Comment: Organic chemistry seems different than the general chemistry you studied. For example, an organic oxidation is the addition of oxygen, nitrogen, or chlorine to a molecule, or the subtraction of a hydrogen from the molecule. An organic base is a molecule that is capable of lending electrons to a molecule and an organic acid is an electron acceptor. That's a long way from sodium hydroxide and hydrochloric acid. I started digging back into my organic texts to try to give you a better answer to your basic question, what is an electrophile and how does it bind to DNA? Let me keep that for our special topics lecture, module 14.

**Q. The book discussed the effects of nitrates on the vascular system. I've also read about “blue baby” syndrome as a result of nitrate toxicity and I thought that this had something to do with oxygen being absorbed by the blood. How is this different that the effects discussed in the book?
A. Nothing. Your book on page 115 describes methemoglobinemia, where the iron in hemoglobin is oxidized from ferrous (++) to ferric (+++) by the nitrate. The ferric iron cannot bind oxygen. Adults have an enzyme that converts the iron back, but infants often lack that enzyme.

* Q. For all the week that I have done around old gas and diesel contamination, I never found (never looked much either) a description of the problems that were as clear as the ones in this module. I know for the breakdown ot PCE [perchloroethylene, 4 chlorines] and TCE [trichloroethylene], there are patterns that emerge in the percentages of breakdown DCE [dichloroethylene] that allow differentiation of breakdown products vs. manufactured DCE.
A. That may be cis and trans isomers,[ http://www.enter.net.au/~fairsci/chemistry/yr12/cis.htm ] or where the chlorines are in industrial compounds is different than where they are in the breakdown of TCE. I was not aware of that, but it is certainly possible, microorganism might take the chlorine first from one site on the TCE.
* Q. Is there a similar situation for benzene that you can back calculate the original concentrations from the breakdown products in natural environments or find some sort of other clues to the source?
A. Not for something as simple as benzene. For crude oils, which are mixtures, there are characteristic components of the various crude oils that lend themselves to "fingerprinting."

*Q. Lead and mercury are indicated in many neurotoxic conditions due to there ability in part to displace calcium in the nervous system, thus causing many complications. Cadmium does not seem to be indicated as a neurotoxin even though it has a 2+ oxidation state similar to the previously mentioned elements. To your knowledge, has cadmium been indicated as a neurotoxin?
A. Cadmium is toxic lots of ways. See the ASTDR monograph on cadmium. There are several reasons that its neurotoxic effects are not featured. First, in inhalation exposures, the exposure is usually not to cadmium, but an oxide or salt. These may be different than lead or mercury exposures. Second, cadmium might be more toxic to the respiratory system, so that it kills by that route before it would kill by the neurotoxic route. Finally, lead and mercury may stay in the body longer.

*Q. For the past week I attended a practical course on aquatic toxicity testing. We had hands on testing on fish toxicity (thalapea), bacterial and algal growth inhibition (can't remember the species), Ames salmonella, Daphnia Pulex, Frogs (in Afrikaans it is a Plat anna, I believe its something like African clawed anna) and Ureaze test. Of all the tests we did only the Daphnia (what a mission to count!) and the algal growth showed good results, the rest just giving garbage.
In our discussion at the end we were shown results of tests they did previously, one of the contaminants being benzene. In their tests benzene reported with a rather low toxicity and its carcinogenic potential was almost nonexistent. I don't know what test they did to test this (probably Ames) except that the control was an estrogen mimic.
My question is this, if all chemicals has such a specific mechanism such as benzene (and I suppose most of them do) how can we use a test such as Ames to screen for this?
A. You have just discovered why they use several tests of mutagenicity, not just one. It sounds like you were testing for ecological toxicity, which is different from human health effects.

