If you had told me that the article was by Derek Lowe and that there are a number of nitrogen atoms involved, I would have indeed (wrongly) guessed that it were Things I Won’t Work With, that the compound had been created by the Klapötke group at Munich University and that it would go boom ;)
Well, not quite. This time at least.
It sounds like this stuff is only mildly dangerous and easy to keep safe with if you know what you're doing. Considering that it's been used as a chemotherapy drug for years, it'd be surprising if it wasn't.
Most of the "Stuff I Won't Work With" is fantastically dangerous even when you know exactly what you're dealing with and take all of the right precautions.
Chemotherapy is basically cave man medicine. That a therapeutic drug is explosive only adds to that sentiment. The idea that we'll basically poison you just up to a point that's nearly fatal in order to kill the cancer is such a terrible way to treat someone. Now I'm not saying don't ever do it -- unfortunately that's where we're at in 2021. It's just kind of unbelievable that cancer remains so elusive that we're still using medical treatments that started from mustard gas usage during world wars, when we're so advanced technologically in so many other ways.
Interestingly, cancers for children are largely successfully treated. I was at a fancy conference a few years ago where some cancer researchers were socializing over wine, and I asked them why that was versus adults. They said the difference was that parents are willing to do almost anything (aka enroll their kids in experimental treatments) to cure their kids, but adults aren't quite so willing for themselves. Thus the rate of experimentation was just so much higher for children to the point where it's often curable. Perhaps one day we'll be able to simulate the body well enough to the point where we can brute force treatments computationally to fix this gap.
Many of the modern treatments are much more targeted, any antibody-based treatment is by nature extremely specific. But then you also have the problem that cancer isn't a single, unified disease, so a very targeted approach doesn't work for every cancer.
I agree with your wine-drinking physicians on clinical trial participation, and your question on how to improve broader participation. I also believe that there are fundamental difference in cancers that arrive in a young person versus cancers that have slowly evolved in the patients bodies, perhaps over a decade or more-the latter are likely much more stubborn.
The cancers that are treated successfully in children are the blood borne ones (mostly leukemias) and generally because they’re easier to wipe out and replace the marrow with. Some Childhood brain tumours are also very successfully treated, and most other adult cancers children don’t get. Sarcomas still kill people left right and centre though.
The truth is that we’re already peeking out of the dark ages of chemotherapy. Immunothérapies have revolutionised the field and new stuff coming online is incredible. When I started medical school 11 years ago the 5 year survival of metastatic melanoma was close to 0%. It’s now close to the population average (well, not really, but it’s greater than 50%). Records are being smashed
Metastatic melanoma? I haven’t seen any data showing close to 50% survival rate, where are you looking? Just managed a young patient with metastatic melanoma and very poor prognosis.
I think they were referring to pd-1 inhibitors. I’m not an oncologist but that generally fits with what I’ve seen as a hospitalist. FWIW I personally know someone who has survived > 5 years who received it right when it cane out.
Unfortunately they don’t work in every case, but it’s abundantly clear when they do that the immune system is good at killing unwanted cells roaming around the body. *smacks forehead*
A rather surprising number of chemo compounds trace directly to chemical warfare and compounds used during WWI, including several mustard-gas-related compounds.
Some years ago, a close friend died of a relatively rare and aggressive form of cancer. Among my roles was running interference against those who were pitching various miracle cures, with that tired old scam laetril playing a significant role.
In the decades since, I've watched developments in the science and development, as well as traced the history. It turns out that the treatment received a few decades ago was little changed from that of the 1960s, and has progressed little since. Genetic sequencing identified the affected chromosome of the triggering mutation in the 1980s, and we now know the specific codons involved. There remains no cure.
Five year survival remains about 20%. Laetril is still a fraud. And several of the other patients we came to know during the course of my friend's treatment have died since of conditions related to the treatment itself, though yes, they did buy another 10--20 years.
Cancer is brutal.
I will note: "cancer" is a symptom cluster manifested by malignant growth, and virtually always due to genetic mutation within the affected cells (I'd say "always" though I'm not completely sure of that). The specific triggers, and the possibilities for cure, vary tremendously. Some bladder cancers are virtually entirely treatable by, of all things, tuberculosis baccili. Skin cancers if caught early pose little risk. Others are tremendously aggressive, and an online friend's posts progressed from announcing their partner's diagnosis with liver cancer to the partner's death over the course of less than two months.
Broad-brush statements are virtually always false.
There's a weird wedding here, toxic/warfare compounds dropped into your blood stream and nowadays it's used with administrative processes (for repeatability and liability purposes). Back in the days the people who came with the chemotherapies were also aggressive in the way the approach treatment (and according to De Vita it gave better results [but maybe cost more])
There's also a direct connection to vivisection and human-subjects research during wartime which would fail to meet most ethical review board standards today.
References are pretty easy to find:
After promising animal research, physician researchers connected with Yale University and the University of Chicago tried injecting sulfur mustard and its somewhat milder relatives, the nitrogen mustards, into the veins of cancer patients in the early 1940s. This was the first time a systemic treatment was given for cancer. “It would upset the whole body,” says Smith. “That proved to be valuable when you deal with certain kinds of leukemia or lymphoma.”
Not long after the discovery of nitrogen mustard, Sidney Farber of Boston demonstrated that aminopterin, a compound related to the vitamin folic acid, produced remissions in children with acute leukemia.
I'm not certain Japan's Unit 731 was engaged in research with chemotherapy precursors, though the range of testing was extensive, and the US provided a grant of immunity after the war.
Please note that pretty much anything horrific you can imagine, and then some, is discussed in the links which follow.
> and virtually always due to genetic mutation within the affected cells
I haven't followed up on this, but I seem to remember hearing about research about 20 years ago that even with cancer-associated mutations, cancer usually required physical damage to the intercellular matrix before it would manifest.
If that's true, I’m not sure identifying the genetic mutations as the cause (at least the proximate cause) of cancer might not be entirely accurate, or at least might be somewhat misleading.
I am not surprised the a Class 1 HAZMAT is used as the chemo agent for glioblastoma, the most malignant form of brain tumor. My father in law just recently passed with glioblastoma stage 3, from admitted to hospital to passing in a couple of month.
Remember how Steve Jobs suicided on fruitarianism instead of getting his cancer treated when it was found in its early stages? The biggest tech company on the planet was basically led by an anti science lunatic with millions of followers.
