Armin E. Elsaesser Fellowship – 2017/2018
Pallanza Bay, Italy. 2010. This is where this project started. [This is also where Alessandro Volta discovered methane in the reed beds way back in the 1770s and where plumbing still goes whang-o now and again when his discovery bubbles up in the wrong places]. I was there for a chlor-alkali site characterization and the question of who did what when and how that might make different parties more or less liable in the apportioning of remediation costs. There were many, many parts of that site characterization that were interesting, but what caught my attention up there along the shoreline was this: The Museum of the Art of Hat-Making. Yeah. There was the seed of a story there.
Mercury Nitrate – (Hg(NO3)2) – The Hatters
Did you ever think about the Hatter? I mean, really think about the Hatter? That story is Alice’s, after all. She follows a rabbit in a waistcoat down a hole and she shrinks and she grows and she marvels at the strangeness of it all. But there’s the Hatter. And he speaks in riddles and appears confused and alternates between timidity and irritability and eccentricity. And whether or not it was what Lewis Carroll intended, and recognizing that Carroll never used the phrase specifically in his works, there is that association: Mad as a hatter. The Mad Hatter. And we’ve carried that association with us and may not really think about where it comes from. But where it comes from is this: occupational exposure to the vapors of mercury nitrate (Hg(NO3)2). Mad hatter syndrome. The Danbury shakes.
Beginning in the 1600s, mercury nitrate was used in the treatment of animal pelts to make hats. To make a hat from an animal pelt the fur must be separated from the skin and matted to form felt. The process of making a hat: matting or felting (or “carroting”) fur, shaping it, boiling it to shrink fibers and give structural stability, re-shaping it, then allowing it to dry – historically employed mercury during the felting stage. During the subsequent shaping, boiling and drying, mercury vapors were released. For those employed in poorly ventilated workshops, exposure to mercury vapors was an occupational hazard.
Not all forms of mercury are created equally. And not all occupational exposures are equally hazardous. And the felting of hats was not the first enterprise in which exposure to mercury vapors was recognized as a danger. It is, however, the enterprise that brought a particular set of symptoms into the popular consciousness; mercury poisoning through chronic occupational exposure – erethism – may result in symptoms including confusion, loss of coordination and muscular weakness, and behavioral traits including shyness, irritability and anxiety. Physical expressions of erethism may include redness in fingers, toes and cheeks, bleeding from the ears and gums, loss of teeth and nails, and excessive sweating. Likely the most common physical expression of erethism in those suffering from chronic mercury exposure is tremors.
And where else had these symptoms been seen? In alchemists, in mine laborers, and in those seeking treatment from conditions—such as syphilis—that presented with a similar, but distinct, set of neurological effects.
Mercuric Chloride (HgCl2) – The Alchemists
First, the name: mercuric chloride. It is not technically a salt. It is a chemically unstable, linear, triatomic molecule. That chemical instability means that the crystalline solid will directly vaporize. It will sublime. Mercury chloride can be made in several ways: by reacting mercury nitrate with hydrochloric acid and/or by mixing mercury sulfate with sodium chloride. Following either methodology, crystals of mercury chloride will form. Mercuric chloride has had many uses—in photographic manipulation, tanning, wood preservation, medical treatment (most specifically for syphilis, from which poisoning was so frequent that it was often unclear whether the patient was suffering the effects of their illness or the cure) and in alchemy.
It was the alchemists who first called mercuric chloride by the names corrosive sublimate or Venetian sublimate. A simple recipe for its preparation included elemental or sulfide of mercury (i.e., cinnabar), green vitriol (i.e., iron (II) sulfate), salt (NaCl) and nitre (i.e., saltpeter KNO3). When heated or roasted, a white, acrid crystalline sublimate of mercury is formed.
And what was it that the alchemists wanted with corrosive sublimate? Was the goal to use it, or simply to make it? What did it do?
