Key Concepts in Environmental Toxicology

Hi everyone, welcome to PubH 462, Environmental Toxicology and Health. We just finished the introduction lecture, which was just really an introduction, right? So today we are going to get started with the meat and potatoes of toxicology. So today's topic is... absorption, distribution, and elimination. Actually, one thing that's missing within these three words is what we call biotransformation. So biotransformation is another important aspect of toxicology and because it takes a little more discussion to go over biotransformation. So topic three will be just on biotransformation. We'll start talking about the membrane transport and specifically we'll talk about the phospholipid bilayer. It is the foundational structure that makes membranes and understanding its physical characteristics of the phospholipid bilayer will help us understand how chemicals can move through the body including absorption, distribution, and elimination. Then we'll talk about some physical properties of toxicants. Specifically, we'll talk about whether a chemical is polar or nonpolar. And then we'll talk about these three important things, absorption. We'll talk about skin absorption, or known as dermal absorption, respiratory absorption, and also GI tract absorption. And then we'll talk about distribution. And then lastly, we'll talk about the elimination of chemicals that have entered into our body. and what are some of the pathways of illumination All right, this is a general schematic of what actually happens once a person or an organism is exposed to toxic chemicals. So this toxicological process can be broken down into three different categories here. Toxicokinetics represents how the toxic chemical actually gets to the site where it actually causes toxicity. And this is the... point where the toxic chemical meets with the target molecule and causes some kind of disturbance in that target molecule or the cell in which it resides. This is the point where the initiation of damage actually starts. And lastly, once the target molecule has been damaged or altered, it leads to cascade of problems resulting in some kind of disease, or it could be cellular. death or it could be organ destruction or it could be eventually lead to organism responding to the damage that may lead to for example liver damage kidney damage or even cancer and this is referred to toxicodynamics so the toxicokinetics and toxicodynamics are the two big things whereas in this middle part initiation it's really important but it's that very short span of time in which the target molecule and the toxic chemical, they come together and cause the damage and initiate the process of disease outcome. So I would say this is very short in relation to toxicokinetics and toxicodynamics. There are many ways to describe the different steps in which toxicity can occur to an organism. This is one way to describe the different steps. Here it's broken down into four steps. The first step in toxicity or development of toxicity is delivery. That is, the chemical or toxic chemical has to get to the site where it will cause damage. Let's say the target site for chemical X or toxic chemical X is the brain, but if it never gets to the brain, then that chemical cannot do any damage. Eventually, that chemical will be eliminated without any type of disturbance to the body, right? So if the toxic chemical is going to cause disturbance, it has to get to the target site. So step one is delivery. It's referring to the absorption and the distribution and get to the target site. In step two, now that the toxic chemical has reached the target site, they react. Toxic chemical and the target molecule or a target atom or target cell or target organ, they react. And ultimately, it causes a disturbance to that target molecule or the atom. and etc. We use this phrase called ultimate toxicant and we're going to talk a little bit more about it. Ultimate toxicant is the chemical that actually interacts with the target molecule because once you're have absorbed the chemical, it may go through some metabolism and it changes into a different chemical before it actually reaches the target molecule. So we use the phrase alternate toxicant to refer to the one that causes disturbance to the target molecule. And the step three in the process is cellular dysfunction and resultant toxicity. It leads to some kind of damage, right? And it could be damage to a molecule. and which can lead to damage to atoms and group of atoms are damaged can lead to dysfunction in the organ and if organ failure occurs then obviously it leads to disease in the living organism. So step three is this cellular dysfunction and result in toxicity. Whatever the damage that was caused your body is going to try to fix it and if it's fixed completely or your body has adapted to that toxic chemical, then you're good to go, right? You're fine. However, the fact that the toxicity has occurred usually means that there was inappropriate repair and inappropriate adaptation to the toxic chemical, hence disease has occurred. Let me provide you with an example of toxicants and target molecule. You've probably heard of tetrahydrotoxin if you've taken 415 already. And even in the first lecture, I may have referred to tetrahydrotoxin. tetrahydrotoxin. Tetrahydrotoxin is a nerve agent, that is, it actually damages the nerve cells. And tetrahydrotoxins are found in certain type of reptiles, certain type of fish. And tetrahydrotoxin is well known for being present in puffer fish. So who eats puffer fish? Well, it is a very expensive delicacy, especially in Japan, as they eat the sashimi of puffer fish. Well, tetralotoxin resides in the organs of puffer fish. So the chef has to be well trained to make sure that tetralotoxin does not contaminate. the food that people will be eating. However, every single year, number of people die in Japan because of tetrahydrotoxin poisoning. So the toxicant that we're talking about is tetrahydrotoxin. And what is a target molecule? Well, the target molecule, as I mentioned, is the nervous system. Of course, more specifically, it's a nerve cell. And if you want to get into even more specific than that. tetraodotoxin targets voltage-gated sodium channels. So inside a nerve cell, there's a way in which signals are transmitted across the cell. And this happens because of what we call voltage-gated sodium channels. If this gets disrupted, then information stops flowing. So here's your brain or your muscles. right there has to be this constant movement of information between the two when what tetrahydrotoxin does it breaks that connection particularly the tetrahydrotoxin impacts involuntary muscles like diaphragm. If your diaphragm does not contract, then you cannot breathe. Although it causes damage to the nervous system, it's the breakdown of the nervous system that prevents diaphragm muscle from working and you suffocate to death, basically. So what is the target molecule? Target molecule, you can say it is a nervous system or the nerve cell. And another example of toxicant in a target molecule is melamine. Melamine is a chemical that's used to make certain type of plastics and if you are into cooking you probably have seen plates or cookware. that's made of melamine. It's very sturdy type of plastic. In China, people who are, I would say, just very, very bad, they ended up adding melamine to formula milk to deceptively boost the protein content. And how does that work? Well, melamine has a lot of nitrogen, as I mentioned. And that deceives the tests and makes it the tests show that the milk has high levels of protein, when in fact it's the melamine. Now, when infants drink this contaminated formula milk, what ends up happening is that inside the kidney, melamine starts to form crystals. And they form into these tiny melamine stones where it causes kidney damage. And as a result, children can easily die or have... other kinds of kidney problem issues. You can almost think of it as, you know, tiny plastics, a melanin is formed inside the kidney, right? So what is the toxicant? Toxicant is a melanin, right? Well, it's not a toxicant if it cannot get to the target molecule, right? never gets to the kidney and it gets eliminated, then it's not really toxic. The reason why melamine is toxic is because it gets to kidneys. Well, the kidneys is the target site in this case. particularly target molecule, but it's a target organ. Usually I have a lot of YouTube videos that's related to the topic that we're discussing. And since this is a pre-recorded lecture, I strongly encourage you to watch these videos. Some are fun, some are interesting, right? But all of them are very informative. So what are some of the factors that affect toxicity? And there are many different factors. And as we go through some of the lists... you realize that it doesn't take a rocket scientist to realize how whose factors affect the toxicity, right? So what are some of the whose factors that affect the toxicity of the chemical? Well, it's the size of a person. If you compare a football player who's 300 pounds as opposed to a very petite woman who's 100 pounds, there's a lot greater blood volume in the football player. Therefore, he might be able to tolerate more of the toxic chemical as compared to petite women. Size is important. Age is also important because older the person, your bodily organs don't function as well, especially organs like the liver or the kidneys. Sex is also important because depending on whether you're male or female, your body has different kinds of hormones and the different levels of hormones. and that may impact the toxicity. And if you're talking about animals, right, different species, or if you're talking about microorganisms, different strains of microorganism is going to impact the toxicity. Perhaps even changes in the internal environment, like your gut, right, your gut flora, that may have some impact. Or if you are some habitual drug user, or someone who has to take... medication for long periods of time, that may also impact the toxicity. But today we're going to focus more on the toxic chemical itself, right? The factors that relate to the toxic chemical. The root and the