play with each application. Consider the combination of products and combination of keystrokes that will be involved. Adrian is manager of end-user computing at Shear- son Lehman Brothers, Inc. Py3 Dataproducts. Contact your Dataproducts distributor, or call us direct at 1 , ext.

In CA, 1 In Canada, 1 Beginning with a full day of professional tutorials, the Forum offers in-depth coverage of multivendor and VAX computing topics. Plus you get two days of conferences featuring VAX- specific topics led by industry experts.

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Kortek, Hamilton Ave. Century Analysis, Center Ave. Able Computer, Airway Ave. The expander panel provides 16 Sit back and relax. And that we plan to add more soon. Built-in baluns provide electrical port isolation. Lee Data Corp. Coal Combustion Global coal combustion contributes an estimated t of arsenic to the atmosphere each year, equating to approximately half the contribution from copper smelting [3]. Atmospheric arsenic concentrations in coal combustion emissions are generally lower and typically distributed over a wider area.

However, in heavily industrialized areas such as around Beijing, concentrations may be substantially greater [9]. Given that high temperature processes are typically associated with fine and accumulation-mode particles, arsenic levels in PM10 and PM2.

Comparable average PM10 arsenic concentrations were recorded in Beijing Wind conditions appear to play an important role in the dispersal of atmospheric arsenic emitted by coal combustion sources [9].

Figure 2. Relationship between total atmospheric arsenic concentration and wind speed in Beijing, China, for the period February to March Reprinted from Yang et al. Mine Tailings Research into mine tailings as a source of atmospheric arsenic has gained momentum in the last decade. Mine tailings have the potential to generate high levels of dust with extremely high atmospheric arsenic concentrations, particularly in arid and semi-arid environments [10].

Comparable with the trend observed around smelting operations, the impact of mine tailings on atmospheric arsenic levels are typically greatest at the source [11,17,18,54]. Arsenic enrichment in the finer fractions of size-fractionated mine tailings has been reported [19,21,57].

Although these findings are not reflective of actual atmospheric arsenic emissions from a particular source, the finer size fractions are more susceptible to wind-borne transport and are most likely to be re-suspended by wind or mechanical disturbance. Kim et al. Although there were distinct differences in the arsenic distributions amongst the wastes, there were obvious inverse relationships between grain size and arsenic concentration. The high arsenic content recorded in the dust size fraction of each sample range, — ppm illustrates the potential of their corresponding sources to generate potentially hazardous emissions [21].

The effects of seasonality on particulate arsenic emissions from mine tailings have also been investigated. Meteorological factors associated with different seasons, especially rainfall and temperature, have been shown to have a dramatic impact on arsenic mobility through the air [54,90]. During the dry summer months in the City of Lavrion, Greece, concentrations of arsenic in PM10 increased dramatically more than 6 times compared with concentrations during late winter [54,90].

Similarly, a study in Aznalcazar, southwest Spain, found that sporadic rainfall and low convective atmospheric dynamics during the late winter were associated with relatively low re-suspension of PM from heavy metal mining wastes [54]. During summer, the combination of intensive convective circulation and low rainfall facilitates surface drying leading to enhanced re-suspension of PM.

Low rainfall and decreased humidity lead to increased atmospheric particulates, and therefore, increased atmospheric arsenic concentration [90]. The most common forms of arsenic in the environment include the trivalent arsenite and pentavalent arsenate species [93], and they are often found occurring together [94,95].

It is widely recognized that arsenite species have greater mobility in the environment [97] and are reported to be 25 to 60 times more toxic than the corresponding pentavalent forms [98]. Since the oxidation state of arsenic in soil, water, and other environmental matrices is one of the key factors governing toxicity, speciation analysis is of interest in human exposure studies.

Speciation analysis has been used widely for the identification and quantification of arsenic species in bulk samples of surface soils and mine wastes [94,95,99,]. However, comparatively less work has been conducted in relation to arsenic speciation in atmospheric PM generated by mining operations [9,18,44,74—76,83].

Research conducted to date indicates that both arsenate and arsenite may co-exist in smelter, coal combustion and gold roaster emissions [9,44,45,74—76,83,94] although reported levels for the trivalent species are generally much lower than those for the arsenates Table 1. For example, arsenate and arsenite concentrations in coal combustion emissions in China were 67 and 4. Similarly, Oliveira et al. The presence of arsenite in smelter emissions may result from the reduction of arsenate by aerosol sulphur dioxide S IV complexes during transport of the emission plume [].