The answer begins with the naming: “the mercury”. al-zā’būq in Arabic; azoth in Latin. And with the Caduceus – that symbol of the intertwining: that which is outside doubles back on itself, that which is inside turns outside – the Caduceus was the visual representation of the metaphor that was alchemy: the transmutation of the base into the pure; of lead into gold and, by analogy, of the coarse in human nature into something noble. And mercury, hydrargyrum – the “quick” or the living in the silver – was the physical manifestation of this idea of a transformative essence. Mercury was the genie in the bottle that was earth: pour elemental mercury through a sludge of mineral ore and any gold present will be bound up with the mercury. It will be amalgamated. Decant off the sludge and heat the amalgam and after all the mercury has volatilized, what will remain there in the the pan when the mercury is gone is the gold. And while nothing was created – the gold was present all along, after all, and mass – if both the mercury and the dross were recovered and weighed – would be conserved – the process is an act of concentration and of purification that has the appearance of magic. The process is an alchemy.
And is this not ultimately what the alchemists were after? A laboratory demonstration of essential transformation? A visual proof of a metaphor? That with the addition of spirit – the quick in the silver – something could be created or could at least be liberated that transcended the limits of human experience and shone. That which is inside turns outside. That which is outside doubles back on itself. The Caduceus.
Elemental Mercury (Hg0 ) / Cinnabar (HgS) – The Miners
How do you tell the story of something that is no longer there? Maybe you start with this: It’s a bit less than 5 hours by train from Cadiz to Madrid. There are thirteen trains per day, most days of the year, and you’re on board and you’re thinking about work. Or the weekend. Or the trip you’ve just finished. Or the vacation time you’re about to begin. And ~ 400 km from Cadiz – at a crossing where you might not even see the sign – you’ll pass within 60 km of the Almaden mine. And the name might ring a bell or it might not – we all stare idly out the same window and notice different things – but the train has just passed within 60 km of the single largest mercury deposit in the world. A deposit that – until mining ceased in 2004 – was in continuous operation for ~ 2000 years and in that time yielded approximately 1/3 of the world’s total mercury ore.
This one location.
And nobody really understands it: the distribution of that element. The chemists don’t understand it. The geologists don’t understand it. Why do elements concentrate like they do? In this case, in Spain. Slovenia. Italy. Peru. California. Why is the mercury where it is?
And there at the top of the list – that first location – in Spain – is the Almaden Mine. It is the largest of all deposits – the ore body there so rich in cinnabar that elemental mercury – the mercury in thermometers – sweats from the veins in the rock walls.
If you’re a scientist or an engineer and you’re thinking about mercury in the environment you’re thinking of numbers like this: in terms of concentration, mercury is somewhere around 1/20 of a part per million (ppm) as a “global average background” in soil. As it moves around the globe – in mining waste, in air, in water – that concentration enriches and it increases: it is around 1/10 of a part per million in soil on the otherwise uncontaminated downwind edge of a continent where everything carried on wind currents – in this case, specifically the mercury found in coal – ends up eventually sifting down and depositing; it is up to one part per million in that coal itself; it is up to 10 parts per million in contaminated sediment – maybe downstream of a facility that used elemental mercury in a room-sized battery to make bleach or PVC or DDT – downstream where the momentum of the river changes and whatever is in suspension settles to the bottom and is stored; and it is maybe 100 parts per million in the soil in a place like Kyrgyzstan where mercury is still mined and environmental controls aren’t what they are elsewhere on the planet.
These numbers are context. In the Almaden Mine, the mercury concentration in the ore body reaches 8%. That is, within the rock itself, the concentration of mercury reaches 80,000 parts per million. Working in this environment was – and remains – very hard on the miners.
When mining at Almaden began in earnest in the 1500s – after the discovery of silver in the Americas and the realization that – with the newly invented patio process – access to mercury meant access to silver – the Spanish Crown gave convicts a choice: the galleys or the mine. It is estimated that during the period in which the mines were worked principally by convicts, ~ 25% of those convicts died during their term of labor, mostly and most likely from mercury exposure. An unknown percentage of convicts were released from their term of labor insane. Later, the work force also included slaves and gypsies, arrested, in their case, for anything and everything including the crime of speaking Romany. For slaves and for gypsies, the terms of their sentence were indefinite: for slaves, because they’d been purchased outright; for gypsies because for their term of sentence to end, the Crown required that they prove evidence of a settled home to return to. And they – the Romany – by confluence of culture, vocation and social caste, could never fulfill this criterion for legal release. For these individuals, working the mine at Almaden was a life sentence.
