Detective Conan Toxicology

[Kyuu Nye 425]

I've decided to allow commenting in thread. In the event that I need more space I'll request a mod split the topic for discussion and reference. However for now, I'm opening the thread for comment and critique. This is especially for the APTX analysis.

Welcome one and all to Kyuu's Detective Conan Toxicology thread! I will be posting analysis of the drugs and toxins found in DC that have been used in conjunction with cases (Yes, that includes APTX). There are THREE CATEGORIES of drugs that I'll be doing:

1) Real (Drugs and Toxins that were 100% identified by the series.)
2) Theoretical (APTX basically)
3) Semi-theoretical (Drugs that are possible IRL, but are not identified by Gosho, and can be determined to some degree of accuracy using the information in manga canon) (unnamed poisons and Conan's tranquilizer mostly)

Key Terms that you will need to know and understand before reading my analysis:

LD₅₀ - Dosage of a toxic agent that will cause death in 50% of treated animals
LC₅₀ - Concentration of a toxic agent that will cause death in 50% of the treated animals
T_1/2 - Biological half-life. How long it takes the concentration in the biological system to be halved.
LOAEL - Lowest observable adverse effect level. The amount of a toxin that causes an observable negative effect (your basic symptoms of poisoning without dying, if you have ever seen a drug commercial, you should know most of them)
Bioavailability - How much of a drug reaches circulation unchanged in a biological system. IV is always 100% bioavailability, as it is direct to circulatory system.
ADME - Absorption, Distribution, Metabolism, Excretion
Absorption - How a drug is/can be administered
Distribution - how a drug is distributed throughout the body (and what barriers it needs to pass)
Metabolism - how the drug is metabolized by the biological system
Excretion - how the drug is expelled from the body

Those are the main, if I come to a point where I need to explain the more complex terms, I shall append them. I will make every effort to make this easy to read and understand for all.

Drugs will be completely analyzed most likely using Toxnet a lot. I'll be using some other resources as well as needed. Everything will be fully referenced. If you use this information for any reason, PLEASE do the same.

The drugs currently in planned to be analyzed are: (links will be added as analysis are done)

APTX
Tetrodotoxin
Potassium Cyanide
Sea Snake Venom (erabutoxin)
Curare (possibly from poison dart case)
Batrachotoxin (possibly from the poison dart case)
Chlorine
Potassium Chloride
Phosphoric Acid
Carbon Monoxide
Aconitine (by Kjeldahl)

More may be added as I reread the chapters and watch the episodes that the ones omitted appeared in while I look everything up.

If you want clarification please PM or leave comment on my profile. If you wish to critique feel free to do it in topic.

Also, this is being done on my own time, so I'm not sure how many I can/will get done. The ones that I am sure of are the top 3, and Carbon Monoxide. Everything else depends on my time and schedule.

That all said, I hope you all enjoy this new project of mine and find it illuminating.

[Kyuu Nye 425]

[APTX WiP]

Before reading on, a few things. 1) This is incomplete, that means it is as simple as my mind decided to make it (it sort of reads like an intro to a scientific journal in terms of complexity imo) 2) Criticism is welcome, but please refer to my profile comments, the status update where this will be announced or in PM to make it. I'll take all comments and criticisms into account, and work them in as they are applicable. Please don't tell me you don't understand anything, its too early for that. 3) This is very theoretical, so some things will be a stretch of what science is possible, but I WILL try to make it as realistic as possible. 4) No theories about the BO will be given at any point.

Aptx analysis… What you will find within is a theoretical analysis of the drug. Since it is theoretical, several possibilities will be discussed, I will make clear what I believe to be most likely.

Known facts:

APTX = Apotoxin… meaning it is an apoptosis inducing “drug.”

It remains in the blood stream and can reactivate itself after antidote has run its course.

It is lethal to most. In lab testing there was only one rat to survive by shrinking.

It activates/enhances telomerase.

One pill of unknown dosage is enough to kill almost instantly.

Assumed Drug Data:

Appearance: Unknown. In DC it is delivered through a coated pill

Structure: Unknown. Anime suggests that it is a complex biomolecule. The data on the computer screen that was erased by Night Baron showed several, albeit random, organic reactions for the “Drug Data.” It is highly likely that the drug’s data would include a synthesis of the proteins it encodes for.