Airborne monitoring programs combined with speciation analysis demonstrate clearly that airborne arsenic is a serious and ongoing issue in mining communities and heavily industrialized areas throughout the world.

Summary of the average, minimum and maximum total arsenic TAs concentrations recorded in particulate matter PM from various mining operations, including smelting, coal combustion and mine waste. Where applicable, all units of distance measurement have been converted to metric system. Human Exposure Communities living in the vicinity of mining operations may be exposed to airborne arsenic-contaminated particulates and be at risk of health deterioration though absorption after dermal and eye contact, or by ingestion after inhalation [28].

However, arsenic absorption through the skin following dermal and eye contact is a minor contributor compared with ingestion and inhalation exposures [25] and will not be further discussed here. Furthermore, incidental ingestion of arsenic-contaminated particulates, usually as a result of contaminated food or water supplies, has been the most thoroughly investigated pathway, and its significant range of adverse effects have been well documented following acute, intermediate and chronic exposures [25], negating the need for further detailed review here.

For the general population, ingestion is typically considered the primary exposure pathway to arsenic, and inhalation of arsenic bearing PM has been considered to be a minor exposure route [2]. The relatively neglected topic of inhalation exposure with consequent issues linked to airborne PM containing arsenic species from proximate mining industries needs to be addressed.

For example, exposure assessments of communities living in the vicinity of smelting and coal combustion operations suggest that inhalation may play a similar, if not more important role than ingestion, in the overall exposure to airborne particulate arsenic [4,—]. In addition, it has been shown that children are particularly susceptible to inhalation exposure due to: i their increased likelihood of coming into contact with dust [78]; and ii children inhale a greater volume of air than adults relative to their size [].

Therefore, in the following sections we will consider some of the ways in which inhaled arsenic-contaminated particulates generated by mining operations may lead to systemic absorption, toxicity, and arsenic-related disease endpoints. In order to understand how arsenic becomes mobile or bioavailable and exerts its toxic effects in the human body, we will begin with a discussion on the fate of inhaled particles in the RT with particular emphasis on the role that particle size plays in determining the ultimate absorption or defense mechanisms.

Deposition Location and Particle Clearance from the Respiratory Tract RT The location and manner in which PM is deposited in the RT are critical for understanding how the arsenic-bearing particles might react with different lung constituents. When PM is inhaled, a proportion of the particles are retained while the remainder are expelled via exhalation.

Retained particles are deposited in different regions of the RT according to their size [—] and as a general rule, the smaller the particle the deeper it will penetrate into the RT and the longer it will be retained Table 2; [72,]. To protect the body against foreign materials, the human respiratory system has developed a range of physiological lines of defense [,]. We will review the deposition location of inhaled particles as a function of particle size, the methods of clearance from each location, and pathways for absorption.

Deposition of PM10 in different regions of the human respiratory tract [,] as a function of particle size data from Newman [72] , including the estimated retention time of the particle size in each deposition location data from Bailey []. The vast majority of particles deposited in the extra-thoracic region are removed via a combination of nose-blowing, sneezing and mucociliary transport to the gastrointestinal GI tract []. Nose-blowing clears from 0. Particles in the pharynx may reach the GI tract within one hour following deposition [], and a very small proportion around 0.

Ingestion is therefore the dominant exposure pathway to particles deposited in the extra-thoracic region. This region consists of the trachea, bronchi and terminal bronchioles []. Particles deposited here are of particular importance because lung carcinomas occur preferentially in the bronchial airways [].

Particles trapped in the mucous produced by the bronchial epithelial cells are typically cleared by mucociliary transport into the throat, and then expectorated or swallowed [28,,].

While it is generally accepted that mucociliary transport is the principal clearance mechanism in the first 24 h [], the rate of clearance depends upon on the clearance velocity of the mucous, particle shape, charge and surface geochemistry []. Furthermore, the ciliary movement is ineffective if the mucous is not of the correct viscosity due to illness or pharmacological action [].

As described in sub-Section 4. Alternatively, these particles may be phagocytosed and cleared by alveolar macrophages, and then either absorbed into regional lymph nodes via lymphatic vessels [] or transported into the ciliated airways and cleared via mucociliary transport []. This latter process may take weeks to months to complete []. Alveolar macrophages are important cells of the immune system, exhibiting major phagocytic abilities and in response to inflammatory reactions, release reactive oxygen species ROS.