And you can’t really talk about the metal without also talking about the mineral: cinnabar. Or more correctly, the minerals: cinnabar and metacinnabar. The red and the black. Or in the scheme of the philosophers and the alchemists, the light and the heavy. Even more correctly (though with no greater clarity), there are actually three forms of the mineral: cinnabar, metacinnabar and hypercinnabar. The red and the black and the other black. The transition between these minerals – if it can be thought of as a transition – if one form can actually change into the next – is still a conundrum. Temperature seems important: heat metacinnabar to > 400 C and it can be transformed to cinnabar; continue heating to > 500 C and hypercinnabar may appear. That you can create these transitions in the laboratory does not mean they occur in nature though. And while it is generally agreed that the three forms of HgS are distinct minerals with distinct crystal shapes, what happens outside of the laboratory when high temperature magmas cool and minerals begin to precipitate is anyone’s guess.
In all cases though, the mineral is HgS. And cinnabar – the red form – has been used by people for over 10,000 years – for as long as we’ve had that thing that we call culture, really – as a pigment. Vermillion. It has appeared throughout the world’s history in cosmetics, lacquers, wall paints, ceramics, and medicines. Yeah – I know – in medicines. And if you want to convert HgS to Hg0 you simply roast the ore. The sulfur will be oxidized and the mercury will be liberated. And if you’ve roasted in a retort or some other vessel with a lid, the volatilized mercury will be captured and will cool and condense and dribble down as Hg0. Elemental Hg. The stuff of thermometers.
And here is where I go back to thinking about Almaden. And the richness of the cinnabar deposit there. And the fact that Hg0 occurs at ambient temperatures in the ore body itself. That sh*t’s wild.
Mercurous Chloride (Hg2Cl2) / Mercurochrome (C20H8Br2HgNa2O6) – The Doctors
It’s hard to know where to begin with the medicines. Because there are medicines and there are medicines, you know? Which means, there are doctors and there are doctors. And this shouldn’t come as a surprise, the modern medical practice – and modern physicians – having come, after all, out of the medieval medical practice and the medieval physicians – the chirurgeons and the barbers, the bone-setters and the blood-letters. This was medicine. And so when you needed something other than the bit between the teeth or the scalpel, where you went for remedy really didn’t have a title. If you were lucky and the person in question was observant and had knowledge of plants and minerals, you could call them healers. Or the apothecary. If you were unlucky or naive or desperate and the person in question was dishonest, you could call them charlatans. Or quacks. Or snake oil salesmen. And there’s really no knowing when the process of distinguishing the medicines from the medicines really began – although it took off in earnest in the USA with the creation of the FDA in the early 1900s – but an example of the old style can tell the story here, and one example of that old style is Dr. Rush’s Bilious Pills.
Dr. Rush’s Bilious Pills. also known as Dr. Rush’s Thunderclappers. also known as the Thunderbolts. And before you read any further – take a guess at what they did. What they are (or were – you, of course, can’t get them anywhere anymore) is an approximately 50:50 mixture of mercurous chloride (Hg2Cl2) – also known as calomel – and a Mexican morning glory known as jalap. As a laxative, this mixture was – to use the terminology of the day – cathartically effective. The most famous users of Dr. Rush’s Bilious Pills were Merriwether Lewis and William Clark. Yeah, that Lewis and Clark. And if you are interested – for whatever reason – in finding precisely where they camped you could begin by identifying the general locations of their campsites from their excellent maps and then sampling the soil. Where the mercury concentrations in the soil spike, you’ll have found the camp privies. Yeah – 200 years after the Corps of Discovery Expedition and their journey to the Pacific, and you can identify precisely where they experienced cathartic effectiveness by the residual soil contamination. There was a lot of mercury in that large white bilious pill.
Calomel’s use as a medicine dates to the Middle Ages, where if a little did a little good – rubbed on the skin as an effective topical disinfectant – a lot must do a lot of good, right? From this thinking came the use of calomel – as well as other mercury forms – as a treatment for syphilis – ingested, injected, inhaled as vapor, transdermally administered with the patient placed in a steam box until they drooled, salivation having been considered the treatment for expelling the humors that were causing the symptoms of the disease. One night with Venus, a lifetime with Mercury, went the old saw, and did it work as a treatment? Well, in the sense that the patient didn’t die of syphilis, at least sometimes, then yes, although, also because they sometimes died stark raving mad of mercury poisoning first. And also, yes, in theory, in that Medieval sense of if I have a reaction to something it must be working and if I take it while thinking on my illness then that reaction i’m experiencing must be something like a cure, two statements that tell you nothing about the effectiveness of mercury as medicine and everything about that ancient view of what medicine was and did.