rate of administration obviously is going to be important. And think about how we actually absorb toxic chemicals. What are the different routes? So the main ones are the dermal exposure, right? You have inhalation by breathing and also ingestion when you eat something or drink. something. And there could be some kind of drug-drug interactions. And later we'll talk about how grapefruits actually interact with many kinds of pharmaceutical drugs. And if your body builds tolerance to certain type of chemicals. So I think I've shown you this slide before. Toxical kinetics is what the body does to a toxin. This is just a simple way to describe what toxic kinetics is. To define toxic kinetics in more academic terms, it is the rate in which the toxic chemical moves about inside the body. And this is related to absorption, distribution. Later, we'll talk about storage as well and elimination, as well as biotransfer, which is topic three, as I mentioned. And toxicodynamics, in simple terms, is what the toxin does to the body. Toxicokinetics is about the rate of distribution and absorption and elimination. But toxicodynamics is what actually the toxin does to the body. Does it damage molecules? Does it damage or disrupt some physiological process? Does it damage tissues? Or does it lead to some functional damage like physical and behavioral? These are the disease outcomes, right? So when we're talking about toxicodynamics, talking about toxicodynamics, we're talking about disease outcomes. Toxical kinetics is a quantitation the time course of toxicants in the body. It's the rate of toxic chemicals moving about. It's a reflection of how the body handles the toxicants. The end result of these toxicokinetics process is what we call biological effective dose of the toxicant. We also refer to it as BED. And BED is the amount of substance required to reach target cells or organs and to produce an expected effect. So the endpoint of toxicokinetics, because if a toxic chemical does cause toxicity, at the end of toxicokinetics, it's how fast and how much of the toxic chemical. gets to the target site, whether it's a cell, molecule, or organ. So BED refers to the amount of substance that's required to reach that target site and to cause the problem. absorption is referred to as systematic toxicity in contrast with local toxicity. Systematic toxicity means that basically the chemical itself has distributed throughout the body and can cause multiple toxicities whereas local toxicity is once the toxic chemical has been absorbed it only causes problem around the site of absorption. Chemicals enter the bloodstream after they are absorbed, right? That's the first step. And it could be from ingestion, inhalation, or from thermal exposure. And once the chemical is in the bloodstream, it can be dis- distributed through the body. Once the chemical is distributed throughout the body, at some point, it can't stay inside the body forever. Eventually, it will be eliminated or broken down, in other words, metabolized. And for this course, we will use the word biotransformation. And these chemicals or their metabolites, because they have been biotransformed, are then either stored or eliminated. It's very less likely for your body to store a lot of things. You know, you've got a limitation in your physical size. So your body rather wants to eliminate things. But sometimes your body can store toxic chemicals in places like the bones or the adipose tissue. Here's an interesting video that shows how hair can be tested for mercury poisoning. And in order for mercury chemical to get into the hair follicles and the hair itself, it needs to be absorbed through some exposure route. then it gets distributed throughout the body and then it gets eliminated through hair follicles right so it has gone through the exposure the absorption distribution and also eventually the In order for us to understand the movement of chemicals inside the body, we have to have some specific knowledge about the makeup of cellular structures, specifically the membranes of cells. Ultimately, these chemicals will need to move through these membranes if it wants to go anywhere. The foundational structure that makeup... membrane, different kinds of membranes in cells is what we call phospholipid bilayer. If you see this picture of a cell, you can see chemical cannot cause damage to cell unless it's able to pass through the cellular membrane. Well, what if and what if the target site for this chemical is mitochondria? Well, not only does it need to get inside the cell, it needs to get in to the cell. the mitochondria organelle, right? It's going to have to pass another membrane. If you're talking about a carcinogen that will directly interact with the DNA to cause DNA mutation, well, that chemical first needs to enter into the cell and then it needs to get into the nucleus, right? And where the DNA is. So the movement of these chemicals really depends on how light. likely these chemicals can pass through cellular membranes. So here's what cell membranes look like. But really the foundational structure for the cell membranes are these phospholipids. Each one of these is a phospholipid. But phospholipids usually don't exist as one layer. They tend to exist as two layers. That's why we call it phospholipid bilayer. And I'll talk a little bit more about its... particular chemical physical structure that make them into two different layers. Fossil lipids are made up of two distinct components. We call this the polar head, that's the circle part. And we call the bottom the nonpolar tails. The polar head is composed of a phosphate group. And of course, it's got other things. But the important thing is that they are charged. are charged, water likes to surround the things that are charged. Whereas non-polar tails are mostly composed of carbon and hydrogen and carbon and carbon bonding. Carbon and hydrogen and carbon and carbon bonding. Water does not like that. It's like oil. If you were to dump many fossil lipids in a bucket of water, what ends up happening is that it will either form into a spherical shape. or it will form into these phospholipid bilayer. Why? Because the tail hates water, so they want to stick together. Whereas in the head part of the phospholipid loves water. So water surrounds all of these guys, but it hates water. So the tails want to stick together. So micelles can be formed in this way. Right and once again the idea is that what you're doing is that the tails have very little contact with water because they don't like each other. Here's a very corny video but it really does explain a little bit. phospholipids. It's a rap that's made by some teacher about phospholipids. It's kind of funny, so I recommend you watching it. So the question is why doesn't oil and water mix? And that's because oil is mostly made up of this nonpolar tails, right? It's mostly these carbon-carbon-carbon hydrogen bond. Well, whereas in water is polar. It has a partial negative charge and because it has partial negative charge on one side, it has partial positive charge on the other so they like to kind of stick together almost like a magnet. Water And these carbon tails, they hate each other. They don't like it. They don't want to mix. So oil wants to stay away from water as much as possible. Just looking at the vinegar and olive oil makes me very, very hungry. Balsamic vinegar here is mostly water. Here's olive oil. And they don't like to mix. They want to minimize the interaction as much as possible. As you can see anything that's oily does not want to mix with water. So here's what olive oil pretty much looks like. It's mostly carbon-carbon bond and carbon-hydrogen bond right. There's potentially could be little interaction with water here because the oxygen, but compared to the size of the tail, it's very little. Whereas the water is a very simple molecule that has partial negative charge on top and partial positive charge in the bottom. But what's interesting about phospholipids is that phospholipids contain both hydrophobic, which means that it hates water, And hydrophilic ends, loves water. And detergents are actually made similar to phospholipids. It has both the part where it hates water and part that loves water. And that helps break apart any stains. oily stains. I know that the picture of this molecule is not the sharpest, but you can still see, right? O represents oxygen, right? This is oxygen. H represents hydrogen, and P stands for for phosphorus and of course although it's not written here every single corner right represents carbon so there's many carbons carbon carbon carbon carbon etc single line means it's a single bond if it's two it's a double bond Although you don't actually see the hydrogens attached to these carbons and usually they're kind of left out because it just makes Like your structure is much more complicated than it should be. So these kinks represent carbon, but they also have hydrogen attached to them as well. And this side is the polar head, and this is the nonpolar. Okay, so now let's talk about how chemicals can move across a phospholipid bilayer membrane. Now it really depends on the type of chemical that you're talking about. So just now we separated chemicals according to its physical property hydrophilic versus hydrophobic so let's say that you are exposed to a chemical and this chemical is hydrophilic meaning that it likes water this side is extracellular it's outside here's inside the cell So if this chemical wants to be absorbed or wants to be distributed, it needs to move across this phospholipid bilayer into the cell. One thing that you have to keep in mind is that this phospholipid bilayer or the cell Let's say the cell looks like this right here. Here's a cell and here's a nucleus, mitochondria, etc. Whether it's inside the cell or outside the cell, this is all in water. the matrix in which the cell inside or outside is in water. But what distinguishes between outside the cell and inside the cell is this phospholipid bilayer. So let's imagine that you were exposed to a hydrophilic chemical. Hydrophilic meaning that it likes water. And because there is water all around, it's not going to be able to absorb water. this chemical