We will probably end up almost destroying our selves twice over before we get anywhere near curing every disease. On the plus side wiping out almost all of humanity should also take care of dozens of illnesses.
We still don't understand much of the inner workings of our own body. It's a bit like the divide between quantum physics and the macroscopic world. We have successfully observed and modeled individual processes as they happen at a cellular level, and we can draw some statistical conclusions at the whole body level, but much of the area in-between is basically unknown.
One just needs to look at nutrition or the farce that is "nutrition science". We only barely understand what we are supposed to eat to maximize our health, and that's such a basic and fundamental concept that I feel anything like "brute force treatments computationally to fix this gap." would require multiple generational leaps in our understanding. In other words, I feel like you are extrapolating to space flight when we have just recently invented the catapult.
Hell, we are only starting to suspect that the gut biome affects our consciousness. How crazy is that? And yet it is a very sobering indicator of how little we know. The human body is an incredibly complicated system with so many feedback loops that I'd put it in the same class as solving the halting problem or establishing a grand unified theory of physics.
We have modern robotics and tools like laser knives, but we still have to poke needles into a patient's brain to determine where to cut out tumors. I don't mean to disparage the doubtlessly talented surgeons of today, but to me this seems barely above medieval techniques. Our tools have improved 100 fold, our understanding just barely.
I think at best the prediction we can make is that "we believe eventually all diseases should be treatable". But to say that in the next 50 years we can become functionally immortal (treat all diseases), is a very long stretch IMO.
My understanding is that chemotherapy is indiscrimate when it attacks cells - it affects cancerous and healthy cells alike. However, doctors assume the healthy cells will recover from the weakening effects of chemotherapy. Meanwhile the cancer cells are stressed to a greater degree by the chemotherapy and thus suspectible to death. All this is presented as the "best outcome" scenario for chemotherapy treament.
However, for some patients (and depending on their type of cancer) chemotheraphy can leave lingering side-effects and can even cause cancerous cells to recur or turn even more aggressive. For some cancer patients, chemotherapy is not about curing the cancer but slowing the cancer spread ("treatable but not curable" is the phrase used by doctors for some cancer conditions).
Although chemotheraphy can be succesful for some (many?) patients, as you say it still feels like a crude, blunt approach to treating cancer. Doctors might baulk at that description. But consider: if someone has a non-metasized cancer (i.e. cancer in one part of the body that has not spread to other parts of the body), chemotherapy is applied with blunt force to the entire body including to the majority of healthy cells in the body. I can't see how anyone can say this isn't a coarse and crude treatment method even when the outcome is deemed successful.
Not entirely indiscriminate. For example as I understand it, a lot of chemo drugs attack cells that divide quickly. Which is why a lot of times hair loss is a side effect because they are some of the faster dividing cells in the body.
My understanding was that chemotherapy drugs often affect cells literally as they divide. The exact mechanisms vary, but it's that timing of affecting a cell during division that makes a given substance possible to be used as chemotherapy drug.
Chemotherapy combined with surgery and radiation is still a standard and still does cure a significant portion of people - my father's cancer was cured by this "ordinary method".
The problem is that more selective methods of killing cancers run up against the tendency of cancer cells to mutate and find a defense against them.
And this is definitely stuff that's killing you and the cancer and hoping the cancer dies first. To keep going, you need a strong reason to live.
> That a therapeutic drug is explosive only adds to that sentiment.
Explosivity and toxicity are unrelated. Cyanide can kill you, but it's not explosive IIRC. You can make explosives with aluminum, but it's safe to use as a food container, ...
> Chemotherapy is basically cave man medicine.
The main problem is that cancer cells and normal cells are very similar. Anything that kills cancer cells will probably kill normal cells. Anything that is safe for normal cells is probably safe for cancer cells. Killing one but not the other is like a poll trickshot.
(Killing bacteria or fungus is easier, because some of the molecules they use are different, and sometimes they produce the molecules using a different method, so you can make a drug that attack the difference and hope the best.)
Also, not all the treatment for cancer use chemotherapy methods. Some cancers are affected by hormones, so you can modify the hormone levels. (This also cause problems in the part of you body that use the hormone, so it's a tradeoff.)
> Really? Doesn't something being explosive mean it's highly unstable and reactive?
Not particularly, no. Some certainly are, but others require a great deal of activation energy to detonate. Nitroglycerine (another explosive medication) is notoriously touchy. But C4 is only mildly flammable; you can heat up your meal by lighting a piece of C4 on fire then put the fire out by smashing it with a hammer; it won't detonate like that.
this could be true that as a different example along the lines of the same conclusion: Women-only medical conditions are less known by medical fields, and there are fewer treatments. Its because the society treats women's lives less seriously. For example pregnancy is still pretty mysterious in general medicine. Birth control pills are to prevent women fertility etc. It could be true that children lives are deemed more important by parents and more researched.
Chemotherapy, like cancer, is not one thing. Some of it is a matter of poisoning the body in ways that disrupt rapidly-dividing cells. This is why chemo patients frequently lose their hair (and other things you don't hear as much about, like gametes, fingernails, mucous membranes/digestive lining). You can call this "cave man medicine". Although that's more dismissive than is warranted, there's no denying that it's a blunt instrument.
Other chemotherapy treatments are "holy shit, we live in the future." They're targeted and have almost no side effects.
You specifically reference mustard gas. I had lymphoma, and one of my treatments was bendamustine, which is directly related to that class of chemicals, and the subsequent research. It's broadly toxic. The other treatment was rituximab, which is a monoclonal antibody that targets the CD20 protein that manifests on B cells, which are just one of many cells involved in the lymphatic system.
I have to say the whole thing was a walk in the park. Bendamustine isn't fun, but I never vomited once, never lost my hair, and outwardly didn't look any different at all. I felt pretty shitty for about three days once a month after treatment. Kinda like a mild flu, but honestly I'd take the bendamustine over the flu any day. I usually took three days off work for it, primarily because I had to be at the chemo infusion center for a few hours to get the drugs. I could have worked through it (not that I should ever have had to, but I could have). The rituximab was a walk in the park. I took that once a month for a year, then every two months for two more years. Aside from an allergic reaction the first time (solved with Benadryl subsequently), I barely noticed it at all. It was, at its worst, nowhere near as bad as a hangover.