Mercury was, and is still, an ingredient in skin lightening creams, that sought after pallor actually an early sign of the anemia that can accompany mercury poisoning, and, until recently, in topical disinfectants, the two most commonly still recognized by name being Bag Balm (which contained mercury until the mid-20th century) and mercurochrome. The dark red swab and sting. Mercurochrome wasn’t banned until 1998, and while applying a tincture of mercury directly to your skin probably wasn’t the smartest of ideas, it was far from the stupidest either: as a disinfectant there is no disagreement that mercury works and as a method of administration, topical application of a large organo-mercurial molecule in small doses is relatively benign. As a disinfectant and anti-microbial added to multi-dose vaccines, however, you get thimerosal and a whole new chapter in the book on medical quackery.
Thimerosal – (C9H9HgNaO2S) – The Controversy
There are two stories to tell here. Or maybe one. Or maybe none at all, there being no actual link between mercury exposure and autism. Because that is the story – or the question, really: does exposure to thimerosal – a mercury compound used as a microbicide in multi-dose vaccines – increase the potential for childhood development of autism? And even knowing that the answer is no – that the original research on which this link was hung was so flawed that the editorial body of the publishing journal took the unusual step of retracting the publication and the doctor in question lost his medical license over the accompanying conflicts of interest, the association in people’s minds still lingers. And we could ask the question why? And the answer would have more to do with sociology and our need to attribute causation where there may have only been temporal correlation; or an observation that adding something – however suspect – to the storytelling databank remains far easier than removing it again – pop culture and the love of controversy doing what they do to keep misinformation circulating far longer than it should; or simply that the original publication landed where and when it did – at a time that we’d come to understand that that 1950s promise of Better Living Through Chemistry masked a relationship between industry and regulation that was only ever incidentally about the protection of human health.
But there are two stories to tell here. Or maybe only one, the other having caused the problem that began with this: Wakefield, A.J. et al. 1998. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 351: 637 – 41. The original paper – since stamped retracted and with an editorial addition to view the commentary page – can still be found on-line: http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(97)11096-0.pdf
12 children, many of whom, it later became apparent, were already suffering from observable developmental delays, had been given the MMR vaccine and had presented to their physician with symptoms including language regression and gastrointestinal distress. As described in the paper, while the authors’ observations were not consistent with causality – that is, there was no explicit claim in the paper that the vaccine caused those symptoms – they did present an association that, while later proving to be more complicated than had been initially described, suggested an interesting coincidence in timing between administration of the vaccine and onset of symptoms. So, there was the paper. And thousands of papers are published every year, but this one hit a nerve. And there are many many details here that are important but two things happened in the aftermath that were so disjointed that it is fair to say that if you see one you can’t see the other: 10 of the 13 authors on the original paper signed a formal retraction of their names as well as the paper’s conclusions, and (the then still) Dr. Wakefield began to inch his public discussion of the paper’s conclusions away from interesting coincidence and towards causality: that some aspect of the MMR vaccine was causing autism. And the ingredient in the vaccine that he proclaimed was the culprit was the mercury-containing preservative thimerosal.
The second story – or maybe the one story that actually matters – addressed the problem that was (and still is) the now former Dr. Wakefield’s opinions. Or it addressed one of the problems – the other larger problem still being the experiment we have collectively decided to conduct on ourselves by testing the limits of herd immunity and continuing to be surprised when the result is outbreaks of mumps and measles – this story addressed the problem of what to do with a discredited research study that continues to mainline conspiracy theory to those who need their fix. For that problem, the only real answer that science can provide is better science, and so the second story begins with this: Gerber, J.S. and P.A. Offit. 2009. Vaccines and Autism: A Tale of Shifting Hypotheses. Clinical Infectious Diseases. 48:456–61. This study can be found here: http://cid.oxfordjournals.org/content/48/4/456.full.pdf
In unusual and greatly appreciated eloquence for a scientific journal, this paper summarizes the 20 peer-reviewed epidemiological studies that have tested for any perceived association between either the MMR vaccine or thimerosal and autism. For these 20 studies, exactly zero support an association between the vaccine, the preservative, and the disorder. Zero. Ecological, case-controlled, retrospective cohort, and prospective cohort studies. Zero. Thousands and thousands of children versus the 12 in the original study. Zero. If you see the other, you can’t see the one: that there is no rational explanation for the continued belief that exposure to thimerosal causes autism. But controversy goes round and round like it does, and, along with those who now contract diseases that shouldn’t still exist in the Developed World, it is our understanding of what science is for that suffers.
