**Q. Another one I should know the answer to…the 1,2,4 in 1,2,4-Trimethylbenzene should tell me where the methyl radicals [groups] are located on the benzene ring. What does the o in o-Xylene mean and how is it different from p and m?
A. These refer to the relative position of the substituents. Ortho is abrivated "o," meta by "m," and para by "p."

**Q. What is the difference between body burden and dose?
A. Dose is what you take in, body burden is what is in the body at some later time. In that sense, the chemical in your GI tract is not part of the body burden until or unless it is absorbed.

**Q. I am having a little trouble understanding the tox tudor concepts. It seems to me that if you take the dose(mg)/plasma conc(mg/l) to get the volume distribution, then how do you multiply that by the plasma conc(mg/l) and get the "body burdern."
A. Yes, if you know Vd and blood concentraion you can solve for the body burden directly.

**Q. Can you take a second stab at defining/explaining VD? "The total volume of body fluids in which a toxicant is distributed is known as the apparent volume of distribution (VD )." To me this implies that if I increase the "pool" the number goes up so if interstitial and plasma are an option and yet …"If a toxicant is distributed only in the plasma fluid, a high VD results; however, if a toxicant is distributed in all sites (blood plasma, interstitial and intracellular fluids) there is greater dilution and a lower VD will result." The definition of dose over plasma concentration to me seems garbled as well since plasma concentration is like an effective dose per "weight". I don't know I think I am coming at this all wrong somehow.

A. First of all, Tox Tudor has that backwards. Here it is correctly: "If a toxicant is distributed only in the plasma fluid, a low VD results; however, if a toxicant is distributed in all sites (blood plasma, interstitial and intracellular fluids) there is greater dilution and a higher VD will result." What follows is an alternative explanation:. The paragraph starts off with the words, "a one compartment model." There are two ways we could have a one compartment model, either the only compartment into which the xenobiotic is distributed is the blood (of which I can't think of an example), or the xenobiotic distributes very quickly through the entire body, methanol would be a good example. A one-compartment model treats the body like a CSTR, continuously stirred tank reactor, and you assume the concentration in the tank is the same as the exit concentration. OK. Suppose you have a concrete tank with an unknown volume of water in it. If you had a mixable chemical, like a dye, you could throw it in the tank, measure your output concentration, and quickly determine the volume of water in the tank. You could say the Vd would be the volume of water in the tank. What would happen if the tank had sludge on the bottom that was not stirred, but absorbed some of the chemical? If you did not know about the sludge, but you would know the amount of chemical you threw into the tank and the concentration that came out. You would calculate that the tank had a much greater volume then the water in it, but you would still call that the Vd. Once you knew the Vd, you could easily relate concentration leaving in the effluent to amount of chemical that you throw in, that is the virtue of Vd. Of course your sludge in the tank can become saturated, but then so can some of the things in the body that are sequestering or binding the chemical.

** Q. "chemical i.p." what does i.p. stand for?
A. "inter peritoneal," a needle given in the gut. An i.p. injection gets to the liver quite quickly.

**Q. I have gathered quite a bit of information already about 1,4-Dioxane and Acetaldehyde. I found out that in 1992 there were only 3 producers of dioxane (Ferro Chemical, Dow Chemical, and Stephan Co.), and 2 producers of acetaldehyde (Kodak Eastman and Hoechst Celanese). There are quite a number of animal studies that have been performed for these chemicals. I would think that the studies would be expensive with the planning process, lab time, assessment…..where does the money come from to do all these studies? There was a study for dioxane in 1976 where the researchers exposed 12 volunteers to a concentration of dioxane in air…does this type of testing still occur on humans? It seems a bit surprising, especially with documented deaths from the same year.
A. Manufactuers of commercial products, Procter and Gamble or General Foods, will commission toxicity testing before they put out a new product, in fact early in the development process. It's part of their R&D costs. Chemical manufactures are reluctant to do this. For one thing, they have been making the stuff for years, if something was bad, they'd be aware (right?). Also, some make hundreds of chemicals, and there are many intermediate chemicals in their plants. It would be daunting to test them all. So their toxicology departments tend to "put out fires." That is, respond and test only when there is a problem with a chemical (and the toxicology department gets some budget to test it).