I know I'm fortunate in that these treatments existed for my cancer, and that my cancer has a high survival rate (I've been clear for over a decade). Many people are far worse off, even if they survive. I like to take these opportunities to dispel some of the misconceptions that are out there.
I'm glad that worked out well for you. I have friends who haven't been as lucky. Again, I'm not suggesting don't do chemo, I just wish we were much further ahead in targeted and less toxic treatment options such that chemo wasn't in the picture.
You’re right that we haven’t made much progress but this drug is the only advancement in brain cancer in decades and has very few side effects for most people. Compared to traditional chemotherapy, it is a game changer for many patients’ quality of life.
> It's just kind of unbelievable that cancer remains so elusive
One of the problems with cancer is that it's really an umbrella term that covers a huge variety of problems to solve. There are many, many ways for the normal cell lifecycle to get disrupted, and they will all respond differently to different treatments. I'm not sure if a single technology will ever appear to allow all cancers to be treated.
The idea that we'll basically poison you just up to
a point that's nearly fatal in order to kill the
cancer is such a terrible way to treat someone.
TBH that's how a _lot_ of drugs work - for instance, sabotaging certain parts of cell division can be an effective treatment because the disease needs that mechanism more than the patient.
It's also a hazard in drug discovery - the linked blog has plenty of examples of compounds that did a GREAT job of disrupting biological activity of a pathogen in a Petri dish because they're GREAT at wrecking biology in general.
One other note, re: "started from mustard gas" - many antibiotics are really just chemical weapons we're borrowing from fungi.
I’d say this is a pretty unfair assessment. Sure chemotherapy such as nitrogen mustards are still used (because they are effective) but plenty of newer drugs are very targeted.
And it’s not like our approach is all that different for other life threatening diseases. Multi-drug resistant infection? Let me use antibiotics on you that will make you deaf and maybe damage your heart.
I said started with, not continued to be exactly that. Of course new drugs and treatments have come out since.
Many other drugs/treatments can also be really bad! I'm on some pretty bad drugs myself right now (not cancer related), and wish other options existed here too. Cancer isn't the only area of medicine where I wish I was born hundreds of years in the future!
"That a therapeutic drug is explosive..." seems sensationalistic. Reminds me of when people say things like "x contains chemicals used in x!". What's the practical problem with this?
This is a very ignorant and low effort comment. Let me illustrate:
> Chemotherapy is basically cave man medicine
A meaningless statement. Actually, there is a sophisticated system of diagnosis and staging to work out who needs chemotherapy at all. This includes CT scans, ultrasound, MRI, positron emission tomorography. Chemotherapy agents are modern pharmaceuticals with a variety of supportive care measures to help patients who can benefit from them. How is nanoparticle bound paclitaxel a cave man medicine?
> The idea that we'll basically poison you just up to a point that's nearly fatal in order to kill the cancer is such a terrible way to treat someone.
Again, ignorant. Highly toxic multi-agent chemotherapy is used in acute leukaemias, because the patient will literally die next week or sometimes in a day unless you start treating. In that case you are trying to help someone who is already very sick, so of course there is a high mortality rate, but it is less than the 100% without treatment. How do you suggest we work out the best dose of chemotherapy, apart from giving it at increasing doses and monitoring what happens in a phase I trial? Anyway, many chemotherapy agents are given at a dose that controls disease and maintains quality of life in incurable disease, in direct opposition to your off-hand comment.
> Now I'm not saying don't ever do it -- unfortunately that's where we're at in 2021.
Do you realise that there are malignancies which are 100% fatal without chemotherapy, but curable with chemotherapy? Germ cell tumours in men for example. Acute leukaemias. Lymphomas. Gestational trophoblastic tumours. So what on earth are you talking about?
> It's just kind of unbelievable that cancer remains so elusive that we're still using medical treatments that started from mustard gas usage during world wars, when we're so advanced technologically in so many other ways.
Most chemotherapy agents in use today are not based on mustard gas, for a start. Many of them come from plants. One of the most useful and well tolerated chemotherapy agents comes from the bark the pacific yew tree. Anyway, the argument is stupid - your car engine is based on explosions, so car engines cannot be sophisticated or useful?
> Interestingly, cancers for children are largely successfully treated. I was at a fancy conference a few years ago where some cancer researchers were socializing over wine, and I asked them why that was versus adults. They said the difference was that parents are willing to do almost anything (aka enroll their kids in experimental treatments) to cure their kids, but adults aren't quite so willing for themselves.
This is bullshit. Walk into a clinical trials unit in an adult cancer centre and you'll see. The reason cancers in children are different are because the biology is different, to state the bleeding obvious. Also children are much more physiologically resilient and don't have other medical problems, so their response to treatment is fundamentally different.
Not only did you misinterpret a lot of what I said (including the fact that I wasn't particularly making an argument, but rather an observation and opinion), your aggressive response certainly doesn't invite dialog and is in violation of multiple HN guidelines. I suggest you read them and consider being kinder in your word choice.
"What they found was rapid onset of decomposition at 170 degrees"
So this seems to be more about people in a lab situation rather than it being so unstable it reacting sitting in someone's hot car.
Suspecting it to react at 212 and finding it reacting at 170 could ruin a lab tech's day to be sure. Those are the jobs that sound fun "for the science" lets see what happens when...
And just handling/storage. Things that are flammable or explosive have more-stringent requirements.
A familiar example: one should take much greater care when storing rubbing alcohol (or Bacardi 151 or vodka) than wine. One will magnify a house-fire. The other will help to douse a flame.
At every people’s house, I see a cupboard with the chemicals. WD-40, 90° alcohol, acetone, white spirit, all in the same IKEA (=plywood) cupboard (although it would be hard to protect children if they were each in a different cupboard too). I wonder how many fires start from the chemicals cupboard. We know that a lot of artists had their rag pile spontaneously heating up then catching fire…
Those things are fine in their separate containers. They will not spontaneously combust. If the containers are leaking, or fire starts elsewhere, yeah they could become fuel. But really no more than any other hydrocarbons in your house (e.g. wood, plastic, cloth, upholstrey and foam cushions, etc.)
In case of fire, does it matter that they are all in one cabinet together? Should they be stored separately so that a fire that does reach one won't cause a serious acceleration through combinations?
Linseed oil or other drying oils can if they have enough exposure to air.
A couple years ago, my wife re-oiled our wooden patio furniture and threw all the paper towels in the trash. Ten minutes later, smoke was pouring out of the trash can. Fortunately, I managed to get it out of the house before the fire spread.
