HOUSEHOLD PRODUCT : SOLVENT TOXICOLOGY

Solvent = dissolved substance.

When we said 'dissolved substance', its a volatile (meruap) substance, aerosol substance. Thus, most of them are an inhalation substance. Here I put a picture of dissolved substance that have widely used and misused. Amyl Nitrate :

Amyl Nitrate have not much of medical therapautic. It was growing widely in the west, and now has spread to Malaysia. In Malaysia, for the past three years, it have being misused and abused. Initially it was used as vasodilating material, can dilate the blood vassels. People then used them as socially and recreationaly. Men love them. They used them for sexually activity function to get the erection and make their penis to become longer. Amyl Nitrate sold in a name of poopers in a bottle. Brown bottle. Its very pungent and smelly (like stinky socks. yukks). But, when you are the one that opened it, you will not feel the smell of the stinky socks, but only by people around you. It have become notorious in Malaysia.

For a household product, it have at your house, your exposure to it are increased, people who works at factory very exposed to them, since the factory need to be always clean, sterile. 

BENZENE

When we talk about heterocyclic amines and polyaromatic hydrocarbons, do the benzene is an aromatic compounds? Yes. Why? Because of their cyclic molecular structure. it have single bonds, double bonds. When it is benzene rings, and its name itself aroma,  it have distinct smell, where people love the smell especially kids. So, aromatic compounds is dangerous or not? As a dissolved substance it have functions. But, to be exposed to humans, it have toxic effects. For the Polycyclic aromatic hydrocarbon (PAH) and amines, did they have only one benzene ring? No. They have POLYaromatic hydrocarbons. Thus,the higher its toxicity effects.

So, why they are toxic. Go back to the mechanism of toxicity of PAH or the benzene rings. Its a story how the double bonds being metabolized. When double bonds being metabolized, it is going to be broken (this happen in a body since it need to be metabolized) to an oxidize products. The intermediate products will give you the epoxide.  When the double bond breaks, the rings still there, and at the top of the molecule have oxygen, then it is called Epoxide.

Epoxide is a reactive product. It need to react or bind with other molecules, ASAP. Fineee if it want to react fast BUT, in benzene, is there only one double bond? No. it have three double bonds. After one double bond break, the others can break or not? Yes. Meaning here, your body need to work up more to metabolize and excrete one benzene. But, in one solvent compound, is there only one benzene? No. it have a lot of benzene!

Tell you what, Sate and BBQ, have POLYbenzene rings! So, MORE double bonds need to break out. One PAH did not finished yet, another ring have been broken down. That's why its very difficult to actually excrete the polyaromatic hydrocarbons. PAH have a lot in grill foods and vehicles and factory emissions. 

Ok, lets go to first activity. Look this picture :

This is a picture about glue sniffing. The world most widely recorded in glue sniffing activities is in the southern asian countries typically in Filiphines. In Filiphine, even you go to Manilla, by the roadsides, you can always see a lot of these people. They are called Glue, Kick, Bang, Sniff, Huff, Poppers, Whippets, Texas Shoeshine. They are sounds as a blows things. Its all about the solvents. The solvents is the volatile things, evaporate. They put the glue in a plastics and then they sniff them. Why people addicted to it? Why they cannot be controlled? Why glue sniffer pronds to be among childrens? (90% children. For adults, they start to take ecstacy etc.) Socioeconomic factor also one of the reasons. Mostly glue sniffer among low socioeconomic people.

In factory, you want to dissoved something, to get something. Then you can extracted the things, this dissolved extract also need to used solvents. Solvents also widely used for sterility functions. Same with household product, that used for cleaning purposes. So, exposure to general populations, can easily happen. 

So, why the uses of solvents can easily to be misused and abused and addicting? Especially to children, poor people? Especially to glue, why not chlorox? (people do not addict to chlorox eventhough it also a solvents)

1. AROMA

Chlorox, chlorine etc have pungent or distinct smell. With the benzene solvents with the aromatic rings is why the people love them. The smell also have to do with why children loves them more than the adults. You can see when you fill in petrol, they love to came close to smell the petrol, when you in a house that had just being paint, modelling car etc. children like to come closer. (You need to move them away from it) So, why children more susceptible, why children will start with glue sniffer first? It have to do with the smell. The different smell, new smell, children love it more than the adults. When they love it, they want to smell them more and more. When it become continues/addicts, that's how the dangerous come. Those dangerous we didn't see them at first, but the dangerous came when the children in growing stage,  they did not want those glue anymore, they start to take prohibited substance that can give the same effects. Then they will get coccaine, ecstacy, and at the end of the day they end up with heroine. That's why prevention is better than cure. Need to avoid the children from all of this.