LD₅₀ (oral): 50-150mg/kg

LD₅₀ Reasoning: This is a drug that is administered through the mouth in a coated pill form. Assuming that it is a collection of virus vectors, it would be low weight but in high dosage to get global effect on the host once administered.

T_1/2: N/A (It is a virus, it can exist so long as the host’s body allows it and has the means to survive)

ADME:

Absorption: GI Tract (oral administration) (as far as we have seen this is the only method)

Distribution: Likely the cardiovascular initially, but it is possible that the virus is similar to HIV and exists with the lymphatic system and circulatory system once it affects the host.

Metabolism: No known metabolism method known. Likely there is none outside of completed antidote.

Excretion: After the virus is eaten it is likely expelled as any other, through urine sweat and mucosal ducts. After the host is dead it likely has a self terminating chain, which kills it and allows it to be expelled through the urine, making it impossible to detect within the system.

Conclusions to be drawn from the above:

Apoptosis is the main pathway in which it kills. Implications of this are that it causes global cellular death. Consequences of this are numerous, including the degradation of skin tissues and other tissues overtime if the biological system is sustained long enough to survive. However, if the drug targets certain tissues first this may be a nonissue.

It cannot be a standard drug. Standard drugs have a specific half-life within a biological system. Once the drug has either run its course or been used by an antidote (incomplete or not) it is done, and should not reactivate. Thus, the drug is actually most likely a recombinant strand of DNA that codes for a lethal protein(s) that is delivered by virus vectors and is constantly replicated within the host’s system. Thus, the antidote does not expel and the virus becomes resistant to the antidote, meaning more is needed each time it is administered. This is confirmed by Haibara’s explanation of the dangers of taking the incomplete antidote. (Thus it is actually akin to being afflicted with a virus that will eventually die, and will likely render it undetectable by normal drug analysis)

Why does the antidote work while in the system? There are a few possibilities. The first possibility is that it binds to the sites of the activated proteins that the recombinant DNA the virus vector is introducing, and thus disables the activity. The other main possibility is that it binds to the activation site of one of the cofactors or more likely mechanism of reproduction of the proteins that the recombinant DNA encodes for. The latter possibility is highly more likely, acting as an inhibitor would account for several parts of this “incomplete antidote.” By acting as an inhibitor for certain proteins, it may allow in the cease of the reproduction of these proteins. The inhibition can be a factor of heightened antibody presence, which when the components of the alcohol bind, may lead to a secondary binding site being created to bind to the foreign virus, which the APTX is delivered on. This would also explain the cause for alarm for the possibility of resistance, as the virus is likely to mutate to prevent this antidote from working. If the real antidote has the same properties, the incomplete, then it poses a serious risk.

To Be Done:

-Explanation of the two pathways (apoptosis and telomerase)

-Proposed mechanism

-Possible metabolism (antidote/regular)

[Kyuu Nye 425]

[Complete]

Updates:

11 May 2012: added perspective for LD₅₀

11 May 2012: Added oral LD₅₀ and LD₁₀₀ data for mice and approximate LD₅₀ for humans. Added note on comparison to amounts used in DC.

*all information provided here is from Toxnet unless otherwise noted*

Structure:

Chemical Formula: KCN

Appearance: White crystalline powder

_{image from Wikipedia}

LOAEL (lowest observable adverse effect level): 1.2mg/kg

LD₅₀(Inhalation): ~150-300mg/kg (Time to death ranging from 30min to immediate) from HPA

LD₅₀ Inhalation Perspective: The average adult in the USA is 86kg (~190lbs). So it would take approximately 25,800mg (or 0.9oz) of KCN to kill an average USA Adult male. To further simplify, that is slightly less than 1.5 tablespoons (estimated, based on the the molecular weight of NaCl, which is slightly lighter, using this converter)

LD₅₀(oral human): 0.7-2.9 mg/kg (Of CN^-) (from health canada)

LD₅₀ Perspective estimate (oral human): It would take about 0.25 teaspoon to kill an adult human male, using 1.5mg/kg as an average of pure Cyanide ion. (so it would actually take about double that because Potassium more than doubles mass of cyanide ion)

LD₅₀(oral mice): 5-10mg/kg

LD₅₀Perspective (oral): Using the same as before, the calculations come to 0.15 teaspoon to kill.