Fires can start anywhere, and a small explosion can make the difference between the firefighters arrive on time vs the building burns down and people die.
Or the firefighters getting killed in the explosion because something blew up 45 degrees early than expected.
All sorts of things can go wrong when things react at unexpected times. Are we really going to attempt to list all of them? It'll be a long list of replies.
"Decomposition" doesn't usually mean 'explodes', either.
Curiously, Wikipedia still shows the old definition [1]:
> Temozolomide is an imidazotetrazine derivative. It is slightly soluble in water and aqueous acids, and decomposes at 212 °C (414 °F).[15]
The [15] citation from Wikipedia is to a 1982 book, untranslated from German. That may be one example of "the literature" that Derek cites. The factoid was added in this edit [2] by an Austrian Wikipedia editor who works on a lot of chemistry articles. I'd wager that the number of people who are English-German bilingual chemists with this book from 1982 on their shelf who edit Wikipedia is exactly one, and further, that he did not experimentally test or have other familiarity with the compound to sanity check the fact. This puts "the literature" in a very different context than the broad consensus of well-known, agreed-upon facts that I'd usually assume a constant value to have.
> I'd wager that the number of people who are English-German bilingual chemists with this book from 1982 on their shelf who edit Wikipedia is exactly one, and further, that he did not experimentally test or have other familiarity with the compound to sanity check the fact.
Well of course he didn't, he'd be violating their "no original research" policy if he did.
Something about that part of the article had me wondering. It seems they ran some sophisticated tests to determine the physical properties which would lead to it decomposing, but they didn't actually put a sample of the stuff on a source in a vent hood? It does say they later ran some standard tests for explosivity on it, I suppose that counts?
Exactly. Every drug manufacturer has a safety lab where drugs and intermediates are run through a safety evaluation (drop hammer test, heating until decomposition).
This drug is unique in that it’s highly exothermic when it decomposes at 170C, but yeah, not exactly a risky “explosive” to work with.
When nitrogen compounds combust, they tend to produce nitrogen gas (N2). Since nitrogen molecules contain a very strong nitrogen-nitrogen triple bond, a lot of energy is released when they form.
Nitrogen-Nitrogen bonds inside larger molecules are never quite stable because 1) nitrogen “wants” to form stable di-nitrogen (N2) molecules containing a very stable triple bond (an exothermic reaction) and 2) the result of such decompositions is nitrogen gas increasing the amount of entropy released (due to more molecules being created).
Reactions are driven both by the amount of heat released (enthalpy) and the amount of “disorder” created (entropy). Explosive reactions tend to be the ones where both factors add to the driving force.
The opposite, or oxygen wouldn't be such a strong oxidiser, which implies it readily and energetically leaves its double bond behind for either single bonds (H2O) or double bonds with non-oxygen atoms (CO2).
Oh, yes. Every substance carrying a „peroxo“ in its name is usually nasty stuff. Concentrated hydrogenperoxide for example can explode creating gaseous water (aka steam) and dioxygen (aka oxygen) in the process. While O2 is a corrosive, it is quite inert under normal conditions (which is why our clothes don’t burst into flames spontaneously).
Diatomic oxygen is less stable than many other oxygen-containing compounds like CO2 (that is why charcoal burns) but diatomic nitrogen is pretty much as stable as nitrogen can get.
"High-concentration H2O2 is referred to as "high-test peroxide" (HTP). It can be used either as a monopropellant (not mixed with fuel) or as the oxidizer component of a bipropellant rocket."
They can form molecules where nitrogen is not in its lowest energy bond (which is the triple-bond N2 gas) and where a reaction to this lower energy molecule can be triggered with some small activation energy. The energy released provides the activation energy for nearby material so you get a chemical chain reaction.
I certainly remember looking with great suspicion at my granddad's medicine and was very much disappointed when my attempts to light his pills on fire did not yield rapid and uncontrolled decomposition.
Miners used to burn it in their headlamps when they found that it burns with a cleaner flame than the alternatives they had. This was obviously violently opposed to by the mine owners -- less so because of the explosion hazard, and more so because it's way more expensive than lamp oil.
Kind of surprising nobody thought to check until now. Even as a non chemist (albeit a regular reader of Derek Lowe), I look at that and say “boy is that a lot of nitrogens, I wonder if they’re itching to become an expanding cloud of hot nitrogen gas and broken lab equipment”.
Reminds me of how DNP, a chemical used for creating explosives, has been used as a weight-loss drug. It's surprisingly effective, but overdosing on it will result in a long, hot, agonizing death.
DNP was banned after causing a lot of deaths. Still a fascinating drug, I don't remember exactly how it worked but it disrupted respiration so that less ATP was produced from electrons while their energy instead was 'spent' increasing heat
So has Clenbuterol (pure stimulant), Sibutramine (an ADHD medication way before its time, marketed as a weight loss drug by some idiot marketers), and many others.
Really should stop banning drugs because a few morons overdosed on them.
I mean, no one has banned stairs yet. They tried to ban alcohol, but the conviction turned out paper thin.
I guess it is easier to ban something that only benefits a sad small minority. Bonus evil points when the rich can get the drug regardless.
The fundamental reason why 2,4-Dinitrophenol (DNP) burns fat is surprisingly complicated. Basically, it intoxicates mitochondria in your cells being their power houses. These organelles create ATP, a universal metabolic energy carrier, by maintaining a proton gradient across its membrane. By means of chemical osmosis this gradient is what drives the ATP synthase enzyme under normal conditions. Now, DNP is capable of shuttling protons along the gradient and short-circuits this process catalyzing the conversion of fatty acids into worthless heat.
Interestingly, babies use a controlled variant of this mechanism to help maintain their body temperature thanks to their brown fat tissue. It makes babies look cute and keep warm. :)
There’s a surprising amount of this. Nitroglycerin is both an explosive and a heart drug, of course, and gunpowder was probably originally developed as an alchemical ‘medicine’.
"You could say that TMZ is a prodrug for a prodrug for methyldiazonium, which is never going to be a drug that can just be administered by itself. ... temozolimide is genotoxic and tetratogenic, so it has to be handled carefully, but honestly, anything that generates a small diazonium compound so readily is going to be similarly hazardous. ... Indeed, drop-hammer tests showed that these TMZ samples decompose suddenly with smoke on impact."