Under normal exposure conditions, the components of the inflammatory reaction interact synergistically with ROS to eliminate foreign material from the respiratory system [].

Effects of Exposure Duration and Solubility Variation in the solubility of different arsenic compounds is important for exposure and risk assessment studies [57]. Deposited particles containing soluble arsenic compounds may expose nearby cells to a high concentration of arsenic [], which rapidly declines as the dissolved arsenic is removed from the lungs [] via absorptive mechanisms through the airway epithelium []. Lantz et al. Less soluble particles on the other hand that are retained in the lung expose the target tissue to arsenic for a longer period of time up to weeks , as observed in rodents after intratracheal instillation of inorganic arsenic compounds of varying solubility [,,,].

In the case of long-term exposure days to years , a steady state between deposition and clearance will be reached and the retained fraction will remain in the lungs for most of the exposure period []. Consequently, retention of particles containing soluble and slightly soluble arsenic compounds, especially those particles deposited in the alveolar region and sequestered in the lymph nodes, may expose cells to low doses of arsenic for a prolonged period of time.

It is frequently reported that long-term, low-level exposures to arsenic may be predictive of toxic effects [,,] and the pathogenesis of lung diseases, such as lung carcinoma []. Figure 3 illustrates that following inhalation, arsenic can follow different pathways leading to systemic absorption, and each pathway is highly dependent upon particle solubility and method of clearance.

Systemic exposure to arsenic may occur as a result of ingestion following mucociliary clearance, by dissolution in the lung fluid, direct entry into lymph nodes, or by phagocytosis. Systemic exposure to arsenic following inhalation of arsenic-bearing particulates could therefore be considered as a multi-pathway process with differing durations and intensities of exposure. Potential pathways leading to systemic absorption of inhaled arsenic, including clearance mechanisms and their associated durations and intensities of exposure.

Adapted from Wang []. Pulmonary Bioavailability of Inhaled Arsenic The bioavailable fraction of arsenic is considered to be an important determinant of toxicity and the associated disease response []. The term bioavailability may be interpreted in a number of different ways [], however and for the purposes of this review paper, the terms bioavailability and bioaccessibility will be used in accordance with the definitions prescribed by Ng et al.

Briefly, the portion of a contaminant that is absorbed into the body following exposure is referred to as the bioavailable fraction and is typically measured in vivo []. Bioaccessibility on the other hand refers to the soluble fraction of a compound following in vitro gastrointestinal or pulmonary extraction, and may be used as a surrogate for estimating the bioavailability of a contaminant [].

ALF is analogous to the fluid produced by macrophages during phagocytosis [] and has a pH of around 4. Biological fluid pH is an important parameter governing the solubility of arsenic and other metals. For example, arsenic solubility measured as a percentage of the total arsenic concentration of mine waste, was reported as When determining pulmonary arsenic bioaccessibility, it may therefore be prudent to also investigate the behavior of arsenic in the more acidic ALF solution.

A limited number of studies aimed at comparing the bioaccessibility of other metallic compounds in SLF and ALF solutions reported significantly higher dissolution rates of potentially toxic metals in ALF [,].

Conversely, Plumlee et al. Furthermore, the differences may also be attributed to the contrasting dissolution times used in each study: the mine waste and the dry lake dust samples underwent dissolution times of around 2 h [57] and 24 h [], respectively. Given that fine particles may be retained in the RT for prolonged periods of time Table 2 , incubation duration is a particularly important parameter in bioaccessibility studies.

Pulmonary bioaccessibility tests may be more reliable predictors of bioavailability than the widely-used aqueous solubility tests, since Rhoads and Sanders [] reported that arsenic, and other metals with low aqueous solubility, were highly soluble in the lungs of rats. Summary A summary of some of the key factors governing bioavailability of inhaled arsenic-bearing particles is proposed Figure 4.

Particle size governs the deposition location of inhaled particulates in the RT. Knowledge of the location and solubility of deposited particles is important for predicting the methods of clearance from and retention time in the RT, and therefore the types of lung fluids with which the particles may interact. Contact with pulmonary fluids can then release arsenic from inhalable arsenic-bearing particulates.

Since the retention of arsenic in the body is predictive of toxicity and the pathogenesis of disease [,,], the long-term pulmonary bioavailability of arsenic represents important consideration in the health risk assessment of populations living in mining-affected regions. Figure 4. Diagrammatic representation of the interactions between key factors governing the pulmonary bioavailability of arsenic. Importance of Metabolic Transformation in Arsenic Toxicity 5. Arsenic Biomethylation The role of metabolism in arsenic toxicity has been the subject of several detailed reviews [—] therefore the following discussion will provide an overview of the key concepts only.