let's say it's chemical x it's just going to be around outside it's happy where it is right it has no real desire to move across why should it go inside itself there's no real force to do that So when you are exposed to hydrophilic chemicals, it tends to kind of float around. and there isn't enough force for it to move across. Yes, there is some passive diffusion, meaning that outside there are lots of chemicals, right, and inside there's no X. So there's some innate, almost like gravity, that wants these chemical X to move across, okay? And that's one of the important forces. Really for this hydrophilic chemical to get inside the cell it has to pass through this region and this region is hydrophobic. There is no water in there and chemical X does not want to linger between these two phospholipids. Hence it's very unlikely for hydrophilic chemicals to move across. even though there's more outside than inside. Nevertheless if the hydrophilic chemical is really small and there is a lot of them outside some of them will quickly move across and this can happen. This is what we call passive diffusion. But if you're talking about bulky very hydrophilic chemical or molecule it's unlikely to pass through. On the other hand, if the chemical that you're interested in studying or the chemical that you're exposed to is hydrophobic, that it hates water, right? Remember, cells are surrounded or in water, right? All of this is water. This is water. So as soon as hydrophobic molecule enters into its environment, oh, it hates it. It hates to be here. So what is it going to do? It's going to find a way to get into this nonpolar tail section of the phospholipid bilayer. So it's already halfway there, right? So it resides here, but you can't... reside there forever. Maybe there are more guys that are trying to enter and it's pushing them to go out. and they'll then look for other places where they can attach itself that's not so water soluble. And it could be certain type of proteins or molecules or other organelles. So if you're talking about a chemical that's hydrophobic, it's much, much easier for them to pass through the phospholipid bilayer because of the fact that it likes to interact with the middle part of the phospholipid. but by layer. Like I said, it has to be in water. So whether you're in the outside of the cell or inside a cell, it really doesn't matter for them because it's all water, right? The point is that they'll enter into this middle layer and eventually it's going to be kicked out. If it gets kicked out towards where it came from, then nothing has happened. But if it gets kicked down to the other side, so the assumption is that let's say you've took some kind of medication, it's... mostly hydrophobic. Well, then you are going to get a lot of these guys in here and there's going to be a traffic. There's so much of these guys eventually that will be kicked out. Okay. I hope that makes sense. So here's food for thought. And this is the reason why, you know, you can't dip your hands in sugar water and expect to absorb sugar through your skin. Why? Because sugar is water soluble. Sugar dissolves in water. Once you put sugar in there it completely goes away unless it's saturated obviously even if i want to put my hand in here i'm not going to be able to absorb that sugar because sugar itself is hydrophilic it has very difficult time passing through the membranes that makes up the cellular structure of my skin so it's unlike for humans to be able to absorb hydrophilic chemicals thermally. However, if you're talking about something that's very hydrophobic, then you can actually absorb these chemicals through your skin because hydrophobic chemicals are much more likely to pass through the phospholipid bilayer. Now let's try to put this together. At the point where you are exposed, let's say it's either dermal or ingestion. In order to get to the target site, you have to kind of see that there are many, many membranes that the chemical has to pass through before it reaches the target site. So how many layers, how many phospholipid bilayers do these xenobiotics need to pass through in order to reach? For example, the nerve cell, if that's the target molecule. Well, let's think about it. Let's say you are absorbing this through your skin. From outside of your body, it's going to have to pass through one phospholipid bilayer. Then you will get into the cell, the skin cell, let's say. And let's just say that skin has only one layer of cell. We're talking about dead skin, so that it's just going to go through, needs to go through once. And then it needs to pass through the capillary because it wants to get into the systematic blood. So you will need to go through the capillary phospholipid bilayer to get into the blood vessel. Well, then inside the blood vessel, it gets distributed. Well, if it wants to get to the target site, it's going to have to get out of the capillary. And now you are in the interstitial fluid, which is a fluid between spaces in tissue cells. In order to get into the target cell, then you're going to have to move through another phospholipid bilayer. And now you're inside the cell. Now, let's say if you're talking about DNA of the brain, well, you're going to have to pass through another organelle phospholipid bilayer until you actually reach the target molecule, target cell. So at minimum, you're going to have to pass through one, two, three, four, five different phospholipids by there. It's going to be a lot more than this, but you get the idea. The point is that in order for the toxic chemicals to get to the target site, there's no easy pathway. And the type of chemical it is, whether it's hydrophobic and hydrophilic, is going to have huge influence whether it will ever reach that target site. Now I already mentioned that chemicals can pass through the phospholipid bilayer, but there are some conditions that these chemicals have to meet. And I didn't say that If the chemical that wants to be absorbed or distributed is hydrophobic, it's more likely to pass through the phospholipid bilayer. So let's talk about these factors. Number one. It's the charge of the chemical. If a chemical or molecule has a charge, it's probably not going to move across the phospholipid bilayer because charge means it's very water-soluble. It's going to be surrounded. by water molecules. Number two, it depends on the molecular size. If the molecule is really large, chances are large molecules will have both hydrophilic and hydrophobic sides, and it's going to have difficult time passing through the phospholipid bilayer. However, if you're talking about a very small molecule like oxygen gas or even carbon dioxide, especially if they're really small, even if it's hydrophobic, phyllic, it can still pass through the phospholipid bilayer. And I did mention number three, it's the lipid solubility. Lipid soluble or hydrophobic, really the same thing. are more likely to pass through the phospholipid bilayer. Although number four is not related to the chemical properties of the chemical, the membrane composition and the thickness of the membrane, for example different types of skin, will have impact on the ability for chemicals to move across the phospholipid bilayer. So let's go through these. First one is that membrane transport depends on charged state of the chemical. Chemicals that are positively or negatively charged means that they can't move across. the phospholipid bilayer. So sodium ion, potassium ion, calcium ion, magnesium ion, etc. They all have a charge. So if you think about sodium plus, what in fact happens is that this is surrounded by water. If you want to be a little more specific, the oxygen end is going to be towards the sodium ion because this has partial negative charge and sodium plus has positive charge. The sodium ion that's surrounded by water is less likely to merge with the hydrophobic tail side of the phospholipid bilayer. It's very unlikely for charged atoms or molecules to pass through the phospholipid bilayer. So same thing with anything that has negatively charged. Although we won't really go into the details of charge due to acids and base, remember when the pH of the environment changes, these acids could lose hydronium ion H+, and that would change the charge. And you've probably heard about conjugate acids and conjugate bases. So depending on the pH, a chemical can become positively charged, neutral, or negatively charged. So here's a periodic table of the elements. I know some of you, it's been a long time you've looked at a periodic table. These are all metals right here. And what ends up happening, especially in these two groups, If you can dissolve them in water, once they're in water, they will become ionized. So lithium becomes lithium plus calcium, for example. You can lose two electrons and it becomes calcium too. plus and they become ions. Same thing on this side. These non-metal ions can gain electrons. So fluorine can gain one electron and becomes fluoride and becomes charged. Right so anything that is charged it's not going to be able to move across the phospholipid bilayer. Second the membrane transport depends on the size of the chemical. For non-charged small molecules they will usually pass through the membrane quite freely, quite easily. Remember if it's not charged, although it may be somewhat polar, that it may dissolve in water, but because they're so small that it can actually move through that hydrophobic section of the phospholipid bilayer relatively quickly. So things that are non-charged but small molecules are able to pass through the phospholipid membrane. quite freely. Third, membrane transport depends on polarity, meaning The movement of these molecules depends on how polar these molecules are, how many polar atoms there are, right? If it's more likely to dissolve in water, then it's less likely to move across the phospholipid bilayer. Most polar molecules diffuse into cells very slowly or not at all. So any large polar molecules that dissolve in water, for example, sugar is an example. It is not charged. Sugar is not charged. But it has all of these oxygen in which it forms a hydrogen bond with water and it dissolves very easily in water. So polar molecules