So, uh, what are the explosive decomposition products?
I mean in fairness we still use nitroglycerine for some heart ailments, so chemo - a field filled with horrific chemicals - having an explosive shouldn't be too surprising.
Its dosage as a drug is in the milligrams range, and in that form it will be combined with many times more inert filler material, so I suspect it could simply be because a sufficiently large amount of it has never been subjected to enough energy to produce an actual explosion.
The discovery is the opposite of nitroglycerin, whose explosive properties (and the production of massive amounts) were discovered before its medicinal ones.
Derek's stuff is awesome in general... "Things.." is really funny, but I find his columns about the inner workings of pharma companies to be really interesting as well.
Maybe helpful to note that the phrase "Class 1 Explosive" isn't denoting a certain type, or power of "Explosive". "Class 1" in Hazmat is all explosives. Class 2 is Gases. Class 3 is Flammable or Combustible liquid, and so on.
Fair point. The sub-classification gets into those weeds.
For example:
1.1 being "mass explosion hazard", typically high-explosives.
1.4 being "fire or projection hazard", typically consumer fireworks, small arms ammunition.
1.5 is "may mass explode in fire", things like AN fertilizer (Beirut; West, Texas), many industrial blasting agents.
According to some research, combustible dust is not an explicit category under the GHS (United Nations Globally Harmonized System of Classification and Labeling of Chemicals), let alone a sub-division of Class 1. I pulled up some Safety Data Sheets[1] for various flours and Combustible Dust is listed under "Hazards Not Otherwise Classified" in section 2, Hazard Identification. Likewise, section 5 (Fire-Fighting Measures) mentions the explosion hazard posed by dispersed dust.
Per Chapter 2.1[2] of the GHS, the definitions of explosives is: "...a solid or liquid substance (or mixture of substances) which is in itself capable by chemical reaction of producing gas at such a temperature and pressure and at such a speed as to cause damage to the surroundings..."
Which led me down a rabbit hole to see why Combustible Dust is listed as "Not Otherwise Classified", going through amendments to the CFR and some papers on working groups looking to add Combustible Dust to the GHS. Of note, page 16 of this[3] presentation.
>"Argentina Intervention
> Concern over the definition of "combustible dust" produced by flours, grains and cereals because of the trade implications that such an inclusion could produce
> Dust originated from flours, grains and cereals should not be classified as "hazardous chemical substances"
> Reasoning:
>> Flours, grain and cereal dust are not a chemical substance
>> Dust originated from flour, grain and cereal have no intrinsic explosive property
>> Dust is not a dangerous substance in itself
> Requested explicit exclusion from definition"
Luckily saner minds prevailed, and we ended up with GHS Annex 11 which is why Combustible Dust is listed on the SDS I linked. But hey there we see, once again, economic interests trying to muddy up the waters when it comes to safety. But that is a whole different (and rant-y) tangent I could go off on, and I should probably get back to work.
No, meaning that only "Class 1" are explosives. Other classes are not explosives. The classes are US DOT types of hazardous materials you might ship. Like "Class 6" is poisons.
In other words, there's no "Class 2" or "Class 3" explosives. If it's explosive, it's "Class 1", including firecrackers.
As one comment there notes, just looking at all the Ns lined up ought to cause concern, at least for anyone that has read this authors "things I won't work with" series.
The chemical structure is the clue to the explosive potential. The N-N-N triad is a strange beast that shows up in a lot of explosive materials. They're explosive for similar reasons that ammonia nitrate is explosive.
Think of energy as a vertical scale increasing upward. Including a nitrogen triad (like in the drug) pushes the entire molecule up on the energy scale. It's like riding the elevator to the 42nd floor.
In contrast, the N-N triple bond (i.e., atmospheric nitrogen) is way down at the ground floor. This is one reason that despite nitrogen being the most abundant gas in the earth's atmosphere, it requires large amounts of energy to process into fertilizers and other materials.
CO2 and H2O also sit near ground level. So there's a large energy difference between the drug and the combustion products N2, CO2, and H2O.
All it takes to release all of that stored energy is a trigger. For example, if someone were to push you off the top of the building, you would spontaneously release the stored energy. Hopefully you'd be equipped with an air braking device to dissipate it gradually, but if not - well, that energy will be released into your body and the pavement all at once.
A chemist can usually make an educated guess on most of them based on similarity to other substances, but it's hard to be very accurate and there's still a lot of potential for surprises.
A simple example is solubility. Molecules with amines generally are soluble in acid. Molecules with carboxylic acid groups are usually soluble in base. Molecules with flexible hydrocarbon chains tend to be soluble in oils. Molecules with lots of polar groups tend to be soluble in water. Large, rigid molecules are rarely soluble in anything.
Trained chemists can do this sort of thing with specialized properties (such as metabolic stability, brain penetrating ability, and oral bioavailability) as well, although success depends on specifics.
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[ 2.0 ms ] story [ 195 ms ] thread> I have personally worked with compounds that are this hazardous, but at least I knew up front that they were!
Most of the "Stuff I Won't Work With" is fantastically dangerous even when you know exactly what you're dealing with and take all of the right precautions.
Interestingly, cancers for children are largely successfully treated. I was at a fancy conference a few years ago where some cancer researchers were socializing over wine, and I asked them why that was versus adults. They said the difference was that parents are willing to do almost anything (aka enroll their kids in experimental treatments) to cure their kids, but adults aren't quite so willing for themselves. Thus the rate of experimentation was just so much higher for children to the point where it's often curable. Perhaps one day we'll be able to simulate the body well enough to the point where we can brute force treatments computationally to fix this gap.
The truth is that we’re already peeking out of the dark ages of chemotherapy. Immunothérapies have revolutionised the field and new stuff coming online is incredible. When I started medical school 11 years ago the 5 year survival of metastatic melanoma was close to 0%. It’s now close to the population average (well, not really, but it’s greater than 50%). Records are being smashed
Here’s a paper supporting:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019511/
Unfortunately they don’t work in every case, but it’s abundantly clear when they do that the immune system is good at killing unwanted cells roaming around the body. *smacks forehead*
Some years ago, a close friend died of a relatively rare and aggressive form of cancer. Among my roles was running interference against those who were pitching various miracle cures, with that tired old scam laetril playing a significant role.