Methylation is the major metabolic pathway for ingested inorganic arsenic in most mammals, and occurs via alternating reduction of pentavalent arsenic to the trivalent state, followed by oxidative addition of a methyl group [,—]. The remaining portion deposits differentially in other target organs and tissues including the kidneys and the lungs, as well as keratinized tissues such as skin, nails, and hair [—].

Various studies have demonstrated that the unstable trivalent intermediary products, MMAIII and DMAIII, are highly reactive and substantially more toxic than the inorganic and pentavalent compounds [,,,,]. Arsenic methylation is therefore widely considered to be a bioactivation pathway rather than a detoxification process [], with the resulting toxicity closely linked to the methylation status and valence state of the metabolites [].

Therefore, understanding the arsenic biomethylation pathway is critical to elucidating its subsequent action as a toxin and carcinogen []. Figure 5. Metabolic pathway of inorganic arsenic. Reprinted from Chilakpati [] with permission from Elsevier. Oxidative Stress as a Mode of Action for Arsenic Carcinogenesis Although several modes of action for arsenic carcinogenesis have been presented in the literature including oxidative stress, suppressed DNA repair, altered methylation patterns, genotoxicity and cell proliferation [], the oxidative stress theory has been intensively investigated and is supported by a substantial mass evidence [—].

Oxidative stress refers to an imbalance between the production of reactive oxygen species ROS , or free radicals, and antioxidant defense mechanisms [].

Free radicals are characterized by the presence of unpaired electrons and the associated reactivity can lead to tissue injury []. The first oxidative stress theory for arsenic proposed that a minor metabolite of DMAV, dimethylarsine a trivalent arsenic compound , is produced via a process of reduction in vivo [], possibly following a reaction between DMAIII and specific coenzymes important for cellular respiration [].

Dimethylarsine is estimated to be around times more toxic than DMAIII which is a potent genotoxin in its own right []. Through the addition of another molecule of oxygen, the dimethylarsenic radical forms the dimethylarsenic peroxyl CH3 2AsOO radical. The generation of oxidative stress as a potential mode of action of arsenic for its disease endpoints is an ongoing area of research and the associated complexities have been comprehensively reviewed [,,,]. The Human Lung as a Target Organ for Arsenic Toxicity Remarkably, arsenic is the only reported human lung carcinogen for which there is sufficient evidence of pulmonary carcinogenicity as a result of both inhalation and ingestion exposures [25,].

Smith et al. Distinguishing between the different routes of exposure is complicated not only by the arsenic transformations that take place in the body, but also the common target organs following the different exposure pathways []. The high variability in pulmonary solubility observed for different arsenic compounds [,,] also represents a confounding factor. For systemically absorbed arsenic, via inhalation or ingestion, research suggests that the pulmonary system may function as a target tissue for toxicity based on the observation that dimethylarsine is excreted as a gas from the circulation via the lungs [,].

High partial pressures of molecular oxygen in the lungs may promote dimethylarsenic and dimethylarsenic peroxyl radical formation as dimethylarsine is excreted and passed through to the respiratory system [,,]. According to Styblo et al. A reduced capacity to methylate arsenicals could be associated with an increased risk of toxicity due to prolonged retention of inorganic arsenic in the lung [].

In support of these observations, various in vivo studies have reported that arsenic toxicity is closely linked with a prolonged retention of inorganic arsenic in the lungs of rodents [,].

Further studies to examine the direct effects of inorganic arsenic compounds on pulmonary cells in order to elucidate the carcinogenic mode of action of retained arsenic-bearing particulates are suggested.

Direct Effects of Arsenic on Pulmonary Cells Some of the key effects of arsenic exposure on a range of different pulmonary cell lines are summarized in Table 3. Since the dose response of arsenic can be substantially different in animal models compared with in vivo human exposure [], this section will primarily focus on studies involving pulmonary cell lines, specifically human bronchial epithelial HBE cells derived from human lung epithelium [], alveolar macrophage AM cells, which are typically harvested from animals [], and human pulmonary fibroblast HPF cells.