that tends to dissolve in water is unlikely to move across the phospholipid bilayer unless they're really, really small. Even if there are hydrophiles. non-polar molecules diffuse rapidly across plasma membranes. If it's like for example ethane, right? Well ethane has two carbons and has six hydrogens. Well this is non-polar and because it's non-polar it will interact with the hydrophobic side of the phospholipid bilayer, hence it's much more likely to move across the the memory. So how do we know whether a molecule is polar or not? Now I'm going to try to teach you this in simplest terms. This is not like a magic bullet in understanding polarity of molecules, but you can use what I'm about to teach you right now and gauge whether a molecule is most likely polar or most likely non-polar. Okay and the way you're going to do this is by looking at certain atoms and these are atoms. that tends to be polar or give polarity to molecules. So these are nitrogen, oxygen, phosphorus, sulfur, and of course there are other kinds. And also if there are metals in the molecule. Now here's an example of water molecule. This is water molecule right here. And the reason why water has polarity is because oxygen likes to pull these electrons from hydrogen and try to keep those electrons around itself. And it also has these two additional lone pairs of electrons. So usually an oxygen is happy or neutral if it has six valence electrons or outer shell electrons around it. Now when it's chemically bound to two hydrogens, it seems as if there are a total of eight electrons around it. That is what gives this partial negative charge. Now for hydrogens, it seems as if the hydrogen atom has lost its electron. Now remember, hydrogen has one proton, and it has one electron. Right? And that makes it neutral. But now what has happened is that hydrogen sort of lost its electrons because Oxygen has higher electron negativity. It pulls those electrons toward itself. And hydrogen is almost left without an electron. And that's what gives that partial positive charge. Now, so on the oxygen side, it has a partial negative charge. On the hydrogen side, it has a partial positive charge. And this is what gives polarity like a magnet, right? Magnet that has north on one side and south on the other. So if your molecule has oxygen, nitrogen, and phosphorus, or sulfur, or even metal atoms, it tends to create this sort of a separation of charge, separation of positive and negative charge. And that's what gives polarity. Here's another example. This is ammonia, right? Nitrogen that has three hydrogens attached to it. Once again, nitrogen has higher electronegativity. So it pulls those electrons. towards itself. So the hydrogen feels like it's lost its electrons, tends to have this partial positive charge and because nitrogen has itself gathered, try to pull these electrons towards itself, now it feels like it has more electrons and that gives partial negative charge. Same thing, right? On the nitrogen side it's partial negative, on hydrogen side it's partial positive, creating this polarity. So whether it's nitrogen, oxygen, phosphorus and sulfur, they tend to do this. So one way to look at. Whether a molecule is polar or not is to see whether how many or what percentage, I don't know, there's no, like I said, magic bullet for this. If there are lots of oxygens and nitrogens and sulfur and phosphorus, it tends to be more polar. and water soluble. On the other hand, there are atoms that tends to create no polarity. We call these nonpolar atoms. At least this is the way I describe it. If there are many carbons, and you have many carbon-carbon bonds, and also if you have many carbon and hydrogen bonds, or carbon and halogen bonds. An example of carbon and halogen bond will be carbon and fluorine, carbon and bromine, or carbon and chlorine. These tend to be nonpolar. There is really no separation of positive and negative charges in these bonds. So here is an example of benzene. Benzene is all carbon-carbon, carbon-carbon, and carbon-hydrogen. There's something called resonance structure. We sometimes put... These ring structures as a circle because the double bonds, they tend to move around, they alternate. Anyways, this would be a nonpolar molecule. Same thing with the butane. Butane, remember, each corner represents carbon. And this is just hydrogen, right? And all it really has are these carbon-carbon bonds and carbon-hydrogen bonds. And this is nonpolar. and you don't see any oxygen, nitrogen, phosphorus, or sulfur. So things that are polar or charged, water surrounds it. If water surrounds it, it means that it likes water. It's hydrophilic. So when we say either an ion or an atom, or a molecule is water soluble, it means that water can surround it. How can water surround a molecule? And that's because the molecule itself has some separation of charge. Remember, water has this partial negative charge. Partial positive charge, almost like a magnet. You know, if the ion in this case, this is chloride ion, it has a negative charge. It's that hydrogen side that has positive or partial positive charge will be attracted. And it can surround that chloride. Once the chloride is surrounded by water molecules, it's been solubilized by water. Opposite happens with sodium ion. Sodium ion has a positive charge and oxygen side has a partial. negative charge and water surrounds that sodium ion now sodium ion is water soluble so on the other hand if water cannot surround it then it's not water soluble it's really non-polar molecule so this is a chemical structure of a soap molecule interesting about some molecule is like the phospholipid. That is, it's got two sides. It's got one side that's charged. So water will surround this side. However, water does not like the tail. Water does not like the tail. Water will not be near the tail. So this side is nonpolar. This side is polar. And the way the detergents work is that detergents have one side that's water soluble and the other side that's not water soluble. If you think about oil stain in your clothes, the soap molecule... the tail side because it doesn't not want to interact with water it rather wants to stick around the stain the oil stain so the tail sticks to them eventually it forms what we call my cell and Because the head side is polar, it can actually lift that dirt out. And that's how detergents actually work in cleaning stains, especially if it's oily stain or dirt. So what do you think? Lipophilic, which means it's non-polar. or hydrophilic, which means that the chemical is either polar or is charged. Chromium 6, this is charged. Well, if it's charged, it's water soluble. What about formic acid? Yes, there is carbon and hydrogen bond, but you've got these two oxygens. This oxygen, water will surround the oxygen. And all in all, this is water soluble. How about TCDD? Well, you've got two oxygens here, right? But everything else is carbon-carbon bond, carbon-halogen bond, or carbon-hydrogen bond. So it's very little water-soluble. And I would say the non-polar section will take over, and this will be more likely to be non-polar. Therefore, non-water soluble. It's lipophilic. How about benzoapyrine? Well, benzopyrene or benzoapyrine, it's all carbon-carbon bond and carbon and hydrogen bond, right? So this is nonpolar. Therefore, it's lipophilic. What about aldrin? If you look at aldrin, it's all carbon-carbon bond and carbon-chlorine bond. So this is nonpolar once again, therefore it is lipophilic, right? How about acetone? Acetone is, what do you think? It's got three carbons, but at the same time it has that oxygen. Acetone has both properties. So acetone is slightly polar, so it has some ability to dissolve in water at the same time because of these carbon-carbon bonds and carbon-hydrogen bonds. It also dissolves in nonpolar solvent, so it actually has both properties. But you won't see a question like this on a quiz or a big set. Lastly, membrane transport also depends on the membrane composition and the thickness, especially if you're talking about absorption. Depending on the route of absorption, whether it's dermal, ingestion, or inhalation, the chemical is going to come across different kinds of skin composition. So the idea is that if the cells that compose the skin is really thin, it's much more likely to allow chemicals to pass through. If it's like a stratified layer, like a stratified squamous, it's typically found in your skin. Then it's much more difficult for the chemicals to pass through. It's harder because you've got multiple layers. So for sure, single layer Membrane is more likely to allow chemicals to pass through. If it's stratified or has multiple layers, then it's less likely. So the membranes like blood vessels. and body cavities tend to have simple squamous. These type of membranes are much more likely to allow chemicals to pass through because it's very thin. As opposed to stratified squamous which tends to lie in your mouth, skin, vagina. It tends to be thicker and if it's thicker and has multiple layers it tends to be much more difficult for chemicals to move across. So the membrane transport depends on the thickness and the composition of the membrane. So simple squamous epithelium tends to be the thinnest tissue of the body and they allow transport across membranes in lungs and capillaries and lines of cardiovascular systems and covers organs. If you're breathing oxygen, you want that oxygen to move through that simple squamous epithelium very, very quickly so that you can absorb that oxygen. If you want to get rid of carbon dioxide, you want it to pass through the membrane quickly. So by design, some epithelial tissues are very thin. And it's important that it is thin, which really is like a double-edged sword, right? Because it allows important molecules to pass through. through. At the same time, it can also allow toxic chemicals to also easily pass through. Here is what capillary tubes look like. Capillary tubes really, in this case, is composed of here's cell number one, here's second cell, and here's a third cell. Three cells make up a capillary tube, right? Just imagine how thin this layer is. Nutrients have to be able to move across the capillaries readily.