2. EASY ACCESSIBILITY.

Thats why its popular among to low socioeconomic people. Thats why also this problem is difficult to control. When you buy heroine, its easily to being detected and arrested. But, when you go to market/shop. you buy a glue, you can just simply said I want to glue papers for homework or something like that. Others will not have a reason to arrested you. Easy accessibility. Children can get those glue easily. 

3. TOXICOKINETICS OF SOLVENTS - EASILY TO BE ABSORB

Why children easily to addict to them? Easily to be absorbed. Because they are in form of gas, volatile, small molecules --> easily to be absorbed, easy to distributed, easily go into CNS. Other factors? lipid solubility of solvents. If not at CNS, first organ that it will attack would be the LUNGS (pulmonary). Then your CNS.

These is the general for all solvents.

Lot of solvents have difference in target organ toxicity. Not all will give effects on pulmonary and CNS. Solvents have their own target organ toxicity. It means, when it gets into your body, absorption and distributions, then, why they go to difference organ? That one at blood, others at nerve, here at pulmonary, liver, eyes and also reproductive?

Why not all same? while all are lipid soluble, small size but at the end they give difference effect? Why? The first reason would be due to the toxicokinetics. No longer just about absorption and distributions, now you have to considor also the metabolism and extractions also.

So, I give you another activity.

This activity is about Toluene. An alkylbenzene. I already had explained about benzene. Now we have benzene attached with methyl group. The alkylbenzene have effects on CNS. But Benzene on blood?.Benzene that without alkyl group effects on blood, you become anemic. Why difference in target toxicity??

Reasons have to do with ADME.

Toluene also can break double bond like benzene. But for benzene, it need to be broken to produce epoxide to give toxicity effects. So, the breaking up of double bond should be conducted at what place? by what? Before answering that, lets answer "Why need the breaking up of the double bonds at the first place?" The answer is "for metabolism and and metabolism is needed for extractions". The problem is, when it being metabolized, it become epoxide, which is very reactive compounds. So, if it have toxic effect, actually it reactivity is not in ASAP mode. and its not balance at all. Since metabolism mostly in liver, the reactions may be balancing because there are a lot of compound that it can binds to. The problem is when they have higher affinity, they love at the bone marrow. When they go to the bone marrow, is it a major organ for metabolism? Not really. But body still can metabolize. Is there enough compounds for them to binds to? Not enough. Balance or not? Not balance, reactive compounds are much higher then the compounds that they need to react to,  so, they will attack the bone marrow, binds to the blood cells progeny, then blood cells cannot be produced: damage, low in numbers, and that's why you get metaplastic anemia.  

Compared to alkylbenzene, did not need metabolism already since it is already a very reactive compound, direct toxic effect, directly go to CNS, directly get the effect.

NOW, Activity three.

CHLORINATED HYDROCARBONS. Where is their target organ toxicity? Lungs/pulmonary system. Because you inhaled them. We will talk about Chlorine and Phosgene.

Phosgene = very potent chemical warfare. It smells like musty hay (jerami basah), not a nice smell at all, and pungent. They can failed the pulmonary systems. The problem is, phosgene used as solvents at factory but at the same time, they are also a reactive compounds that you probably also get from other solvents.If they have metabolic activations, they can produce phosgene. And with phosgene, no need metabolim because they are already toxic (as the toluene). For this solvents you get the aerosol and Anasthatic agents

Come to the question, whats the industries do with the level of exposure of the solvents at the work place?

They do the Dose-Responds Measurements. You draw the graph and you will get the NOAEL and LOAEL. Since NOAEL, you are exposed but give you no toxic effects. But the NOAEL is so small since you are exposed to them everyday (I means if you are the workers). If not NOAEL, take the LOAEL. If LOAEL, it have the toxic effect but then you need to do the MANAGEMENT OF THE RISK. 

MANAGEMENT OF THE RISK. 

Yeah, if you dot wear goggles, lab jacket, all others safety attire, of course you will get at least LOAEL. But, you can change LOAEL to NOAEL. Occupational toxicologist call of this as TLV = Threshold Limit Value.