HBE and AM cells represent the first lines of defense against foreign particles [], while HPF cells are important for regeneration and repair of chemically or mechanically damaged tissues []. As discussed by Dodmane et al. Pulmonary Cytotoxicity of Arsenic Cytotoxicity assays, and the measurement of representative parameters associated with cell pathology, are widely used to quantitatively assess the in vitro potency of a toxicant in the whole animal.

Clear dose-response relationships between arsenic concentration and cytoxicity have been established in HBE cells [,,—], HPF cells [—] and AM cells []. Figure 6 shows a notable decrease in HPF and HBE cell survival, in a time- and concentration-dependent manner, following 24 and h treatments with sodium arsenite []. A similar study found that arsenic trioxide was also toxic to HPF cells, however greater concentrations were required to produce similar effects [].

The differential cytotoxicities observed between these two trivalent arsenic compounds can be attributed to the fact that arsenic trioxide has a lower solubility in the lung than sodium arsenite []. Consistent with other lines of evidence presented in previous sections, recent studies confirm that methylated arsenicals are more cytotoxic to pulmonary cells than the inorganic trivalent forms [,,]. Cytotoxicity was quantified by measuring reductions in cell number, cell volume and colony formation following a 24 h exposure period [,].

Differences in arsenic-induced cytotoxicity endpoints reported in the literature may be attributed to variability in a number of experimental parameters: i the arsenic species or compound; ii the cell exposure duration; ii the cell systems used in each study; and iii the methods for assessing cytotoxicity endpoints.

Moreover, chronically exposed arsenic-transformed HBE cells constitutively generate cellular ROS probably hydrogen peroxide in the absence of further arsenic exposure []. Constitutive generation of ROS was found to be necessary for activating certain signaling pathways that regulate cell survival and cell proliferation [].

Enhanced arsenic-induced ROS generation and accumulation have been associated with dose-dependent responses in rates of cell proliferation and colony formation in HBE cells [—] as well as anti-apoptotic signaling []. Increased cell proliferation is a distinguishing characteristic of cancer cells and is crucial for tumor formation, while apoptosis plays an important role in killing abnormal cells so that they cannot form tumors [].

One study reported that increased cell proliferation of arsenic-exposed cells was mediated by anti-apoptotic-signaling induced by cyclooxygenase, COX-2 [], an enzyme associated with inflammation and other pathogenesis []. Cytotoxicity of sodium arsenite in: A human lung fibroblast cells, and B human lung epithelial cells, following 24 and 12 h treatments. Reprinted from Xie et al.

ROS production has also been linked with gene expression changes in HBE cells consistent with several of the proposed mechanisms for arsenic carcinogenesis [] including oxidative stress, DNA damage and a weakened tumor-suppression response [,,].

Suckle et al. The in vivo study identified phenotypic characteristics consistent with malignant lung epithelial cells [], and whole genome expression profiling identified potential mitochondrial oxidative stress and increased metabolic energy output, which is indicative of increased mitochondrial energy production [].

Importantly, chronic arsenic exposure may therefore target mitochondrial function leading to enhanced ROS generation and cancer-related gene signaling []. Antioxidants that target mitochondrial function could play a role in ameliorating some of the effects of arsenic in chronically-exposed populations [].

The Warburg effect is a metabolically supportive phenotype for the increased energy demands associated with the growth, proliferation and invasion of cancer cells see the review by Vander Heiden et al.

Unlike normal cells which produce lactate under anaerobic conditions only, the Warburg effect states that cancer cells generate large quantities of lactate regardless of oxygen availability [].

This study was potentially the first to link an environmental toxicant with the induction of the Warburg effect, and thus this discovery may assist in identifying the role of arsenic toxicity in other diseases associated with disrupted energy metabolism, such as diabetes and atherosclerosis [].

Arsenic-Induced Suppression of Alveolar Macrophage AM Function Alveolar macrophages AM serve as the front line of cellular defence against foreign material by clearing the air spaces of any infectious, toxic or allergenic particles that have penetrated mechanical defences, such as the nasal passages and mucociliary transport system [].

Under normal conditions, ROS are secreted by alveolar macrophages in response to phagocytosis or stimulation with specific agents, and play a key role in efficiently killing invading pathogens []. Various detrimental effects of arsenic on these important cell functions have been observed Table 3. For example, Palmieri et al. Soluble trivalent arsenic was notably more potent at inhibiting ROS production than the corresponding pentavalent form, with superoxide inhibition occurring at respective concentrations of 0.