absorption, distribution, and elimination. Actually, one thing that's missing within these three words is what we call biotransformation. So biotransformation is another important aspect of toxicology and because it takes a little more discussion to go over biotransformation.

So topic three will be just on biotransformation. We'll start talking about the membrane transport and specifically we'll talk about the phospholipid bilayer. It is the foundational structure that makes membranes and understanding its physical characteristics of the phospholipid bilayer will help us understand how chemicals can move through the body including absorption, distribution, and elimination. Then we'll talk about some physical properties of toxicants. Specifically, we'll talk about whether a chemical is polar or nonpolar.

And then we'll talk about these three important things, absorption. We'll talk about skin absorption, or known as dermal absorption, respiratory absorption, and also GI tract absorption. And then we'll talk about distribution. And then lastly, we'll talk about the elimination of chemicals that have entered into our body.

and what are some of the pathways of illumination All right, this is a general schematic of what actually happens once a person or an organism is exposed to toxic chemicals. So this toxicological process can be broken down into three different categories here. Toxicokinetics represents how the toxic chemical actually gets to the site where it actually causes toxicity. And this is the... point where the toxic chemical meets with the target molecule and causes some kind of disturbance in that target molecule or the cell in which it resides.

This is the point where the initiation of damage actually starts. And lastly, once the target molecule has been damaged or altered, it leads to cascade of problems resulting in some kind of disease, or it could be cellular. death or it could be organ destruction or it could be eventually lead to organism responding to the damage that may lead to for example liver damage kidney damage or even cancer and this is referred to toxicodynamics so the toxicokinetics and toxicodynamics are the two big things whereas in this middle part initiation it's really important but it's that very short span of time in which the target molecule and the toxic chemical, they come together and cause the damage and initiate the process of disease outcome. So I would say this is very short in relation to toxicokinetics and toxicodynamics. There are many ways to describe the different steps in which toxicity can occur to an organism.

This is one way to describe the different steps. Here it's broken down into four steps. The first step in toxicity or development of toxicity is delivery.

That is, the chemical or toxic chemical has to get to the site where it will cause damage. Let's say the target site for chemical X or toxic chemical X is the brain, but if it never gets to the brain, then that chemical cannot do any damage. Eventually, that chemical will be eliminated without any type of disturbance to the body, right?

So if the toxic chemical is going to cause disturbance, it has to get to the target site. So step one is delivery. It's referring to the absorption and the distribution and get to the target site. In step two, now that the toxic chemical has reached the target site, they react.

Toxic chemical and the target molecule or a target atom or target cell or target organ, they react. And ultimately, it causes a disturbance to that target molecule or the atom. and etc. We use this phrase called ultimate toxicant and we're going to talk a little bit more about it.

Ultimate toxicant is the chemical that actually interacts with the target molecule because once you're have absorbed the chemical, it may go through some metabolism and it changes into a different chemical before it actually reaches the target molecule. So we use the phrase alternate toxicant to refer to the one that causes disturbance to the target molecule. And the step three in the process is cellular dysfunction and resultant toxicity.

It leads to some kind of damage, right? And it could be damage to a molecule. and which can lead to damage to atoms and group of atoms are damaged can lead to dysfunction in the organ and if organ failure occurs then obviously it leads to disease in the living organism.

So step three is this cellular dysfunction and result in toxicity. Whatever the damage that was caused your body is going to try to fix it and if it's fixed completely or your body has adapted to that toxic chemical, then you're good to go, right? You're fine. However, the fact that the toxicity has occurred usually means that there was inappropriate repair and inappropriate adaptation to the toxic chemical, hence disease has occurred.

Let me provide you with an example of toxicants and target molecule. You've probably heard of tetrahydrotoxin if you've taken 415 already. And even in the first lecture, I may have referred to tetrahydrotoxin. tetrahydrotoxin. Tetrahydrotoxin is a nerve agent, that is, it actually damages the nerve cells.

And tetrahydrotoxins are found in certain type of reptiles, certain type of fish. And tetrahydrotoxin is well known for being present in puffer fish. So who eats puffer fish? Well, it is a very expensive delicacy, especially in Japan, as they eat the sashimi of puffer fish. Well, tetralotoxin resides in the organs of puffer fish.

So the chef has to be well trained to make sure that tetralotoxin does not contaminate. the food that people will be eating. However, every single year, number of people die in Japan because of tetrahydrotoxin poisoning.

So the toxicant that we're talking about is tetrahydrotoxin. And what is a target molecule? Well, the target molecule, as I mentioned, is the nervous system. Of course, more specifically, it's a nerve cell.

And if you want to get into even more specific than that. tetraodotoxin targets voltage-gated sodium channels. So inside a nerve cell, there's a way in which signals are transmitted across the cell.

And this happens because of what we call voltage-gated sodium channels. If this gets disrupted, then information stops flowing. So here's your brain or your muscles.

right there has to be this constant movement of information between the two when what tetrahydrotoxin does it breaks that connection particularly the tetrahydrotoxin impacts involuntary muscles like diaphragm. If your diaphragm does not contract, then you cannot breathe. Although it causes damage to the nervous system, it's the breakdown of the nervous system that prevents diaphragm muscle from working and you suffocate to death, basically.

So what is the target molecule? Target molecule, you can say it is a nervous system or the nerve cell. And another example of toxicant in a target molecule is melamine.

Melamine is a chemical that's used to make certain type of plastics and if you are into cooking you probably have seen plates or cookware. that's made of melamine. It's very sturdy type of plastic. In China, people who are, I would say, just very, very bad, they ended up adding melamine to formula milk to deceptively boost the protein content. And how does that work?

Well, melamine has a lot of nitrogen, as I mentioned. And that deceives the tests and makes it the tests show that the milk has high levels of protein, when in fact it's the melamine. Now, when infants drink this contaminated formula milk, what ends up happening is that inside the kidney, melamine starts to form crystals.

And they form into these tiny melamine stones where it causes kidney damage. And as a result, children can easily die or have... other kinds of kidney problem issues.

You can almost think of it as, you know, tiny plastics, a melanin is formed inside the kidney, right? So what is the toxicant? Toxicant is a melanin, right? Well, it's not a toxicant if it cannot get to the target molecule, right? never gets to the kidney and it gets eliminated, then it's not really toxic.

The reason why melamine is toxic is because it gets to kidneys. Well, the kidneys is the target site in this case. particularly target molecule, but it's a target organ. Usually I have a lot of YouTube videos that's related to the topic that we're discussing.

And since this is a pre-recorded lecture, I strongly encourage you to watch these videos. Some are fun, some are interesting, right? But all of them are very informative.

So what are some of the factors that affect toxicity? And there are many different factors. And as we go through some of the lists...

you realize that it doesn't take a rocket scientist to realize how whose factors affect the toxicity, right? So what are some of the whose factors that affect the toxicity of the chemical? Well, it's the size of a person.

If you compare a football player who's 300 pounds as opposed to a very petite woman who's 100 pounds, there's a lot greater blood volume in the football player. Therefore, he might be able to tolerate more of the toxic chemical as compared to petite women. Size is important. Age is also important because older the person, your bodily organs don't function as well, especially organs like the liver or the kidneys. Sex is also important because depending on whether you're male or female, your body has different kinds of hormones and the different levels of hormones.

and that may impact the toxicity. And if you're talking about animals, right, different species, or if you're talking about microorganisms, different strains of microorganism is going to impact the toxicity. Perhaps even changes in the internal environment, like your gut, right, your gut flora, that may have some impact.

Or if you are some habitual drug user, or someone who has to take... medication for long periods of time, that may also impact the toxicity. But today we're going to focus more on the toxic chemical itself, right?

The factors that relate to the toxic chemical. The root and the rate of administration obviously is going to be important. And think about how we actually absorb toxic chemicals. What are the different routes? So the main ones are the dermal exposure, right?

You have inhalation by breathing and also ingestion when you eat something or drink. something. And there could be some kind of drug-drug interactions. And later we'll talk about how grapefruits actually interact with many kinds of pharmaceutical drugs. And if your body builds tolerance to certain type of chemicals.