Solvents, also can give effects also to the enviroment when you not dispose them properly or at right method. A lot of this have been happening. Escpecially with the chlorinated hydrocarbons. Do not how to dispose them, you buried them in soil. What the Fishhhhhhhhhh??? If you do that, at first, it seems nothing wrongs, but after a while, if rain come, it will become volatile NOT at the place where you buried them, but it will to be elsewhere. In ecotoxicology, distributions from one place to another due to winds, rains. It can go to another place, such as residential place, where there would be mother, pregnant mother, young children (because the father go to work)

Another activity - the ALCOHOL, METHANOL, ETHYLENE GLYCOL

They have different organ target toxicity. Alcohol at liver, methanol at the eyes, and ethylene glycol at the kidney and reproductive organs. WHYYYYYY? Again, it have to do with toxicokinetics, it have to do with metabolism. First, we go to alcohol.

Alcoholism mostly a subject of the Fetal Alcohol Syndrome (FAS). The mother is an  alcoholic and her child have a characteristics of FAS. So, the questions is, why the effect goes to the child, not the mother? 

This is due to several factors, 

1. Age

    *Undeveloped fetus cannot do the metabolism. 

2. Alcohol - volatile, small - good diffusion and distributions. Anything that can go through BBB can go through also the placenta

When you take alcohol, in your body there is already enzyme that recognize the alcohol. (If they not recognize, alcohol need to through Phase 1 and Phase 2).  Alcohol will be directly metabolized by enzymes. The enzymes is called as alcohol dehydrogenase (ADH). They already in our body, more price, in the liver. They can metabolize alcohol ASAP. People who are intoxicated with alcohol, their metabolism are NOT COMPLETE. Because when alcohol being metabolised by ADH, it will become aldehyde. Aldehyde still cannot be extrected out from the body because its water solubility is not high enough. Aldehyde need to be changed to carboxylic acid to become water soluble. But aldehyde to become carboxylic acid, it need to metabolise with aldehyde dehydrogenase (ALDH) enzyme. 

The problem is, when you are expose to alcohol too much. The enzyme are not that much acually. So, they will metabolize the alcohol but they cannot extract them out. Aldehyde dehydrogenase not enogh and aldehyde will build up in the body, and that's how you get aldehyde intoxication. But the body loves you!, Your body, eventhough there are no ADH and ALDH, it will switch to catalyste, an antioxidant enzyme that can metabolize the alcohol. But, then, you drink a lot of alcohol again. What will happen, they will switch on to the conventional metabolism, Phase 1 and Phase 2. It will used the Cytochrome 2P42E1. This is what we called as Microsomal Ethanol Oxydizing System (MEOS). Microsomal because they will send to liver --> oxidize --> conjugate --> excrete out. Why there will be liver toxicity? Your ADH, ALDH, Catalyse, compound that it need to be conjugate already finished, whats remained are the reactive compounds produced by the Cytochrome 2P42E. This remaining active compounds will attack your own nearest cells in the liver -->  LIVER TOXICITY

Genetic polyphorism also can occur. Caucasian people do not easily drunks, but Oriental (Estern) people easily to be drunks. Girls easily to be drunk than the guys. These have to do with your own enzymes. 

METHANOL

Methanol attack the eyes. Methanol is a contaminants or it is an alcoholic drink that are not pure. (Alcohol, the cheaper it is, the more impurities in it, the more not pure they are). Methanol is one carbon.

Metabolism : Methanol enters the body, directly metabolize by ADH and ALDH and causes an increase in aldehyde. Aldehyde is very retinotoxic, attack retina, thus make you blind. 

ETHYLENE GLYCOL

They attack kidney and reproductive systems. Why? Due to incomplete metabolism. (Complete metabolism : alcohol -> aldehyde -> carboxylic acid). Incomplete metabolism make you drunk fast. That's make you hangover till the next day. Because the level of aldehyde is too much. With the ethylene glycol, you get them from coolant, lubricant for the vehicles. Sometimes children drink them because they think the coolant is a drinking water. They die due to accidental exposure. 

ETHYLENE GLYCOL -- > Glycol aldehyde (oxalate) --> Oxalic Acid

Aldehyde wanted to be extrected out but did not have time to be excreted. Thus it will send to the kidneys and at the wrong reproductive organs and form a crystals. Sharp crystals will injured the organs and hence the Target Organ Toxicity only at the reproductive systems and the kidneys.