Gercken et al. Both the studies by Lantz et al. Suboptimal phagocytosis by AM cells has been associated with a decreased ability to clear dead or dying cells from the respiratory system thereby leading to pathological inflammation [] as well as an increased susceptibility to pulmonary infection such as pneumonia, in respiratory health-compromised individuals []. Arsenic-Induced Inhibition of the Wound Healing Response in Human Bronchial Epithelial HBE Cells As the respiratory epithelium is frequently injured by inhaled pollutants or micro-organisms, the epithelial wound repair response plays a critical role in the maintenance of epithelial barrier integrity [].

Concentration-dependent arsenic-induced inhibition of wound healing in mechanically-wounded HBE cells has been demonstrated Table 3. The highest concentration ppb resulted in the expansion of the wound area in the first hour, followed by Further analyses indicated that overexpression of matrix metalloproteinase MMP-9 , an enzyme important for human respiratory healing and wound closure [], leads to dysregulated wound repair in the presence of arsenic and reductions in cellular migration [].

Furthermore, general interference with airway ATP signalling has been linked with chronic lung diseases, such as chronic obstructive pulmonary disease COPD [].

Arsenic-induced suppression of the wound healing response as a result of both acute and chronic exposures well below levels typically associated with inhalation where arsenic has been linked with disease presentation may ultimately result in a reduced ability of the lung epithelium to effectively and sufficiently close a barrier breach [,,].

Wound healing assay of 16HBE14o- cells exposed chronically 4—5 weeks to 0, , or nM sodium-arsenite: A Representative images of initial wounding left column , 30 min post-wounding middle column , and 1 h post-wounding right column. Reprinted with permission from Sherwood et al. Direct effects of arsenic exposure on human bronchial epithelial HBE cells, human pulmonary fibroblast HPF cells, and pulmonary alveolar macrophage AM cells. All experiments were conducted in vitro, unless otherwise specified.

Specific cell lines are listed in accordance with the abbreviations used in each study. Human bronchial or alveolar epithelial cells Dose-dependent reduction in cell survival; chromosomal aberrations Na-arsenite 0. Epidemiological and Exposure Monitoring Epidemiological studies provide an important link between health effects and air pollution exposure, because they provide an accurate representation of the health records and environmental conditions pertaining to a well-defined population [].

In this regard epidemiological studies of industrially-exposed cohorts conducted during the mids have provided strong evidence of a causative role for airborne arsenic in respiratory cancer mortality. This has resulted in a diverse but important body of historical epidemiological evidence accrued on the health risks and disease outcomes associated with known, high level occupational inhalation exposures [—]. However, with increasing concerns regarding the effects of peripheral exposure to potential carcinogens, there is increasing attention directed at the health of communities living in the vicinity of smelting and mining operations and uncontained mine wastes and tailings.

Notwithstanding the common source of the concerns, it has been observed that there are important differences between the situations of occupationally- and environmentally-exposed cohorts. Occupational studies usually differ methodologically from the environmental investigations in that there is a contained area of contamination and a restricted population who are exposed to high levels of airborne material.

Whereas studies of environmental exposure in communities living in arsenic-affected areas usually start at birth, and the exposure itself may not be recognized for many years and may be intermittent, thereby rendering epidemiological studies more difficult to design and interpret, particularly since they are observational only. For these reasons, we report separately on the findings for each exposure type, since they will address different aspects of the effects of airborne particulate matter on health.

Similar conditions were reported at the Ronnskar smelter in Sweden []. Lower values for airborne arsenic were typically found in areas such as the administration departments, electrical and machine workshops, outdoor environment, building department and general office area [,]. Symptoms of severe arsenic exposure among smelter workers observed during the s included a notable rise in the rate of sick days due to various acute and chronic respiratory disorders [].

Arsenic trioxide-laden dust generated as a by-product of the copper smelting process deposited in the nose and respiratory airways forms arsenous acid on contact with moisture, resulting in necrosis of the mucous membranes []. Emphysema and ischemic heart disease were also noted [].

Despite the prevalence of these non-malignant respiratory disorders, meta-analysis of the available epidemiological data did not detect any statistically significant excesses in mortality among smelter workers compared to the control cases [,]. The first cases of lung cancer that were traced to the work environment occurred at a Swedish smelter in the s whereby a five-fold increase in lung cancer mortality compared with controls was observed []. Occupational health investigations at other smelting operations, as well as comprehensive reassessments and meta-analyses of previously reported data, demonstrated strong links between airborne arsenic exposure and respiratory cancer [—,,].