We'll do some more ethics later. There are certainly some substances for which there is ample proof that below a certain level they don't harm otherwise healthy people. If the compound is also not known to be carcinogenic, then it would not be unethical to test with it. Keep in mind they are never testing to get people sick, they are testing details about metabolism and biochemistry, and these are done at levels far below what might make the sick. Also, the subjects are usually the researchers themselves. "dioxane" is not "dioxin."

**Q. Does the UAF library offer any type of search form for various local newspapers (to address previous releases in other communities)?
A. You should find those through EBSCO search.

** Q. Is one single exposure limit (ACGIH, NIOSH, OSHA) considered more relevant than another when addresssing impacts on a community, or should the lowest threshold value (highest safety factor) be utilized?
A. None of them. They are all related to workplace exposures, based on healthy adult workers exposed 40 hours per week for 35 years. By the "community" you mean the general population, which includes very young, very old, very sick and exposure of some of them 24/7 for a lifetime. Different values are needed for such "environmental exposures."

*Q. Decabromodiphenyl oxide is used as a flame retardant in plastics. The main toxicological pathway is through inhalation and ingestion. Vague references are made to possible liver and kidney effects due to chronic exposure. There is little reference to possible hazards of the substance under extreme heat. All that is indicated in the MSDS is "UNDER FIRE CONDITIONS, TOXIC AND IRRITATING FUMES MAY BE EMITTED". Is there any reference to specifications that flame retardants have to meet with respects to toxic vapor emissions per m³? Or are there LD50 studies that are done with the vapors of heated chemicals involved in flame retardation?
A. Most chemicals released during a fire are burned, so you would need to do whatever toxicology you did with the product. Here is a chemical that does not burn, but is vaporized during a fire, so if you were concerned, you would somehow have to vaporize the material in order to test it. "Irritation" is tough to test in animal models. Irritation in humans is highly dependent on their attitude and other psychological factors.

*Q. In the Enzyme Kinetics section of the module, there is a situation where the Vmax is indicated as 500. The Km for the same example is equal to 100. If Km =Vmax/2, then the Km should be 250. Are there times when the Km would be less than Vmax/2? If there is competitive inhibition in a reaction, Vmax decreases and cannot return to the unaltered state. [It can after the inhibitor is removed] If there is non-competitive inhibition, the Vmax decreases but with the addition of more substrate, the inhibition is thus accounted for. Is there ever a reason for the Km of a reaction to change or decrease assuming the environment (i.e. pH, or buffer systems) remains constant?
A. Yes, a non-competitive inhibitor can increase the Km. That is, shift the curve to the right, so that more substrate would be needed to reach Vmax.

*Q. How is hexachlorobenzene chemically different from other current fungicides or pesticides? Or stated differently: How can the two chemicals give the same result in the agriculture world but not in the human health world?
A. Probably the chief difference is legal. Today pesticides that are "persistent" in the environment cannot be licensed. Hexachlorobenzene has been outlawed for a long time as a pesticide. Most biological breakdown involves oxidation. Chlorine is a oxidizing agent, so highly chlorinated compounds are essentially already oxidized.

*Q. What is chemically happening to the receptors when someone becomes "addicted" to caffeine?
A. Caffeine blocks phosphodiesterase, leaving more cAMP inside the cell. The body strives for homeostasis, so you would suspect it would respond to chronic high doses of caffeine by producing more phosphodiesterase. That is exactly what happens in addiction to many chemicals. Drug withdrawal occurs when you cut off the caffeine and an the high levels of phosphodiesterase remain, making your bod unresponsive to signals that set off production of cAMP, i.e., switch on cellular function.