So I think I've shown you this slide before. Toxical kinetics is what the body does to a toxin. This is just a simple way to describe what toxic kinetics is. To define toxic kinetics in more academic terms, it is the rate in which the toxic chemical moves about inside the body.

And this is related to absorption, distribution. Later, we'll talk about storage as well and elimination, as well as biotransfer, which is topic three, as I mentioned. And toxicodynamics, in simple terms, is what the toxin does to the body. Toxicokinetics is about the rate of distribution and absorption and elimination. But toxicodynamics is what actually the toxin does to the body.

Does it damage molecules? Does it damage or disrupt some physiological process? Does it damage tissues?

Or does it lead to some functional damage like physical and behavioral? These are the disease outcomes, right? So when we're talking about toxicodynamics, talking about toxicodynamics, we're talking about disease outcomes. Toxical kinetics is a quantitation the time course of toxicants in the body.

It's the rate of toxic chemicals moving about. It's a reflection of how the body handles the toxicants. The end result of these toxicokinetics process is what we call biological effective dose of the toxicant. We also refer to it as BED. And BED is the amount of substance required to reach target cells or organs and to produce an expected effect.

So the endpoint of toxicokinetics, because if a toxic chemical does cause toxicity, at the end of toxicokinetics, it's how fast and how much of the toxic chemical. gets to the target site, whether it's a cell, molecule, or organ. So BED refers to the amount of substance that's required to reach that target site and to cause the problem.

absorption is referred to as systematic toxicity in contrast with local toxicity. Systematic toxicity means that basically the chemical itself has distributed throughout the body and can cause multiple toxicities whereas local toxicity is once the toxic chemical has been absorbed it only causes problem around the site of absorption. Chemicals enter the bloodstream after they are absorbed, right?

That's the first step. And it could be from ingestion, inhalation, or from thermal exposure. And once the chemical is in the bloodstream, it can be dis- distributed through the body.

Once the chemical is distributed throughout the body, at some point, it can't stay inside the body forever. Eventually, it will be eliminated or broken down, in other words, metabolized. And for this course, we will use the word biotransformation.

And these chemicals or their metabolites, because they have been biotransformed, are then either stored or eliminated. It's very less likely for your body to store a lot of things. You know, you've got a limitation in your physical size. So your body rather wants to eliminate things.

But sometimes your body can store toxic chemicals in places like the bones or the adipose tissue. Here's an interesting video that shows how hair can be tested for mercury poisoning. And in order for mercury chemical to get into the hair follicles and the hair itself, it needs to be absorbed through some exposure route. then it gets distributed throughout the body and then it gets eliminated through hair follicles right so it has gone through the exposure the absorption distribution and also eventually the In order for us to understand the movement of chemicals inside the body, we have to have some specific knowledge about the makeup of cellular structures, specifically the membranes of cells.

Ultimately, these chemicals will need to move through these membranes if it wants to go anywhere. The foundational structure that makeup... membrane, different kinds of membranes in cells is what we call phospholipid bilayer.

If you see this picture of a cell, you can see chemical cannot cause damage to cell unless it's able to pass through the cellular membrane. Well, what if and what if the target site for this chemical is mitochondria? Well, not only does it need to get inside the cell, it needs to get in to the cell.

the mitochondria organelle, right? It's going to have to pass another membrane. If you're talking about a carcinogen that will directly interact with the DNA to cause DNA mutation, well, that chemical first needs to enter into the cell and then it needs to get into the nucleus, right?

And where the DNA is. So the movement of these chemicals really depends on how light. likely these chemicals can pass through cellular membranes. So here's what cell membranes look like.

But really the foundational structure for the cell membranes are these phospholipids. Each one of these is a phospholipid. But phospholipids usually don't exist as one layer. They tend to exist as two layers.

That's why we call it phospholipid bilayer. And I'll talk a little bit more about its... particular chemical physical structure that make them into two different layers.

Fossil lipids are made up of two distinct components. We call this the polar head, that's the circle part. And we call the bottom the nonpolar tails. The polar head is composed of a phosphate group.

And of course, it's got other things. But the important thing is that they are charged. are charged, water likes to surround the things that are charged.

Whereas non-polar tails are mostly composed of carbon and hydrogen and carbon and carbon bonding. Carbon and hydrogen and carbon and carbon bonding. Water does not like that. It's like oil. If you were to dump many fossil lipids in a bucket of water, what ends up happening is that it will either form into a spherical shape.

or it will form into these phospholipid bilayer. Why? Because the tail hates water, so they want to stick together.

Whereas in the head part of the phospholipid loves water. So water surrounds all of these guys, but it hates water. So the tails want to stick together.

So micelles can be formed in this way. Right and once again the idea is that what you're doing is that the tails have very little contact with water because they don't like each other. Here's a very corny video but it really does explain a little bit.

phospholipids. It's a rap that's made by some teacher about phospholipids. It's kind of funny, so I recommend you watching it. So the question is why doesn't oil and water mix?

And that's because oil is mostly made up of this nonpolar tails, right? It's mostly these carbon-carbon-carbon hydrogen bond. Well, whereas in water is polar.

It has a partial negative charge and because it has partial negative charge on one side, it has partial positive charge on the other so they like to kind of stick together almost like a magnet. Water And these carbon tails, they hate each other. They don't like it.

They don't want to mix. So oil wants to stay away from water as much as possible. Just looking at the vinegar and olive oil makes me very, very hungry.

Balsamic vinegar here is mostly water. Here's olive oil. And they don't like to mix. They want to minimize the interaction as much as possible. As you can see anything that's oily does not want to mix with water.

So here's what olive oil pretty much looks like. It's mostly carbon-carbon bond and carbon-hydrogen bond right. There's potentially could be little interaction with water here because the oxygen, but compared to the size of the tail, it's very little. Whereas the water is a very simple molecule that has partial negative charge on top and partial positive charge in the bottom. But what's interesting about phospholipids is that phospholipids contain both hydrophobic, which means that it hates water, And hydrophilic ends, loves water.

And detergents are actually made similar to phospholipids. It has both the part where it hates water and part that loves water. And that helps break apart any stains. oily stains.

I know that the picture of this molecule is not the sharpest, but you can still see, right? O represents oxygen, right? This is oxygen. H represents hydrogen, and P stands for for phosphorus and of course although it's not written here every single corner right represents carbon so there's many carbons carbon carbon carbon carbon etc single line means it's a single bond if it's two it's a double bond Although you don't actually see the hydrogens attached to these carbons and usually they're kind of left out because it just makes Like your structure is much more complicated than it should be. So these kinks represent carbon, but they also have hydrogen attached to them as well.

And this side is the polar head, and this is the nonpolar. Okay, so now let's talk about how chemicals can move across a phospholipid bilayer membrane. Now it really depends on the type of chemical that you're talking about.

So just now we separated chemicals according to its physical property hydrophilic versus hydrophobic so let's say that you are exposed to a chemical and this chemical is hydrophilic meaning that it likes water this side is extracellular it's outside here's inside the cell So if this chemical wants to be absorbed or wants to be distributed, it needs to move across this phospholipid bilayer into the cell. One thing that you have to keep in mind is that this phospholipid bilayer or the cell Let's say the cell looks like this right here. Here's a cell and here's a nucleus, mitochondria, etc. Whether it's inside the cell or outside the cell, this is all in water. the matrix in which the cell inside or outside is in water.

But what distinguishes between outside the cell and inside the cell is this phospholipid bilayer. So let's imagine that you were exposed to a hydrophilic chemical. Hydrophilic meaning that it likes water. And because there is water all around, it's not going to be able to absorb water.

this chemical let's say it's chemical x it's just going to be around outside it's happy where it is right it has no real desire to move across why should it go inside itself there's no real force to do that So when you are exposed to hydrophilic chemicals, it tends to kind of float around. and there isn't enough force for it to move across. Yes, there is some passive diffusion, meaning that outside there are lots of chemicals, right, and inside there's no X. So there's some innate, almost like gravity, that wants these chemical X to move across, okay? And that's one of the important forces.