Lubin et al. Over a 50 year period, deaths due to respiratory cancers were observed, comprising lung cancers and 14 cancers of the larynx.

No other cause of death was found to be associated with arsenic exposure, with the possible exception of COPD []. In addition to smelting, other studies have demonstrated a link between lung cancer and arsenic exposure at hard rock mining operations [].

One of the most comprehensively investigated cases relates to four tin mines and three associated smelting operations in southern China, where underground miners were exposed to respirable concentrations of arsenic ranging between 0. Chen and Chen [] reported that the rates of lung cancer were strongly associated with cumulative dust exposure, arsenic exposure and duration of exposure. While the magnitude of risk from mining odds ratio OR , 8.

The potential additive carcinogenic effects of inhaled crystalline silica, cigarette smoking and exposure to radon could not be ruled out []. To examine the distribution of arsenic in the body following long-term exposure, researchers collected and analysed tissues from deceased workers from the Ronnskar smelter in Sweden, and from various controls, and correlated these with the cause of death []. Post-mortem investigations discovered elevated levels of arsenic and seven other metals of concern in the lung, liver and kidneys of the deceased workers [,].

Although the arsenic content diminished in liver tissue, a longer biological half-life of arsenic was observed in the lung []. Similar findings have been reported in animal studies []. An extended biological half-life and retention of arsenic in lung tissue may have implications for the development of respiratory disease. Lung cancer risk in a cohort of Chinese tin miners was more dependent on the duration of arsenic exposure than then intensity [].

Conversely, exposure intensity was more important in determining the lung cancer risk than duration in smelter workers [,], indicating a need for comparative studies with consistent exposure and outcome criteria. However, occupational inhalation exposure to airborne arsenic remains a serious health issue in some localities. Urinary arsenic speciation analysis revealed that higher occupational exposures and skin damage cases were associated with a decreased capacity for arsenic methylation [].

Similar results have been reported elsewhere []. These findings support the premise that suppressed methylation capacity results in an increased risk of arsenic toxicity due to the retention of arsenic in the body []. Inadvertent Environmental Exposures It has been found that a number of populations around the world live in the vicinity of active or abandoned mining operations [28], and there exists overwhelming epidemiological evidence suggesting that there is an increased risk of arsenic exposure for these communities [4—9,78,,].

These studies show that children are particularly susceptible to inhalation exposure since they respire a greater relative volume of air with respect to their size, and may therefore be exposed to correspondingly higher levels of airborne contaminants than adults. Children also have an increased likelihood of coming into contact with soil and dust through playing in dirt contaminated with arsenic residues [78,,]. As a consequence, many human exposure monitoring studies have focussed on measuring arsenic exposure in child populations [4,7,,,,].

Measurement of arsenic in human nails, hair, urine and blood concentrations are commonly used for determining arsenic uptake in humans [78,,,,]. Blood and urine arsenic levels provide a reliable short-term measure of arsenic exposure because arsenic is readily excreted from the bloodstream via the kidneys [25].

Analysis of arsenic deposited in the toenails and hair provides useful indicators when the measurement of long-term, low-level arsenic exposure is required [—]. It has also been shown that analysis of the arsenic content of particles that have adhered to the hands of children can also be used as an indicator of potential exposure [4]. It is important to note that although such biological markers of arsenic exposure as those reported above are useful for predicting the degree of risk, elucidating the exact pathway to environmental uptake of arsenic in localities where multiple exposure pathways exist is not straightforward [].

However, particles that have been deposited on the ground or other surfaces may be either ingested due to physical contact, or resuspended as dust, and then inhaled [19,]. From the work reported in the above investigations, it is clear that human arsenic exposure is governed by a number of variables.

There are important inverse relationships which have been frequently reported between the concentration of airborne arsenic levels and the distance from the source, and between biological arsenic levels and the distance of the home, playground or school environment from metal smelters and other mining operations [4,7,,].

Buchet et al. Correspondingly, the average arsenic concentration on the hands of children living within the 1 km zone was ten times greater than those children living further away [4]. Similarly, Hwang et al. As cautioned by Frost et al. Milham and Strong [] demonstrated that fluctuations in urine arsenic levels among children living near a copper smelter were closely associated with changes in prevailing wind direction.