Please see notes at the end for additional information and context.

LD₁₀₀ (oral mice): ~40mg/kg

LD₁₀₀Perspective (oral): Using same methods and figures from before it would take 0.7 teaspoons to kill lab mice 100% of the time.

T_1/2: 20min - 1hr (conversion from Cyanide to thiocyanate)

ADME

Absorption: Inhalation of airborn crystals (or of HCN after hydrolysis reaction occurs), ingestion, injection (IV), skin absorption

Distribution: KCN is distributed by the cardiovascular system (through the blood) It has a higher affinity for Red Blood Cells than plasma.

Excretion: 72% excretion by feces and urine, 25% through exhalation, 3% retained in one month. Urine is the primary method after cyanide is converted into thiocyanate, which usually occurs in the first 24h of exposure. Sweat and saliva via HPA

Metabolism (Technical stuff incoming):

Note: This works for ALL forms of Cyanide! I know other forms of Cyanide have been used by Gosho, but due to the metabolism and mechanism (next section) being identical, I won't do the others unless I find *significant* differences between the forms of cyanide.

Note 2: All forms of cyanide are converted into HCN when ingested. The acid of the stomach creates a hydrolysis reaction that converts it.

The cyanide ion (just the CN^-) is conjugated with Sulphur, which creates the anion thiocyanate (SCN^-). This reaction is catalyzed by the enzyme Rhodanese. Rhodanese is produced in MOST ANIMAL TISSUES, so this reaction need not occur in the liver or in the kidneys. It does need the cofactor sulphane-sulfer (via HPA) for this conversion to occur. After its conversion to thiocyanate, it is in such a form that it can be excreted through the urine.

Translation for lay people: KCN becomes K⁺ and CN^-. The cyanide reacts with sulphur in the biological system. This is aided by Rhodanese enzyme, which makes this reaction occur faster. After the reaction is done, it is thiocyanate (SCN^-). Thiocyanate can be excreted through the urine, thus being expelled.

Mechanism of toxicity (aka: how it kills you):

Information on the mechanism from Detective Conan Desperate Revival Case is as follows:

According to justwantanaccount, the translation I read was wrong. Gosho did describe it as a electron transfer.

From justwantanaccount "The original Japanese for the 'electron signaling' is 電子伝達系, which directly translates to 'electron transfer system'"

Verdict: Correct.

In reality: Cyanide has an affinity for iron in ferric state (Fe³⁺). This allows it to react with the iron in cytochrome c oxidase in the mitochondria of cells. This interaction blocks cytochrome c's ability to participate in the electron transfers that are involved in cellular respiration. This blocks the cell's utilization of oxygen. Basically what happens is that the Cyanide takes the place of the cytochrome c oxidase's open site for electrons, which would be transferred to oxygen allowing the oxygen to be converted to water for use within the biological system which is for the creation of ATP.

Translation for lay people: There is more to this reaction, but I'm sticking to Cyanide here. Basically, Cyanide interacts with iron, iron interacts with enzyme involved in cellular respiration, this prevents electron transfer between enzyme and oxygen, preventing oxygen from being utilized in cellular respiration. This stops cellular respiration and thus oxygen is not used. This naturally leads to death.