*Q. After doing some research for the Minamata incident (interesting case study by the way) it is obvious that mercury concentrates in fish and marine mammals. What is it about the structure of methyl mercury that causes it concentrate in fish and upper level predators? Other than the regular mechanisms of bio-magnification in upper members of the food chain, that is, the higher in the food chain you are, the more food you eat and the longer you are on the planet. I am guessing that Hg is a lipophilic substance that concentrates in the high amounts of fat present in marine life, such as whales, and in the fats and oils present in most ocean fish. Or, is it because the substance is in elemental from already and really has no more breaking down to do?
A. Methylmercury is a small, lipophilic molecule, so it is readily absorbed. The question is why is it not excreted. There is the mystery. Mercury, being an element, is not biotransformed. The methyl group is very stable, it is hard to transform into anything. Methane is a gas, but methyl is bound to something else. Anyhow I don't know if it not biotransformed, or it somehow bounces back and forth between elemental mercury and the methylated species. The gut is full of bacteria that could methylate it again. The action on the nerves is also unclear, is it the element or methylated species that is toxic? Or again, they could bounce back and forth. Given that it does not biodegrade nor is it easily excreted, bacteria in the ocean are like sponges, sopping up the methylmercury. From there it works its way up the food chain to my tuna fish.

*Q. In http://www.pace8-675.org/articles/heartdisease.html is mentioned, noise leads to an increase in blood pressure. The reasons are the effects of acute stress. What does it mean, physical or psychic stress? What is the mechanism?
A. Psychic stress leads to activation of the sympathetic nervous system, which releases adrenaline (epinephrine and norepinephrine), which cause the increase in heart rate and blood pressure. Note that if someone were exposed to a chemical agent that provoked the increased blood pressure, and also to environment physical stress, or personal emotional stress, it might be very difficult to sort out which caused the high blood pressure.

*Q. Would it be worth my time in doing a comparison of the people impacted by the chromium by PG&E and people impacted by the PFOA by DuPont? Both companies may/have dolled out millions of dollars. Both peoples impacted by the chemicals, in their drinking water, have multiple diseases/disorders. Or do you think that this really goes beyond the scope of this paper? I think it may, however I do believe the results would be interesting.
A. Careful with lawyers and junk science - I call it “lawyer mediated toxicity.” If you take any cohort, say university professors, and ask them on any given day, “How do you feel?” you will get a percentage who say “not very well.” Further, if you examine this cohort further, you will find a percentage that often do not feel well. Their symptoms are often headache, confusion, stuffy nose, blurry vision, difficulty in concentrating, poor sleep, etc. While there are many other symptoms, what they have in common is that they are not verifiable by laboratory methods. Now if an employer has a building, and the employer has poor labor relations, and in winter the building gets stuffy, you will have an outbreak of “sick building syndrome.” A percentage of the employees will complain of precisely those same symptoms noted for the professors. However in this case, the employees will ascribe the symptoms to the work environment. If the matter festers, the employees will hire a lawyer on a contingent fee, who will sue the owner of the building (if it different than the employer). The lawyer will try to “prove” that the building and the employee's callousness were responsible for the employees' illness. Often the lawyer will win. This is a long way from science.

*Q.On the Environmental Health Perspectives web page on benzene, they state that there is an inability to identify an animal model in which benzene produces leukemia. Perhaps this suggests that the animals are able to do something with the benzene that us humans can not do. This would still be beneficial as we could artificially metabolize the chemical as animals do. Does this ever happen?
A. Benzene is not a “classic” carcinogen. Most carcinogens are electrophiles or are converted to electrophiles by P450s. The electrophile then binds to DNA and causes a mutation, etc. Benzene's metabolites are not very electrophilic and do not bind to DNA. They are capable of damaging other cellular machinery and perhaps causing the DNA strand or the chromosome itself to break. These broken pieces of DNA may lead to the same problems as DNA mutations, i.e., the wrong protein. Why this is such a big deal in human bone marrow and not other organs or anywhere in other species (except the “normal” cancers at very high doses, see Ames and Gold) is unknown. “My” chemical, methanol, has very different properties in primates than rodents, but there the mechanism is known, rodents metabolize methanol by a different route.