In this study, the urine arsenic concentrations of children living downwind of the smelter decreased simultaneously with shifts in wind direction []. Another study of children living near a former copper smelter site reported elevated biological arsenic levels during the summer, a time when seasonal factors enhance the mobilisation of dust from uncontained mine wastes, such as tailings and flue dust []. Carcinogenic and non-carcinogenic risks associated with inhalation exposure to atmospheric arsenic emitted by coal combustion have recently been estimated in exposed Chinese populations [9,].

Consequently, it has been estimated that more than two million residents in Beijing have an increased risk of developing cancer as a result of probable exposure to atmospheric arsenic, generated principally from coal combustion [9].

Recent measures of daily total inorganic arsenic inhalation exposure values for Beijing residents 0. These studies indicated that daily intakes of arsenite and arsenate in Beijing were 0.

Based on these exposures and the known effects of both arsenite and arsenate as carcinogens, an estimated excess cancer risk of 4. In a similar study, Cao et al. Impacts of Climate Change The effects of climate change are predicted to have an impact on mine waste chemistry and mobility. The predicted rise in global temperature is expected to increase the rate of mine waste weathering by a factor of approximately 1.

Prolonged weathering of mine waste materials will lead to the formation of a greater abundance of soluble salts [67]. Moreover, the anticipated increase in extreme weather conditions are likely to lead to a greater frequency and intensity of dust storms, as already observed in localities such as Asia, Africa, and Australia [,] which in combination with the weathering, is likely to result in an increase in the occurrence and bioavailability of airborne arsenic.

Investigations surveyed in this review, taken from disparate but complimentary lines of inquiry, strongly support a causative role for inhalation exposure of inorganic arsenic species in the aetiology of lung cancer and other respiratory health disorders, suggesting that a strong focus on this exposure modality is crucial for the long-term health of affected populations.

This review has highlighted the need to conclusively elucidate the exact mechanisms of arsenic-induced toxicity from exposure to PM in order to facilitate the prediction and diagnosis of adverse health consequences, and thereby enable adequate risk assessments to be undertaken. Recent developments in various complimentary areas of research within the overarching field of medical geology including geochemistry, biomedicine, toxicology and epidemiology, have identified a number of factors that play a key role in understanding these varied phenomena.

These include: i the effects of differing environmental variables leading to exposure; ii the influence of particulate characteristics on the initial deposition location in the RT; iii the differing toxicity levels of particulate-borne arsenicals, their species and their metabolites, and iv the complex pathogenesis of arsenic-induced lung disease. While it is clear that absorbed arsenic exerts cytotoxic and genotoxic effects on pulmonary cells following both acute and chronic exposures, important species- and dose-dependent differences in toxicities between the two exposure regimes have been observed.

It is also clear that particle size plays a major role in governing the deposition location, solubility, methods of clearance and retention time of arsenic-bearing species in the RT, and hence has a direct effect on the range of arsenic metabolites released to the body. Current research indicates that the exposure to arsenic and of these metabolites is predictive of the pathogenesis of lung disease, which leads to the conclusion that the long-term pulmonary bioavailability of arsenic in PM requires serious consideration in health risk assessments.

Development of a series of standardized lung bioavailability assays that assess both short- and long-term exposures would be beneficial, particularly when drawing comparisons between studies.

The potential for human exposure to airborne arsenic will inevitably increase in the future due to several key factors.

With increasing wealth and population, consequent increases in urbanization will inevitably lead to encroachment on and disturbance of existing contaminated sites. In addition, it is predicted that climate change will have a considerable impact on mine waste chemistry and mobility, effectively amplifying every other risk factor, and increasing the urgency in gaining a greater understanding of all aspects of arsenic in our environment.

It is strongly recommended that future research prioritizes identifying human populations and sensitive sub-populations at risk of exposure, as well as developing long-term, cost-effective methods to adequately contain or reduce airborne emissions from known sources.

The views of the authors do not necessarily represent those of the CRN. Author Contributions All authors contributed substantially to the work presented in this manuscript.

As principal researcher, Rachael Martin made a substantial contribution to this work which was undertaken in association with her PhD program. Kim Dowling provided critical analyses and commentary during the development of this manuscript, ensuring that the reviewed literature was accurately interpreted. Dora Pearce provided extensive commentary on the epidemiology and other health-related sections of this manuscript, ensuring that all findings related to health outcomes were accurately represented.

With an extensive background in the field of chemistry, James Sillitoe has made substantial contributions to this paper, particularly regarding the technical aspects. Singarayer Florentine assisted with the development of the underpinning theory and conceptual framework for this manuscript, as well as assisting with major re-drafting and editing.

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