Really for this hydrophilic chemical to get inside the cell it has to pass through this region and this region is hydrophobic. There is no water in there and chemical X does not want to linger between these two phospholipids. Hence it's very unlikely for hydrophilic chemicals to move across.

even though there's more outside than inside. Nevertheless if the hydrophilic chemical is really small and there is a lot of them outside some of them will quickly move across and this can happen. This is what we call passive diffusion.

But if you're talking about bulky very hydrophilic chemical or molecule it's unlikely to pass through. On the other hand, if the chemical that you're interested in studying or the chemical that you're exposed to is hydrophobic, that it hates water, right? Remember, cells are surrounded or in water, right?

All of this is water. This is water. So as soon as hydrophobic molecule enters into its environment, oh, it hates it. It hates to be here. So what is it going to do?

It's going to find a way to get into this nonpolar tail section of the phospholipid bilayer. So it's already halfway there, right? So it resides here, but you can't...

reside there forever. Maybe there are more guys that are trying to enter and it's pushing them to go out. and they'll then look for other places where they can attach itself that's not so water soluble. And it could be certain type of proteins or molecules or other organelles. So if you're talking about a chemical that's hydrophobic, it's much, much easier for them to pass through the phospholipid bilayer because of the fact that it likes to interact with the middle part of the phospholipid.

but by layer. Like I said, it has to be in water. So whether you're in the outside of the cell or inside a cell, it really doesn't matter for them because it's all water, right?

The point is that they'll enter into this middle layer and eventually it's going to be kicked out. If it gets kicked out towards where it came from, then nothing has happened. But if it gets kicked down to the other side, so the assumption is that let's say you've took some kind of medication, it's... mostly hydrophobic.

Well, then you are going to get a lot of these guys in here and there's going to be a traffic. There's so much of these guys eventually that will be kicked out. Okay.

I hope that makes sense. So here's food for thought. And this is the reason why, you know, you can't dip your hands in sugar water and expect to absorb sugar through your skin. Why?

Because sugar is water soluble. Sugar dissolves in water. Once you put sugar in there it completely goes away unless it's saturated obviously even if i want to put my hand in here i'm not going to be able to absorb that sugar because sugar itself is hydrophilic it has very difficult time passing through the membranes that makes up the cellular structure of my skin so it's unlike for humans to be able to absorb hydrophilic chemicals thermally.

However, if you're talking about something that's very hydrophobic, then you can actually absorb these chemicals through your skin because hydrophobic chemicals are much more likely to pass through the phospholipid bilayer. Now let's try to put this together. At the point where you are exposed, let's say it's either dermal or ingestion. In order to get to the target site, you have to kind of see that there are many, many membranes that the chemical has to pass through before it reaches the target site. So how many layers, how many phospholipid bilayers do these xenobiotics need to pass through in order to reach?

For example, the nerve cell, if that's the target molecule. Well, let's think about it. Let's say you are absorbing this through your skin.

From outside of your body, it's going to have to pass through one phospholipid bilayer. Then you will get into the cell, the skin cell, let's say. And let's just say that skin has only one layer of cell.

We're talking about dead skin, so that it's just going to go through, needs to go through once. And then it needs to pass through the capillary because it wants to get into the systematic blood. So you will need to go through the capillary phospholipid bilayer to get into the blood vessel.

Well, then inside the blood vessel, it gets distributed. Well, if it wants to get to the target site, it's going to have to get out of the capillary. And now you are in the interstitial fluid, which is a fluid between spaces in tissue cells. In order to get into the target cell, then you're going to have to move through another phospholipid bilayer.

And now you're inside the cell. Now, let's say if you're talking about DNA of the brain, well, you're going to have to pass through another organelle phospholipid bilayer until you actually reach the target molecule, target cell. So at minimum, you're going to have to pass through one, two, three, four, five different phospholipids by there. It's going to be a lot more than this, but you get the idea.

The point is that in order for the toxic chemicals to get to the target site, there's no easy pathway. And the type of chemical it is, whether it's hydrophobic and hydrophilic, is going to have huge influence whether it will ever reach that target site. Now I already mentioned that chemicals can pass through the phospholipid bilayer, but there are some conditions that these chemicals have to meet. And I didn't say that If the chemical that wants to be absorbed or distributed is hydrophobic, it's more likely to pass through the phospholipid bilayer.

So let's talk about these factors. Number one. It's the charge of the chemical. If a chemical or molecule has a charge, it's probably not going to move across the phospholipid bilayer because charge means it's very water-soluble. It's going to be surrounded.

by water molecules. Number two, it depends on the molecular size. If the molecule is really large, chances are large molecules will have both hydrophilic and hydrophobic sides, and it's going to have difficult time passing through the phospholipid bilayer.

However, if you're talking about a very small molecule like oxygen gas or even carbon dioxide, especially if they're really small, even if it's hydrophobic, phyllic, it can still pass through the phospholipid bilayer. And I did mention number three, it's the lipid solubility. Lipid soluble or hydrophobic, really the same thing. are more likely to pass through the phospholipid bilayer. Although number four is not related to the chemical properties of the chemical, the membrane composition and the thickness of the membrane, for example different types of skin, will have impact on the ability for chemicals to move across the phospholipid bilayer.

So let's go through these. First one is that membrane transport depends on charged state of the chemical. Chemicals that are positively or negatively charged means that they can't move across. the phospholipid bilayer. So sodium ion, potassium ion, calcium ion, magnesium ion, etc.

They all have a charge. So if you think about sodium plus, what in fact happens is that this is surrounded by water. If you want to be a little more specific, the oxygen end is going to be towards the sodium ion because this has partial negative charge and sodium plus has positive charge.

The sodium ion that's surrounded by water is less likely to merge with the hydrophobic tail side of the phospholipid bilayer. It's very unlikely for charged atoms or molecules to pass through the phospholipid bilayer. So same thing with anything that has negatively charged.

Although we won't really go into the details of charge due to acids and base, remember when the pH of the environment changes, these acids could lose hydronium ion H+, and that would change the charge. And you've probably heard about conjugate acids and conjugate bases. So depending on the pH, a chemical can become positively charged, neutral, or negatively charged. So here's a periodic table of the elements. I know some of you, it's been a long time you've looked at a periodic table.

These are all metals right here. And what ends up happening, especially in these two groups, If you can dissolve them in water, once they're in water, they will become ionized. So lithium becomes lithium plus calcium, for example.

You can lose two electrons and it becomes calcium too. plus and they become ions. Same thing on this side.

These non-metal ions can gain electrons. So fluorine can gain one electron and becomes fluoride and becomes charged. Right so anything that is charged it's not going to be able to move across the phospholipid bilayer. Second the membrane transport depends on the size of the chemical. For non-charged small molecules they will usually pass through the membrane quite freely, quite easily.

Remember if it's not charged, although it may be somewhat polar, that it may dissolve in water, but because they're so small that it can actually move through that hydrophobic section of the phospholipid bilayer relatively quickly. So things that are non-charged but small molecules are able to pass through the phospholipid membrane. quite freely.

Third, membrane transport depends on polarity, meaning The movement of these molecules depends on how polar these molecules are, how many polar atoms there are, right? If it's more likely to dissolve in water, then it's less likely to move across the phospholipid bilayer. Most polar molecules diffuse into cells very slowly or not at all.

So any large polar molecules that dissolve in water, for example, sugar is an example. It is not charged. Sugar is not charged.

But it has all of these oxygen in which it forms a hydrogen bond with water and it dissolves very easily in water. So polar molecules that tends to dissolve in water is unlikely to move across the phospholipid bilayer unless they're really, really small. Even if there are hydrophiles.

non-polar molecules diffuse rapidly across plasma membranes. If it's like for example ethane, right? Well ethane has two carbons and has six hydrogens. Well this is non-polar and because it's non-polar it will interact with the hydrophobic side of the phospholipid bilayer, hence it's much more likely to move across the the memory. So how do we know whether a molecule is polar or not?