* Q. considering binding heavy metals to enzymes. these heavy metals dont stay forever in the the organism. how does the process of unbinding and "withdrawal" or release look like? i know, milk helps to get rid of heavy metals, and milk with iodine or alcohol- form radioactive materials
A. For the most part, metals are hydrophilic compounds, often ionized. In general, hydrophilic compounds are absorbed from the GI tract by active transport only if they are nutrients that the body needs. For iron and calcium for example, only small amounts are absorbed. Sodium and Potassium, on the other hand, are almost 100% absorbed. For heavy metals to be absorbed, the body's active transport processes must somehow mistake them for a nutrient, and that is how lead and some others are absorbed. It's also how they are sometimes incorporated "by mistake" into tissues such as bone. Once there, however, there is equilibrium partitioning, and in time, when they are no longer being absorbed, the equilibrium shifts and they leave the tissues and are excreted via the urine. (It's a different problem if they enter via the lungs, we'll talk about that in a few weeks.) I don't think that the calcium in milk will help "unbind" the metals that are in the body, but a surplus of calcium would cut down the absorption of new heavy metals. Iodine is a slightly different situation that I'm not studied up on, but I don't see how alcohol could help.

* Q. Can a substance that triggers a negative "allergic"-type of reaction be considered toxic? If so, in determining threshold limits, would the worst-case scenario (eg highly allergic individual) be set forth or would the demographic/mean value be more applicaple?
A. If it's a common reaction, then that is what is used in the standard. For example only 5 or 10% of the population are sensitive to isocyanates or silica, but these sensitive individuals are used to set the standard. If it were a truly rare allergy, one in a million, it would not be considered. If it was somewhere in-between, and it were known, there is often a special warning, but the standard is set based on the "normal" reaction.

*Q. Now for my "homework" question, it relates to my project but is rather dumb -- still I am asking to try to save my sanity. I have a friend who "reminds" me that I am poisoning myself every time I microwave food in Tupperware or plastic. In reading about styrene for some reason I remembered this and thought it might be styrene release that she was concerned about. I did some searching and of course found nothing. Have you ever heard this? I know I have heard it elsewhere (didn't give it much credence obviously). If you have heard it -- is styrene the chemical of concern?
A. Styrene monomer is toxic and a lot is known about its toxicity. It is a liquid with a moderate vapor pressure. Your question would be, how much monomer is released when I microwave the polymer. My guess is very little; otherwise you would not have your Tupperware very long.

Q. Under environmental conditions, vanadium may exist in oxidation states +3, +4, and +5. V3+ and V4+ act as cations, but V5+, the most common form in the aquatic environment, reacts both as a cation and anionically as an analogue of phosphate. How does V5+ react "anionically as an analogue of phosphate"?
A. I don't know. But P can also have the +5 oxidation state, can't it? My old chem book shows +5 as a common oxidation state for both P and V.

Q. Then something I should have asked in module 1:
If I want to relate the toxicity of Vanadium to say dimethylmercury, and I find that DMM's LC50 is ten times lower than Vanadium, can I say that DMM is ten times more toxic?So the LC50 is not an exact mathematical measure to relate the toxicity of compounds. Qualitatively we can say that DMM is more toxic, but how do I quantify it exactly, and which end-point do I use?
A. We'll work with this some more in Module 4, which you have probably seen, since I am behind this week. Vanadium is a dust or particulate that is inhaled, while DMM is a liquid that may be absorbed through the skin. So you would have to describe the exposure scenario.

Q. : How does one relate the LD50 obtained from Rattus norwegicus to the species Homo sapien? I know that this is an enormously complex question, but do toxicologists have any rules of thumb, any generalities that they dare make?
A. Module 4 will try to answer that. Rats are not People.

Q. (in reference to the enzyme weblink, where the author describes what happens to liver cells exposed to hydrogen peroxide). The breakdown of hydrogen peroxide ". . . takes place in organelles called peroxisomes. In some parasites this set of reactions serves to eliminate excess oxygen." My question pertains to that last statement - the breakdown of hydrogen peroxide produces oxygen. Is it incorrect to state that the reaction serves to eliminate excess oxygen?
A. Many enzymes will work as well backwards as forwards. The law of mass balance, Le Chatelier's Principe, will determine the direction of reaction. But I'm guessing, I'd never heard of that in insects. We'll get back to hydrogen peroxide and peroxidase soon.