Note on toxicity as depicted in Detective Conan: Gosho has overestimated the affects of KCN on a human system. From what I have found, that is the estimated in a general system. However, lethal affects are NOT immediate, unless concentrations are significantly higher. 0.25 teaspoons is what can kill on average. According to the data, it took 35-40mg/kg of CN^- to kill mice ~100% of the time (all but one died). Now, the time it took until death was 19 minutes at that dosage. This is further cooroborated with a case I found, that stated a woman, after ingesting 2.5g NaCN, died after 30 minutes. Symptoms occur far before it (tingling sensations, and the like) followed by unconsciousness. Death is NOT immediate. On average for a lethal dose in humans takes approximately One hour to kill. Immediate death (as seen in DC) would take significantly more what could be fit into an ice cube with a small cavity created. The amount Gosho uses is probably around 2-5 times off the minimum lethal amount in humans in Desperate Revival (due to an ice plug being needed, the amount couldn't have been more than about ~10-20 milligrams)

FINAL NOTE: I excluded a few things for simplicity, such as the the treatment for Potassium Cyanide. I also did not include symptoms of nonlethal exposure or chronic exposure. If you want that information included, please leave a comment in my profile or in the status update announcing the completion of KCN analysis!

[Kyuu Nye 425]

[Complete]

*all information provided here is from Toxnet unless otherwise noted*

Forward note: TTX along with many other natural toxins have very sparse toxicological data on them, though constant research is being done.

Structure:

Chemical Formula: C11-H17-N3-O8

Appearance: Crystals

LOAEL: N/A

LD₅₀(GI [assumed]): 0.1mg/kg (from Essentials of Toxicology Second edition by Klassen, C)

LD₅₀Perspective: 8.6mg would be necessary to kill an average weight USA male (86kg). However, according to Toxnet, 1-4mg is the common lethal dose for humans.

(I know that looks LESS toxic than KCN, but remember KCN was just the CN^- ion, let me put the mice values to show you how much more toxic TTX is)

LD₅₀(IV mouse): 0.009 mg/kg

LD₅₀(IP mouse): 0.008 mg/kg (Btw, this "intraperitoneal" injection, which is basically injection into Body cavity... AKA the space where all of your organs are)

LD₅₀(SC mouse): 0.008 mg/kg (This is "subcutaneous," which means under the skin. If you know anyone on insulin, this is the method they usually use to administer their Insulin)

LD₅₀(Oral mouse): 0.435 mg/kg

Perspective on LD₅₀ of TTX Toxicity: I'm at a loss for calculating the lethality in layman's terms. Basically, TTX is so lethal that a minimal amount can kill you if you don't get treatment (Aka life support).

T_1/2: N/A.

ADME

Absorption: IV, IM (intramuscular), GI Tract (Ingestion)

Distribution: TTX is distributed by the cardiovascular system (through the blood)

Excretion: Urine.

Metabolism: Unknown. However it is quickly transferred to the blood and liver upon injection, so it is likely that metabolism at least occurs in the liver, and possibly in the kidneys. However, the exact mechanism of metabolism is still unclear.

Mechanism of toxicity (aka: how it kills you):

Information on the mechanism from Detective Conan File TTX is as follows: It causes nerve paralysis and respiratory arrest. He also mentioned that death from acute injection occurs faster than ingestion.

Verdict: Correct.

Technical explanation: TTX is a relatively small molecule that has an affinity for Sodium ion channels. Sodium ion channels are an important part of neuronal signal induction, which allows for the transduction of action potential. Action potential is basically the sharp rise and fall of negatively charged ions in a cell (neuron), and the sodium is what moves the negative ions. Thus, when the sodium ion channel is blocked by TTX, the action potential is blocked, and neuronal activity ceases. This can lead to respiratory arrest, and loss of feeling.

Translation for lay people: It stops neurons from working by stopping positive ions from moving the negative ions through the neuron (remember, opposites repel). To simplify it further, neurons have what are known as gates, and TTX locks the gate for Sodium (which is necessary), stopping the neuron from working.

Notes on accuracy in DC: Most of what Gosho said was entirely accurate. However, he failed to mention a few things, and also over estimated TTX's lethality SLIGHTLY. 0.5 is not the start of the average. I never found any data that corroborates that value. However, I cannot say that he is entirely wrong, because it is possible for lethality at that dose. What he said about the IV vs GI was also correct, but it lacked perspective. If you look at the numbers, the lethal dosage for IV is MUCH lower than GI. It also has 100% bioavailability from IV injection. Which means that all of TTX can be used, which aids in its toxicity. Also death is not immediate, it is rapid though. Remember that death occurs from respiratory arrest, which is not immediate and would take some time (though not much). Also the other symptoms would also occur (like numbness and muscle paralysis). Overall, there is not much to say, as Gosho was nearly 100% accurate in this case. He just bolstered its abilities as a toxin slightly.