In the decades since, I've watched developments in the science and development, as well as traced the history. It turns out that the treatment received a few decades ago was little changed from that of the 1960s, and has progressed little since. Genetic sequencing identified the affected chromosome of the triggering mutation in the 1980s, and we now know the specific codons involved. There remains no cure.
Five year survival remains about 20%. Laetril is still a fraud. And several of the other patients we came to know during the course of my friend's treatment have died since of conditions related to the treatment itself, though yes, they did buy another 10--20 years.
Cancer is brutal.
I will note: "cancer" is a symptom cluster manifested by malignant growth, and virtually always due to genetic mutation within the affected cells (I'd say "always" though I'm not completely sure of that). The specific triggers, and the possibilities for cure, vary tremendously. Some bladder cancers are virtually entirely treatable by, of all things, tuberculosis baccili. Skin cancers if caught early pose little risk. Others are tremendously aggressive, and an online friend's posts progressed from announcing their partner's diagnosis with liver cancer to the partner's death over the course of less than two months.
Broad-brush statements are virtually always false.
References are pretty easy to find:
After promising animal research, physician researchers connected with Yale University and the University of Chicago tried injecting sulfur mustard and its somewhat milder relatives, the nitrogen mustards, into the veins of cancer patients in the early 1940s. This was the first time a systemic treatment was given for cancer. “It would upset the whole body,” says Smith. “That proved to be valuable when you deal with certain kinds of leukemia or lymphoma.”
https://www.the-scientist.com/foundations/from-chemical-weap...
Not long after the discovery of nitrogen mustard, Sidney Farber of Boston demonstrated that aminopterin, a compound related to the vitamin folic acid, produced remissions in children with acute leukemia.
https://www.cancer.org/cancer/cancer-basics/history-of-cance...
I'm not certain Japan's Unit 731 was engaged in research with chemotherapy precursors, though the range of testing was extensive, and the US provided a grant of immunity after the war.
Please note that pretty much anything horrific you can imagine, and then some, is discussed in the links which follow.
https://nationalinterest.org/blog/reboot/unit-731-japans-sec...
https://en.wikipedia.org/wiki/Unit_731
I haven't followed up on this, but I seem to remember hearing about research about 20 years ago that even with cancer-associated mutations, cancer usually required physical damage to the intercellular matrix before it would manifest.
If that's true, I’m not sure identifying the genetic mutations as the cause (at least the proximate cause) of cancer might not be entirely accurate, or at least might be somewhat misleading.
This is why as a total outsider/non-expert I believe we will cure everything in the next 50 years if we do not regress or destroy ourselves.
We will probably end up almost destroying our selves twice over before we get anywhere near curing every disease. On the plus side wiping out almost all of humanity should also take care of dozens of illnesses.
One just needs to look at nutrition or the farce that is "nutrition science". We only barely understand what we are supposed to eat to maximize our health, and that's such a basic and fundamental concept that I feel anything like "brute force treatments computationally to fix this gap." would require multiple generational leaps in our understanding. In other words, I feel like you are extrapolating to space flight when we have just recently invented the catapult.
Hell, we are only starting to suspect that the gut biome affects our consciousness. How crazy is that? And yet it is a very sobering indicator of how little we know. The human body is an incredibly complicated system with so many feedback loops that I'd put it in the same class as solving the halting problem or establishing a grand unified theory of physics.
We have modern robotics and tools like laser knives, but we still have to poke needles into a patient's brain to determine where to cut out tumors. I don't mean to disparage the doubtlessly talented surgeons of today, but to me this seems barely above medieval techniques. Our tools have improved 100 fold, our understanding just barely.
I think at best the prediction we can make is that "we believe eventually all diseases should be treatable". But to say that in the next 50 years we can become functionally immortal (treat all diseases), is a very long stretch IMO.
However, for some patients (and depending on their type of cancer) chemotheraphy can leave lingering side-effects and can even cause cancerous cells to recur or turn even more aggressive. For some cancer patients, chemotherapy is not about curing the cancer but slowing the cancer spread ("treatable but not curable" is the phrase used by doctors for some cancer conditions).
Although chemotheraphy can be succesful for some (many?) patients, as you say it still feels like a crude, blunt approach to treating cancer. Doctors might baulk at that description. But consider: if someone has a non-metasized cancer (i.e. cancer in one part of the body that has not spread to other parts of the body), chemotherapy is applied with blunt force to the entire body including to the majority of healthy cells in the body. I can't see how anyone can say this isn't a coarse and crude treatment method even when the outcome is deemed successful.
The problem is that more selective methods of killing cancers run up against the tendency of cancer cells to mutate and find a defense against them.
And this is definitely stuff that's killing you and the cancer and hoping the cancer dies first. To keep going, you need a strong reason to live.
Explosivity and toxicity are unrelated. Cyanide can kill you, but it's not explosive IIRC. You can make explosives with aluminum, but it's safe to use as a food container, ...
> Chemotherapy is basically cave man medicine.
The main problem is that cancer cells and normal cells are very similar. Anything that kills cancer cells will probably kill normal cells. Anything that is safe for normal cells is probably safe for cancer cells. Killing one but not the other is like a poll trickshot.
(Killing bacteria or fungus is easier, because some of the molecules they use are different, and sometimes they produce the molecules using a different method, so you can make a drug that attack the difference and hope the best.)
Also, not all the treatment for cancer use chemotherapy methods. Some cancers are affected by hormones, so you can modify the hormone levels. (This also cause problems in the part of you body that use the hormone, so it's a tradeoff.)
Really? Doesn't something being explosive mean it's highly unstable and reactive? Presumably ingesting highly reactive reagents is toxic.
Not particularly, no. Some certainly are, but others require a great deal of activation energy to detonate. Nitroglycerine (another explosive medication) is notoriously touchy. But C4 is only mildly flammable; you can heat up your meal by lighting a piece of C4 on fire then put the fire out by smashing it with a hammer; it won't detonate like that.
https://en.wikipedia.org/wiki/C-4_(explosive)#Detonation
One of the medicines with the longest history is nitroglycerin (for various heart conditions), which is literally dynamite.
Other chemotherapy treatments are "holy shit, we live in the future." They're targeted and have almost no side effects.
You specifically reference mustard gas. I had lymphoma, and one of my treatments was bendamustine, which is directly related to that class of chemicals, and the subsequent research. It's broadly toxic. The other treatment was rituximab, which is a monoclonal antibody that targets the CD20 protein that manifests on B cells, which are just one of many cells involved in the lymphatic system.