Now I'm going to try to teach you this in simplest terms. This is not like a magic bullet in understanding polarity of molecules, but you can use what I'm about to teach you right now and gauge whether a molecule is most likely polar or most likely non-polar. Okay and the way you're going to do this is by looking at certain atoms and these are atoms. that tends to be polar or give polarity to molecules.

So these are nitrogen, oxygen, phosphorus, sulfur, and of course there are other kinds. And also if there are metals in the molecule. Now here's an example of water molecule.

This is water molecule right here. And the reason why water has polarity is because oxygen likes to pull these electrons from hydrogen and try to keep those electrons around itself. And it also has these two additional lone pairs of electrons. So usually an oxygen is happy or neutral if it has six valence electrons or outer shell electrons around it. Now when it's chemically bound to two hydrogens, it seems as if there are a total of eight electrons around it.

That is what gives this partial negative charge. Now for hydrogens, it seems as if the hydrogen atom has lost its electron. Now remember, hydrogen has one proton, and it has one electron. Right?

And that makes it neutral. But now what has happened is that hydrogen sort of lost its electrons because Oxygen has higher electron negativity. It pulls those electrons toward itself.

And hydrogen is almost left without an electron. And that's what gives that partial positive charge. Now, so on the oxygen side, it has a partial negative charge.

On the hydrogen side, it has a partial positive charge. And this is what gives polarity like a magnet, right? Magnet that has north on one side and south on the other.

So if your molecule has oxygen, nitrogen, and phosphorus, or sulfur, or even metal atoms, it tends to create this sort of a separation of charge, separation of positive and negative charge. And that's what gives polarity. Here's another example.

This is ammonia, right? Nitrogen that has three hydrogens attached to it. Once again, nitrogen has higher electronegativity. So it pulls those electrons.

towards itself. So the hydrogen feels like it's lost its electrons, tends to have this partial positive charge and because nitrogen has itself gathered, try to pull these electrons towards itself, now it feels like it has more electrons and that gives partial negative charge. Same thing, right?

On the nitrogen side it's partial negative, on hydrogen side it's partial positive, creating this polarity. So whether it's nitrogen, oxygen, phosphorus and sulfur, they tend to do this. So one way to look at.

Whether a molecule is polar or not is to see whether how many or what percentage, I don't know, there's no, like I said, magic bullet for this. If there are lots of oxygens and nitrogens and sulfur and phosphorus, it tends to be more polar. and water soluble.

On the other hand, there are atoms that tends to create no polarity. We call these nonpolar atoms. At least this is the way I describe it.

If there are many carbons, and you have many carbon-carbon bonds, and also if you have many carbon and hydrogen bonds, or carbon and halogen bonds. An example of carbon and halogen bond will be carbon and fluorine, carbon and bromine, or carbon and chlorine. These tend to be nonpolar. There is really no separation of positive and negative charges in these bonds.

So here is an example of benzene. Benzene is all carbon-carbon, carbon-carbon, and carbon-hydrogen. There's something called resonance structure. We sometimes put... These ring structures as a circle because the double bonds, they tend to move around, they alternate.

Anyways, this would be a nonpolar molecule. Same thing with the butane. Butane, remember, each corner represents carbon.

And this is just hydrogen, right? And all it really has are these carbon-carbon bonds and carbon-hydrogen bonds. And this is nonpolar. and you don't see any oxygen, nitrogen, phosphorus, or sulfur.

So things that are polar or charged, water surrounds it. If water surrounds it, it means that it likes water. It's hydrophilic.

So when we say either an ion or an atom, or a molecule is water soluble, it means that water can surround it. How can water surround a molecule? And that's because the molecule itself has some separation of charge.

Remember, water has this partial negative charge. Partial positive charge, almost like a magnet. You know, if the ion in this case, this is chloride ion, it has a negative charge.

It's that hydrogen side that has positive or partial positive charge will be attracted. And it can surround that chloride. Once the chloride is surrounded by water molecules, it's been solubilized by water. Opposite happens with sodium ion.

Sodium ion has a positive charge and oxygen side has a partial. negative charge and water surrounds that sodium ion now sodium ion is water soluble so on the other hand if water cannot surround it then it's not water soluble it's really non-polar molecule so this is a chemical structure of a soap molecule interesting about some molecule is like the phospholipid. That is, it's got two sides.

It's got one side that's charged. So water will surround this side. However, water does not like the tail.

Water does not like the tail. Water will not be near the tail. So this side is nonpolar.

This side is polar. And the way the detergents work is that detergents have one side that's water soluble and the other side that's not water soluble. If you think about oil stain in your clothes, the soap molecule...

the tail side because it doesn't not want to interact with water it rather wants to stick around the stain the oil stain so the tail sticks to them eventually it forms what we call my cell and Because the head side is polar, it can actually lift that dirt out. And that's how detergents actually work in cleaning stains, especially if it's oily stain or dirt. So what do you think?

Lipophilic, which means it's non-polar. or hydrophilic, which means that the chemical is either polar or is charged. Chromium 6, this is charged.

Well, if it's charged, it's water soluble. What about formic acid? Yes, there is carbon and hydrogen bond, but you've got these two oxygens. This oxygen, water will surround the oxygen.

And all in all, this is water soluble. How about TCDD? Well, you've got two oxygens here, right?

But everything else is carbon-carbon bond, carbon-halogen bond, or carbon-hydrogen bond. So it's very little water-soluble. And I would say the non-polar section will take over, and this will be more likely to be non-polar. Therefore, non-water soluble. It's lipophilic.

How about benzoapyrine? Well, benzopyrene or benzoapyrine, it's all carbon-carbon bond and carbon and hydrogen bond, right? So this is nonpolar. Therefore, it's lipophilic. What about aldrin?

If you look at aldrin, it's all carbon-carbon bond and carbon-chlorine bond. So this is nonpolar once again, therefore it is lipophilic, right? How about acetone? Acetone is, what do you think? It's got three carbons, but at the same time it has that oxygen.

Acetone has both properties. So acetone is slightly polar, so it has some ability to dissolve in water at the same time because of these carbon-carbon bonds and carbon-hydrogen bonds. It also dissolves in nonpolar solvent, so it actually has both properties.

But you won't see a question like this on a quiz or a big set. Lastly, membrane transport also depends on the membrane composition and the thickness, especially if you're talking about absorption. Depending on the route of absorption, whether it's dermal, ingestion, or inhalation, the chemical is going to come across different kinds of skin composition. So the idea is that if the cells that compose the skin is really thin, it's much more likely to allow chemicals to pass through. If it's like a stratified layer, like a stratified squamous, it's typically found in your skin.

Then it's much more difficult for the chemicals to pass through. It's harder because you've got multiple layers. So for sure, single layer Membrane is more likely to allow chemicals to pass through. If it's stratified or has multiple layers, then it's less likely. So the membranes like blood vessels.

and body cavities tend to have simple squamous. These type of membranes are much more likely to allow chemicals to pass through because it's very thin. As opposed to stratified squamous which tends to lie in your mouth, skin, vagina.

It tends to be thicker and if it's thicker and has multiple layers it tends to be much more difficult for chemicals to move across. So the membrane transport depends on the thickness and the composition of the membrane. So simple squamous epithelium tends to be the thinnest tissue of the body and they allow transport across membranes in lungs and capillaries and lines of cardiovascular systems and covers organs.

If you're breathing oxygen, you want that oxygen to move through that simple squamous epithelium very, very quickly so that you can absorb that oxygen. If you want to get rid of carbon dioxide, you want it to pass through the membrane quickly. So by design, some epithelial tissues are very thin.

And it's important that it is thin, which really is like a double-edged sword, right? Because it allows important molecules to pass through. through. At the same time, it can also allow toxic chemicals to also easily pass through.

Here is what capillary tubes look like. Capillary tubes really, in this case, is composed of here's cell number one, here's second cell, and here's a third cell. Three cells make up a capillary tube, right? Just imagine how thin this layer is.

Nutrients have to be able to move across the capillaries readily.

Transcript for:Key Concepts in Environmental Toxicology

Transcript for:
Key Concepts in Environmental Toxicology