*Q. The biggest questions in my mind at the moment include: What are environmental factors that would degrade PCBs? What is the metabolic fate of PCBs in fish, and metabolic fate of PCBs in human? Is there preferential absorption of PCBs into specific tissues? What biological transformations of PCBs occur in fish and humans? Do fish or humans excrete PCBs? I ask these questions at the present not so much because I am looking for answers from you, but rather because these are questions I don't know much about that I think are important for understanding the topic. (Of course, suggested references will not be disregarded.)
A. I'm not an expert on fish. In an oxygenated environment, most of the metabolism that goes on, from bacteria to whales, is aerobic. Oxygen is added to a carbon source and energy is produced. Chlorinated organics have been oxidized by replacing a hydrogen atom with a chlorine atom. Many of them don't burn. PCBs were used as a fireproofing additive in paint. So in general, chlorinated compounds must be degraded by an anaerobic process. These are rare “higher organisms,” although there are some in the soil and sediment. So, once these highly chlorinated organics are absorbed, they are very slow to leave. Most of these chlorinated organics are very lipid soluble and most are stored in adipose tissue. The P450 enzymes will try to add oxygen to these and for some compounds the P450 can make them slightly more water-soluble. Others, especially heavier organics, and be conjugated to something and excrete in the bile. There is always some partitioning and diffusion, so, if no more of the chlorinated compounds are absorbed, they will gradually leave the body by diffusion into the GI tract, although this is a very slow process.

Q. In Chapter 9 of our text, they mention Glycine, primarily generated in the brain stem and spinal cord, having to do with sustained muscle contraction. Being a movie buff, it sounded a lot like the chemical the dinosaurs in Jurassic Park were genetically engineered to not produce. They had to eat Glycine containing food to stay alive. My question on this is how does ingestion of a chemical (amino acid, whatever) supplement or act as the naturally produced chemical? If the cells produce this amino acid based on a need or stimulus, how does the amino acid in the blood fill the gap if the cells can't produce it naturally?
A. I missed that movie. I'm not sure where the body produces amino acids, other than in the liver. There may be other locations, but the liver is chief. The body (liver) can make certain amino acids from other amino acids and some from scratch. There are a few, however, that must be ingested, and the liver cannot make them. Regulation of metabolism is beyond the scope of this course, but in general, their products regulate many enzymes. That is, the product binds to the enzyme and shuts it down. The product is not bound with a covalent bond and is in equilibrium with the surroundings. You take it from there.

Q. After looking into the Minamata disease, only 2,000 patients were certified as having the disease, but about 12,000 were not-certified, do you know why?
A. By certified, I believe they mean eligible for compensation. In the US, people would get compensated if they were worried they might have the disease. In Japan (and most of the world) people would have to be able to demonstrate beyond all doubt that they have the disease. Many might have had a mild form of the disease and got over it and therefore not compensated.

Q. Seems that Sodium plays a crucial role in the electrical signals in the cardiovascular system, as well as the neurological system. Which I expect ties into the fact that many people with heart disease are put on low-sodium diets. How much of the sodium that controls these ‘circuits' are tied into daily diets? I'm just curious if it is 1%, 10%, 50%??
A.The low sodium has to do with blood pressure. Even on a low sodium diet, there is ample sodium for the circuits. Sometimes, in endurance athletes in hot weather, it is possible to draw down the potassium to where it interferes with the circuits.

Q. Benzene: How much exposure does one have at the gas pump? I've heard quite a bit, although I know the pump covers are supposed to prevent some exposure.
A. Perhaps, but the covers and such are mostly to prevent hydrocarbons from venting to the environment. I don't think consumers at the pumps get very much. However shop mechanics can get a significant amount and it will show up in their blood and the metabolites in urine.

Q. The section on benzene metabolism and carcinogenesis mechanisms at low doses reminded me of a theory I've heard about recently called “hormesis”. It's the idea that a dose versus response curve is shaped more like a parabola than a straight line, where the minimum on the parabola is not a zero dose. Hence, a small dose could have a positive effect. In the case of elements like selenium and chromium, this makes sense. We need trace amounts of selenium and (trivalent) chromium for good health, but too much of a good thing has toxic consequences. Could a similar case be possible for benzene? The prima facie case seems absurd, but it's a curious theory.
A. For the trace minerals, hormesis is a fact. It may be that small amounts of a toxic induce some protective enzymes, then when you get a big dose, the enzymes are there for protection. That is my rational for drinking all the carcinogens in my coffee. There is a sub-culture that believe that hormesis is important in radioactivity. This group has a secret password and burns incense. I might believe a little, but have never been invited to there meetings. I don't think anyone could stretch hormesis to benzene. The benzene structure, being the simplest aromatic, is often found in bimolecules. However none of these molecules are made from benzene.