I have to say the whole thing was a walk in the park. Bendamustine isn't fun, but I never vomited once, never lost my hair, and outwardly didn't look any different at all. I felt pretty shitty for about three days once a month after treatment. Kinda like a mild flu, but honestly I'd take the bendamustine over the flu any day. I usually took three days off work for it, primarily because I had to be at the chemo infusion center for a few hours to get the drugs. I could have worked through it (not that I should ever have had to, but I could have). The rituximab was a walk in the park. I took that once a month for a year, then every two months for two more years. Aside from an allergic reaction the first time (solved with Benadryl subsequently), I barely noticed it at all. It was, at its worst, nowhere near as bad as a hangover.
I know I'm fortunate in that these treatments existed for my cancer, and that my cancer has a high survival rate (I've been clear for over a decade). Many people are far worse off, even if they survive. I like to take these opportunities to dispel some of the misconceptions that are out there.
For those interested in this kind of thing I’d highly recommend the book The Emperor of All Maladies.
For Herceptin specifically, there was a book called her-2.
One of the problems with cancer is that it's really an umbrella term that covers a huge variety of problems to solve. There are many, many ways for the normal cell lifecycle to get disrupted, and they will all respond differently to different treatments. I'm not sure if a single technology will ever appear to allow all cancers to be treated.
It's also a hazard in drug discovery - the linked blog has plenty of examples of compounds that did a GREAT job of disrupting biological activity of a pathogen in a Petri dish because they're GREAT at wrecking biology in general.
One other note, re: "started from mustard gas" - many antibiotics are really just chemical weapons we're borrowing from fungi.
And it’s not like our approach is all that different for other life threatening diseases. Multi-drug resistant infection? Let me use antibiotics on you that will make you deaf and maybe damage your heart.
Many other drugs/treatments can also be really bad! I'm on some pretty bad drugs myself right now (not cancer related), and wish other options existed here too. Cancer isn't the only area of medicine where I wish I was born hundreds of years in the future!
> Chemotherapy is basically cave man medicine
A meaningless statement. Actually, there is a sophisticated system of diagnosis and staging to work out who needs chemotherapy at all. This includes CT scans, ultrasound, MRI, positron emission tomorography. Chemotherapy agents are modern pharmaceuticals with a variety of supportive care measures to help patients who can benefit from them. How is nanoparticle bound paclitaxel a cave man medicine?
> The idea that we'll basically poison you just up to a point that's nearly fatal in order to kill the cancer is such a terrible way to treat someone.
Again, ignorant. Highly toxic multi-agent chemotherapy is used in acute leukaemias, because the patient will literally die next week or sometimes in a day unless you start treating. In that case you are trying to help someone who is already very sick, so of course there is a high mortality rate, but it is less than the 100% without treatment. How do you suggest we work out the best dose of chemotherapy, apart from giving it at increasing doses and monitoring what happens in a phase I trial? Anyway, many chemotherapy agents are given at a dose that controls disease and maintains quality of life in incurable disease, in direct opposition to your off-hand comment.
> Now I'm not saying don't ever do it -- unfortunately that's where we're at in 2021.
Do you realise that there are malignancies which are 100% fatal without chemotherapy, but curable with chemotherapy? Germ cell tumours in men for example. Acute leukaemias. Lymphomas. Gestational trophoblastic tumours. So what on earth are you talking about?
> It's just kind of unbelievable that cancer remains so elusive that we're still using medical treatments that started from mustard gas usage during world wars, when we're so advanced technologically in so many other ways.
Most chemotherapy agents in use today are not based on mustard gas, for a start. Many of them come from plants. One of the most useful and well tolerated chemotherapy agents comes from the bark the pacific yew tree. Anyway, the argument is stupid - your car engine is based on explosions, so car engines cannot be sophisticated or useful?
> Interestingly, cancers for children are largely successfully treated. I was at a fancy conference a few years ago where some cancer researchers were socializing over wine, and I asked them why that was versus adults. They said the difference was that parents are willing to do almost anything (aka enroll their kids in experimental treatments) to cure their kids, but adults aren't quite so willing for themselves.
This is bullshit. Walk into a clinical trials unit in an adult cancer centre and you'll see. The reason cancers in children are different are because the biology is different, to state the bleeding obvious. Also children are much more physiologically resilient and don't have other medical problems, so their response to treatment is fundamentally different.
So this seems to be more about people in a lab situation rather than it being so unstable it reacting sitting in someone's hot car.
Suspecting it to react at 212 and finding it reacting at 170 could ruin a lab tech's day to be sure. Those are the jobs that sound fun "for the science" lets see what happens when...
A familiar example: one should take much greater care when storing rubbing alcohol (or Bacardi 151 or vodka) than wine. One will magnify a house-fire. The other will help to douse a flame.
Linseed oil or other drying oils can if they have enough exposure to air.
A couple years ago, my wife re-oiled our wooden patio furniture and threw all the paper towels in the trash. Ten minutes later, smoke was pouring out of the trash can. Fortunately, I managed to get it out of the house before the fire spread.
"Lab setting" implies bench sized quantities in motion and storage cabinet sized quantities at rest.
"Manufacturing setting" implies reaction tower sized quantities in motion and train car sized quantities at rest.
All sorts of things can go wrong when things react at unexpected times. Are we really going to attempt to list all of them? It'll be a long list of replies.
I imagine that hitting it after it’s been inside a hot car would cause it to decompose more enthusiastically.
Curiously, Wikipedia still shows the old definition [1]:
> Temozolomide is an imidazotetrazine derivative. It is slightly soluble in water and aqueous acids, and decomposes at 212 °C (414 °F).[15]
The [15] citation from Wikipedia is to a 1982 book, untranslated from German. That may be one example of "the literature" that Derek cites. The factoid was added in this edit [2] by an Austrian Wikipedia editor who works on a lot of chemistry articles. I'd wager that the number of people who are English-German bilingual chemists with this book from 1982 on their shelf who edit Wikipedia is exactly one, and further, that he did not experimentally test or have other familiarity with the compound to sanity check the fact. This puts "the literature" in a very different context than the broad consensus of well-known, agreed-upon facts that I'd usually assume a constant value to have.
[1]: https://en.wikipedia.org/wiki/Temozolomide#Chemical_properti...