Q. In what environment forum was the chemical released? For instance, dibutyl phthalate is more effective in aquatic systems than soil or air.
A. MSDS concerns itself with worker exposure, primarily, but also mentions some of the cleanup procedures based on its harm to the environment outside the workplace.

Q. What is American Cyanamid; a journal dealing specifically discussing toxicology?
A. No, they are a large manufacture of chemicals.

Q. Why weren't more people killed when the sarin was released in the subway in Tokyo? Was it because of dilution of the gas in the subway system?
A. Probably. The problem with war gasses is that they are difficult to use as weapons. The liquid chemical must be vaporized and spread just right to be effective.

Q. If a drug is distributed only in the plasma of a 70kg human, and assuming the plasma volume is 3L, would it be correct to say that the VD would be 3L?
A. Yes, if it were only in the plasma, that's what you would say. Usually Vd is expressed a L/kg of body weight.

Q. I was curious, because I thought that the development of cancer is not a dose-response relationship, which can be measured in the same way like the LD50 or so. Is the TC05 a common parameter?
A. No it is not a common parameter. We'll get to those carcinogenic dose-response issues in Module 5.

Q. I was wondering about the mode of action of atropine chloride against nerve agents. If atropine blocks the Ach-Receptor, could this lead to a worse reaction like blocking of the heartbeat?
A. Atropine has been around for a long time and its effects, although dangerous, are fairly well known. It is used in emergency treatment of organophosphorus poisoning. In a hospital, the effects of the organophosphorus and the atropine can be measured, and risks balanced. On the battlefield, atropine is used, as the lesser of two evils.

Q. Pralidoxime chloride seems for me safer, because it works more specific against the nerve agent. Is that right?
A. It is used in the second phase of treatment. It turns out that Pralidoxime binds calcium and can result in muscle spasms, not unlike that those from the organophosphorus poisoning.

Q. My question is regarding the chemical fluvalinate. Upon doing some research, I have discovered that this chemical is a pesticide control for mites in the cultivation of bees for honey. Looking at the MSDS, it appears that this chemical has some pretty significant side effect (toxicity effects) on rats, dogs, and rabbits if "overexposed". Reading an article about its implementation, it appears that the proper administration of this chemical (dosage) is key to its effectiveness. If over-administered, the mites become resistant. The article discusses how proper doses will decrease mite populations by 99%, which critics determine may not be good enough based on the mites resiliency. Proponents of the chemical fluvalinate formulated Apistan ® claim this form of the chemical is hydrophobic, and not soluble in honey, although it can contaminate wax over time. My questions are: how does this chemical affect those that consume it through the product? How are the public assured it is not translated to the human with the consumption of honey? Also, what evidence has been done to show how it affects performance of the bee in production? These seem like reasonable questions based on the toxicity effects shown in laboratory animals. I will see what I find..

A. In this course we try to focus on science. In ENVE 649 and 651 we get into politics, a little anyway. But honey manufactures will not report the amounts of chemicals in their product, unless they are compelled to. FIFRA, requires registration of new pesticides and labeling, does not address foods directly, as I read it. http://www.epa.gov/compliance/civil/programs/fifra/fifrastatreq.html here you can find out details. There are a number of laws about pesticides and I'm not up on the latest.

Q. I ran across ototoxcity data for styrene and was wondering if ototoxicity is commonly studied? This was the first time I remember seeing it mentioned.
A. It's certainly not common.

Q. One of my chemicals, Benzo(g,h,i)perylene, I am vaguely aware of from work as one of the PAHs that is part of heavier oils. However, since it is part of the mixture and is not produced commercially, it does not seem like there is much research available on it alone. A quick MSDS search showed that it is a trace impurity in some tar roofing compounds. Am I going to have trouble with the assignment if all my data is for a group of compounds (PAHs) instead of my single compound?
A. That's a problem with some environmental contaminants. No one manufactures them, so there is not much MSDS information. Some lab supply companies make them for test kits to calibrate equipment, VWR might have one. I would suggest staying with just one compound, not PAH's as a whole. You will find lots and lots on some of the individual PAH's.