Mercury Fulminate – (Hg(CNO)2) – The Anarchists
2007. That was the year the chemists finally sorted out the how. That it was explosive – sensitive to fire, friction, pressure and impact – has been known since the alchemists. Mix it with nitric acid and ethanol and, to paraphrase Pogo, it’s that one there what goes whang-o. By the mid-1800s, it had found its way into blasting caps and detonators, Alfred Nobel, amongst others, using it to fire off dynamite and other munitions. And, if it’s that explosive, is it any wonder that the Anarchists found their way toward it too? Felice Orsini had the first go in 1858, lobbing a mercury fulminate bomb at Napoleon III. That one ended poorly for many people, excluding the Emperor, but including Orsini. The design for that bomb still bears his name.
The bomb itself looks like a hedgehog, each spine or horn containing fulminate, and because fulminate is also percussive – exploding in response to shock – all that’s needed for that bomb to detonate is for it to land. Orsini’s bomb was used again in Spain in 1893 – in a tit for tat – you kill my anarchist and I’ll raise you an act of the same – involving a General of the Carlist wars. And in perhaps a sober appreciation or respect for the roll that Worker’s Parties played in the sociopolitical overturning that was in many ways the driver of early 20th Century European politics, that bomb – handed to a laborer with that peculiar combination of the holy and the terror that is the Lucifer, the bringer of light – is enshrined in stone in Gaudi’s unfinished drip castle of a cathedral, The Sagrada Familia in Barcelona. Yeah – in there with what we’ve come to expect in the statuary of saints and angels and the Apostles, is the power of temptation and a hand held bomb. Wild, isn’t it?
And then, finally, in 2007, an X-ray diffraction experiment that began with a synthesis and a cautionary note: that, once crystallized, fulminate must be stored underwater and in the dark. For safety sake, the chemists examined one single crystal – 0.05 x 0.05 x 0.01 mm of it all – behind a blast-proof hood, and what we now know is this: ONC-Hg-CNO, or more precisely: O−N≡C−Hg−C≡N-O, that triple bond in evidence between each carbon and the adjoining nitrogen, and that N-O bond with its well understood instability. What is interesting here is that when it explodes – drop even a single crystal and up it goes – it is the fulminate – the −C≡N-O – that will decompose violently. The quicksilver – the Hg there at the center of it all – holds steady. There are other fulminates as well – specifically gold, silver, and platinum – and maybe all there is to say about them is that you gotta admire that neighborhood on the Table. That’s a pretty stable lot there just doing their thing.
And what of Mister Roberts? and Breaking Bad? – those two cultural touchstones, two generations apart – with Walter White acting in the here and now, maybe, as the most notorious of the chemical anarchists. Perhaps what they’ve left us with is this: the phrase and the palm and the firecracker, for the former; and the warning – there in that Crazy Handful of Nothin’ in the latter: don’t bring a bag of mercury fulminate to a drug deal. There isn’t anything about that situation that can end well.
Mercuric Sulfate – Hg(SO4) – The Castle Town and the Catalyst
The Chisso Corporation and Minamata Bay, Japan. 1956. It was an acetylaldehyde plant and mercuric sulfate was the catalyst. What hadn’t been understood when production had begun was that the reaction of acetylene and water in the presence of mercuric sulfate creates methylmercury as a byproduct. Not all forms of mercury are created equally. And not all exposures are equally hazardous. Exposure to significant concentrations of methylmercury is hazardous, and in the case of Minamata Bay, direct discharge of methylmercury into the environment was a slow motion catastrophe on an industrial scale.