Final note: As before, any requests to further clarify will be done to the best of my ability, and anyone who wants to know further symptoms of acute toxicity let me know and it will be added. And for the record, I even consulted one of my professors who is a Toxicologist and has their own lab for Toxicological research on the Metabolism of TTX. She was stumped too. So I didn't leave blanks from lack of trying.

[Kyuu Nye 425]

[Carbon Monoxide in Progress]

 

*all information provided here is from [url="http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~QtQRQU:1[/url] unless otherwise noted*
 *Information is also from Airgas MSDS*


Structure:

Chemical Formula: CO

Appearance: Colorless, tasteless, gas

LOAEL: 

LD₅₀(GI [assumed]):

LD₅₀Perspective: 

LD₅₀(IV mouse): 

LD₅₀(IP mouse): 

LD₅₀(SC mouse): 

LD₅₀(Oral mouse): 

Perspective on LD₅₀ of TTX Toxicity: 
T_1/2:

ADME
Absorption:

Distribution: 

Excretion:

Metabolism: 

Mechanism of toxicity (aka: how it kills you):
.

Notes on accuracy in DC: 
Final note:

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[Kjeldahl 47]

Time to revive my favourite thread. 

I will be assisting Kyuu in the Tox project so you can also send me any of your queries if Kyuu is unavailable.

 

ACONITINE
 

Introduction: Aconitine is an Alkaloid present in the Aconitum species of Plants. Its roots are highly poisonous. Ironically, roots are often used in traditional Chinese medicine for treatment of Rheumatoid Arthritis.

 

Structure  : 

 

Chemical Formula: C₃₄H₄₇NO₁₁

 

Appearance: Crystals

LOAEL: 0.006 mg/kg

LD₅₀(GI [assumed]): 0.028 mg/kg

 

LD₅₀Perspective: 2-3 mg is lethal.

LD₅₀(IV mouse): 0.1 mg/kg

LD₅₀(IP mouse): 0.1 mg/kg

LD₅₀(SC mouse): 0.27 mg/kg

LD₅₀(Oral mouse): 0.1 mg/kg

Perspective on LD₅₀ of Aconite Toxicity: Aconitine is a fast acting toxin. Although it is seen that pure Aconitine crystals aren’t as toxic as raw aconite products.

T_1/2: 6-12 hours

 

ADME

 

Absorption: Gastrointestinal tract, Intravenous and Intramuscular.

Distribution: Through the blood.

 

Metabolism: Metabolised by CYP P450 enzyme in the Liver.

Excretion: Urine.

 

Mechanism of toxicity (aka: how it kills you):
Information on the mechanism from Detective Conan is as follows : Aconitine is a paralytic nerve poison extracted from the leaves and roots of Aconitum species.

Verdict: Correct.

Technical explanation: The toxin acts on binds on voltage dependant Sodium channels present on the surface of Cardiac muscle, Skeletal Muscles and Neurons. They prolong the opening of Sodium channels, thus causing depolarisation phase to last longer causing an upstroke in the Action potential. As a result, the membrane cannot be repolarized.

Translation for lay people: It allows Sodium ions to move inside the cell causing increased Sodium concentration leading to physical manifestations.

Notes on accuracy in DC: Although it is true that Aconitine has neurotoxic properties, it only causes generalised muscular weakness. Its most adverse toxic effect is seen in the Heart. Death is often due to Ventricular Arrhythmia.

 

Final note: I won’t be delving much into the treatment part but if by any 0.1% chance someone accidentally encounters such a situation, drinking strong coffee can actually hamper the progression of the poisoning. That DOES NOT mean you don’t need to go to a hospital.

 

Something interesting: In numerous lab experiments, it has been observed that Tetrodotoxin is able to act as an antidote in Aconite poisoning since they both show mutual antagonistic effect towards each other. Of course, we don’t administer Tetrodotoxin as it is super lethal and there are way better drugs out there. But still, a poison used to kill another poison and acting like an antidote is pretty cool though :3