[15]: Dinnendahl, V; Fricke, U, eds. (2016). Arzneistoff-Profile (in German). 9 (29 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
[2]: https://en.wikipedia.org/w/index.php?title=Temozolomide&diff...
Well of course he didn't, he'd be violating their "no original research" policy if he did.
This drug is unique in that it’s highly exothermic when it decomposes at 170C, but yeah, not exactly a risky “explosive” to work with.
I would be surprised if it wasn't.
So many common explosive compounds seem to have it.
Reactions are driven both by the amount of heat released (enthalpy) and the amount of “disorder” created (entropy). Explosive reactions tend to be the ones where both factors add to the driving force.
https://en.wikipedia.org/wiki/Hydrogen_peroxide
"High-concentration H2O2 is referred to as "high-test peroxide" (HTP). It can be used either as a monopropellant (not mixed with fuel) or as the oxidizer component of a bipropellant rocket."
https://wtamu.edu/~cbaird/sq/2013/06/27/when-does-the-breaki...
https://en.wikipedia.org/wiki/Nitroglycerin_(medication)
I certainly remember looking with great suspicion at my granddad's medicine and was very much disappointed when my attempts to light his pills on fire did not yield rapid and uncontrolled decomposition.
Miners used to burn it in their headlamps when they found that it burns with a cleaner flame than the alternatives they had. This was obviously violently opposed to by the mine owners -- less so because of the explosion hazard, and more so because it's way more expensive than lamp oil.
Really should stop banning drugs because a few morons overdosed on them.
I mean, no one has banned stairs yet. They tried to ban alcohol, but the conviction turned out paper thin.
I guess it is easier to ban something that only benefits a sad small minority. Bonus evil points when the rich can get the drug regardless.
Interestingly, babies use a controlled variant of this mechanism to help maintain their body temperature thanks to their brown fat tissue. It makes babies look cute and keep warm. :)
https://www.youtube.com/watch?v=OT5AXGS1aL8
This animation and associated narration is much more detailed, but a bit slow for something you haven't vetted your interest in yet :)
https://www.youtube.com/watch?v=kXpzp4RDGJI
So, uh, what are the explosive decomposition products?
[0]: https://www.irishtimes.com/news/voices-told-woman-she-had-br...
The discovery is the opposite of nitroglycerin, whose explosive properties (and the production of massive amounts) were discovered before its medicinal ones.
For example:
1.1 being "mass explosion hazard", typically high-explosives. 1.4 being "fire or projection hazard", typically consumer fireworks, small arms ammunition. 1.5 is "may mass explode in fire", things like AN fertilizer (Beirut; West, Texas), many industrial blasting agents.
According to some research, combustible dust is not an explicit category under the GHS (United Nations Globally Harmonized System of Classification and Labeling of Chemicals), let alone a sub-division of Class 1. I pulled up some Safety Data Sheets[1] for various flours and Combustible Dust is listed under "Hazards Not Otherwise Classified" in section 2, Hazard Identification. Likewise, section 5 (Fire-Fighting Measures) mentions the explosion hazard posed by dispersed dust.
Per Chapter 2.1[2] of the GHS, the definitions of explosives is: "...a solid or liquid substance (or mixture of substances) which is in itself capable by chemical reaction of producing gas at such a temperature and pressure and at such a speed as to cause damage to the surroundings..."
Which led me down a rabbit hole to see why Combustible Dust is listed as "Not Otherwise Classified", going through amendments to the CFR and some papers on working groups looking to add Combustible Dust to the GHS. Of note, page 16 of this[3] presentation.
>"Argentina Intervention
> Concern over the definition of "combustible dust" produced by flours, grains and cereals because of the trade implications that such an inclusion could produce
> Dust originated from flours, grains and cereals should not be classified as "hazardous chemical substances"
> Reasoning:
>> Flours, grain and cereal dust are not a chemical substance
>> Dust originated from flour, grain and cereal have no intrinsic explosive property
>> Dust is not a dangerous substance in itself
> Requested explicit exclusion from definition"
Luckily saner minds prevailed, and we ended up with GHS Annex 11 which is why Combustible Dust is listed on the SDS I linked. But hey there we see, once again, economic interests trying to muddy up the waters when it comes to safety. But that is a whole different (and rant-y) tangent I could go off on, and I should probably get back to work.
[1]http://s3.amazonaws.com/media.agricharts.com/sites/1846/Flou...
[2]https://unece.org/DAM/trans/danger/publi/ghs/ghs_rev03/Engli...
[3]https://schc.memberclicks.net/assets/meetings/fall_2017/lant...
The explosive class mentioned is likely using a different scale or standard.
See https://www.fmcsa.dot.gov/sites/fmcsa.dot.gov/files/docs/Nin...
In other words, there's no "Class 2" or "Class 3" explosives. If it's explosive, it's "Class 1", including firecrackers.
That’s like a teratogen, but four times as bad!
Nothing about explosions other than dust explosion warnings, but this one is kind of amusing:
"H351 Suspected of causing cancer"
https://www.newscientist.com/article/dn23399-texas-disaster-...
Think of energy as a vertical scale increasing upward. Including a nitrogen triad (like in the drug) pushes the entire molecule up on the energy scale. It's like riding the elevator to the 42nd floor.
In contrast, the N-N triple bond (i.e., atmospheric nitrogen) is way down at the ground floor. This is one reason that despite nitrogen being the most abundant gas in the earth's atmosphere, it requires large amounts of energy to process into fertilizers and other materials.
CO2 and H2O also sit near ground level. So there's a large energy difference between the drug and the combustion products N2, CO2, and H2O.
All it takes to release all of that stored energy is a trigger. For example, if someone were to push you off the top of the building, you would spontaneously release the stored energy. Hopefully you'd be equipped with an air braking device to dissipate it gradually, but if not - well, that energy will be released into your body and the pavement all at once.
This makes me wonder - what properties of a substance can you infer from its structure without ever testing the substance itself?
A simple example is solubility. Molecules with amines generally are soluble in acid. Molecules with carboxylic acid groups are usually soluble in base. Molecules with flexible hydrocarbon chains tend to be soluble in oils. Molecules with lots of polar groups tend to be soluble in water. Large, rigid molecules are rarely soluble in anything.
Trained chemists can do this sort of thing with specialized properties (such as metabolic stability, brain penetrating ability, and oral bioavailability) as well, although success depends on specifics.