In Minamata Bay, symptoms started first in the cats. The locals called it dancing cat fever. Cats are, of course, smaller than humans, and they commonly ate the fish washed up on the shoreline or fed to them by fisherman, and in doing so, they ingested what was biologically accumulating (* – see footnote) from the Chisso Corporation discharge. They began behaving strangely with tremors and a muscle weakness that made them appear to dance. What those symptoms represented was acute methylmercury poisoning. When unusual symptoms started appearing in children, they initially included numbness, difficulty in walking and difficulty with fine motor skills. Progressive symptoms including effects on speech, hearing, swallowing and vision. Convulsions could occur. Patients slipped into comas and died. By the time the full range of neurological exposures and effects had been catalogued – both for those living and those who had been exposed in utero – over 2,000 people had been poisoned, an unknown number of them having died specifically from methylmercury toxicity. Litigation against Chisso Corporation and compensatory claims against the Japanese government continue to this day.
One question we can ask is how did this happen? How did this company conduct business in the way it did for as long as it did without a clearer understanding of what was happening while it was happening? And there are many answer here: Cultural naiveté played a role – both about the effects of chemical exposures and the misplaced faith that Chisso Corporation – employing many of the heads of household in town – must certainly be concerned for the town’s wellbeing. The impact of the 2nd World War and the production imperative that allowed the relaxing of already lax environmental controls – most written in those days from either the vantage of efficiency (i.e., polluting the water that a company needs to redraw into circulation as process water is bad business), or ignorance or that combination of classism and racism that permitted the poisoning of the disenfranchised for the greater net good that industry was providing for all – played a role. As did an incorrect understanding of how estuaries function and the extent to which what is discharged is actually recycled by the tides until the majority of whatever it is settles to the bottom rather than flushing out to sea. And, ultimately here, the low cost and ready availability of mercury as an industrial catalyst also played a role – in the case of Minamata Bay, the concentration of inefficiently recovered (i.e., waste) mercury in the sediment adjacent to the factory discharge reaching 2 parts per thousand, a concentration that could be (and later was) excavated and reclaimed.
And it was a different chemical – in this case, it was polychlorinated biphenyls (PCBs) that were discharged – and a different location and industry – in this case, the harbor in New Bedford, MA and the former Aerovox Capacitor Company. But it was the same story – WWII and the rush for production and that blind eye toward whatever basic process regulations might have been in place to even minimally protect human health and the environment – and the impact was the same: once the genie is out of the bottle, there is no easy way to make contaminated places clean again. And sometimes there is nothing else to do about all that mess I witnessed but to cry.
* Regarding biological accumulation – or bioaccumulation – or, more technically in this case, biomagnification – of methylmercury, we are all exposed to methylmercury in low concentrations, principally by eating fish and particularly those fish that are long-lived and high on the food chain – think tuna, swordfish and shark – as examples. In the body, methylmercury is somewhat more fat soluble and protein binding than you’d expect for a metal, the methyl group (CH3 -) providing a key to those cells where we store fat, and mercury itself binding well to certain and specific proteins. For these reasons, we – as well as all other organisms – tend to hold on to methylmercury longer than we hold onto other forms of mercury, and because methylmercury is only very slowly excreted from the body, the higher on the food chain you eat, the greater the percentage of the total mercury burden in the organism you’re eating is as methylmercury. For a mussel, filtering sediment and ocean water – some of both of which may have been contaminated by mercury discharge – somewhere around 10% of the total mercury burden in the tissue of that mussel is in the form of methylmercury. But food chain transfer of methylmercury functions like a ratchet – for every trophic level you increase – from the mussel to whatever eats the mussel to whatever eats whatever’s eaten the mussel – both the total concentration of mercury and the percentage of that total that’s in the form of methylmercury – also increase. For a long food chain – one that click by click of the ratchet reaches all the way from mussels to top consumers- tuna, swordfish, shark and, of course, us – while the absolute concentration of mercury in the tissue of that tuna is certainly problematic, what is even more so is that the percentage of that total that is methylated – that is measurable as methylmercury – reaches nearly 100%. For the majority of top trophic level consumers, the major exposure route for mercury these days is through what we eat. From a human health perspective, it is the neurotoxicity of methylmercury that is the greatest concern.
If you’d like to read a completely nerd-to-the-wall discussion of methylation dynamics – that is, how the methylation of inorganic mercury happens in the environment – here is a link: Merritt and Amirbahman_2009. Understanding in the field has certainly advanced in the past 9 years, and those were, of course, only our opinions, but it is a good place to start. Give a shout, as always, if you have questions.