Module 2
***Q. In the introduction to Toxicology Tutor II, they make the statement "…exposure
dose (outside dose) is only a fraction of the absorbed dose (internal dose)."
Maybe I don't really understand the term dose, or do they have the statement
backward? How can the amounts of chemical you are exposed to be less than the
amount of chemical absorbed?
A. Very good. They said it backwards. Only a fraction is absorbed.
***Q. In MSDS about methylmercury there was no information about how specific
the gloves should be? I am still puzzled a little about what did she do wrong?..
A. The lesson here is that MSDS sheets are not completely trustworthy. Any old
kind of glove would meet the MSDS requirements. In fact, the commonest kind
of glove, latex, is no use at all, and the MSDS should have said that. That
is not unusual. I had some students working with methylene chloride, a very
common solvent. It turns out that the standard gloves are not recommended for
that either, although the consequences are not nearly as severe as dimethylmercury.
I determined the recommended glove material. When we tired to order it from
the standard suppliers, we found the proper material was not available in Alaska.
Since there are thousands of gallons of methylene chloride used in Alaska, which
may mean that virtually all the people who are using it are not properly protected.
The MSDS sheet did not discuss this.
**Q. How long is a "long paragraph?" Maybe, my assignment is too
short. I will see it.
A. No, it is just fine. I try to give an idea of the length,
because some students feel they have to write 8 or 10 pages, while another feels
one sentence is sufficient.
**Q. I have had basic organic chemistry presented I don't know how many times
and I still get the names messed up. Have you ever seen a good one or two page
cheat sheet/reference? They are inside the front cover of many organic chemistry
textbooks.
A. Here's one from the web:
http://en.wikipedia.org/wiki/Functional_group
*Q. As I mentioned above, how can an MSDS give a health hazard rating of 0
then turn around and say it is harmful? Are the NFPA ratings arbitrary or are
there some guidelines such as the LD50 which would define if it is a 0 rating,
a 4 rating, or somewhere in between?
A.. Here's a site with more information,
http://www.ilpi.com/msds/ref/hmis.html
But a specific answer eludes me. It may be in the mixture aspect, the two sheets
refer to very different mixtures. It may also pertain to the nature of the system,
the NFPA is for emergency responders, while the HMIS might be for chronic exposures.
This is more an ENVE 649 issue, so I'll stop here.
*Q. Question #9 in the quiz asks who wrote the MSDS for Death in the Laboratory
exercise. The MSDS was from Eastman Kodak, which was noted as the correct answer.
However, the MSDS also says "Source of MSDS; VWR Scientific Corporation".
Isn't this the company that prepared the MSDS?
A. No, that would be who supplied it to the lab. The sheet was written by the
manufacturer.
*Q. Following up on the question above, how do you determine who actually prepares
an MSDS? I have three others here, and all are different. The first has absolutely
no information at the front of the MSDS except the company name, address, and
customer service phone number. Then at the very end, it states "Prepared
by: Environmental Health & Safety", and gives a phone number. I take
it to mean this company prepared the MSDS for the manufacturer? The second has,
under the Manufacturer's Information section, the company name, address, and
phone number. It also lists "MSDS Preparer's Name: N/P", which I take
to mean that someone in the company wrote the MSDS. The third lists a "Responsible
Party" under the section Product Identification, which includes company
name, address, and phone number. Although, at the very end of the MSDS is a
disclaimer stating this information was "formulated" for use by elements
of the DOD. So I take it that this company prepared the MSDS, but was not involved
in the product manufacture. In instances where I've needed information on a
product, I've always gone to the company listed on the top of the MSDS, as being
responsible for the product. But it seems that they may not have actually prepared
the MSDS.
A. Under the OSHA law, it is the employers' responsibility to provide the workers
with the correct information. So on one hand, it does not matter who actually
wrote it, and the employer is responsible. Now that law also requires the manufactures,
importers, and distributors of chemicals to supply MSDS sheets to the employers.
It does not matter where they get the sheets. So it is common for a chemical
supplier to pass along a sheet it gets from the manufacturer, without commenting
on it. So you are correct, you find a mix of authors and sometimes the responsibility
is not clear from the sheet.
*Q. Is there a provision for companies to update their MSDS sheets every ___
years (5, 10, ever)? What about providing them in multiple languages?
A. No requirement at all. See below/above. If new information 'becomes known
to them," they need to update the MSDS, but they have no need to dig. The
ACGIH TLV's do change, more often than the OSHA PEL's, so that part of the sheet
should be updated, but often it is not.
*Q. http://www.faculty.uaf.edu/ffrap/ENVE_652/Module02/2B_Organic/2B_3_Organic.htm
You explain in the above Org Chem review website that the 2,3,7,8 isomer of
TCDD is extremely toxic, whereas the 2,3,6,7 isomer is not. You state that this
is due to a good fit within a special chemical receptor. This brings up a question
I have had for a long time. Is benzene carcinogenic and more toxic than alkylated
benzenes for a similar reason? Similarly, benzo[a]pyrene is carcinogenic, whereas
naphthalene is not. Here methylation of the aromatic groups and molecular size
don't seem to be the determining factors. Is it as simple as proper fitting
within certain receptors? Perhaps this question is best left to later in the
semester, but I couldn't wait to ask!
A. That is a detail we may get to or not. The 2,3,7,8 fits a specific receptor
and that is the reason for its extreme toxicity - in the guinea pig. Both Benzene
and benzo[a]pyrene from epoxides. The epoxides are very reactive molecules.
So reactive, they will bind to other molecules very close to where they are
formed. On a molecule scale, the epoxides are formed far from the DNA. However
BAP has the expoxide in a "bay region" where it is somewhat protected,
and hence can travel further, and perhaps migrate to where the DNA is at. Naphthalene
will form the epoxide, I think, but it is not protected and will not get to
the DNA, at least very often. Following that reasoning, I can't explain why
the benzene expoxide gets to the DNA, perhaps it is because people can be exposed
to so much benzene that enough of the expoxide will get to the DNA.
*Q. I seem to remember that a side effect of some antibiotics (tetracycline,
I think) can make one's skin more sensitive to the sun. Why is that?
A. Tetracycline is phototoxic in about 1 to 2% of individuals. See
http://www.emedicine.com/derm/topic108.htm
for some general info on phototoxicity. Generally, some of the compound in the
blood or tissue is close enough to the skin such that sunlight can change the
chemistry of the compound. Why this happens in some but not other is probably
immune related, something we will talk about later this semester.
*Q. Why do some companies provide toxicology and ecological information on
their MSDS and some do not? Is it required?
A. Companies only provide the MSDS because it is required by a regulation, the
details are found at 29 CFR 1910.1200 (g)(2) which you can find at,
http://a257.g.akamaitech.net/7/257/2422/20cot20031500/edocket.access.gpo.gov/cfr_2003/julqtr/29cfr1910.1200.htm
but no need to do that for this course. It also there is says, "(3) If
no relevant information is found for any given category on the material safety
data sheet, the chemical manufacturer, importer or employer preparing the material
safety data sheet shall mark it to indicate that no applicable information was
found." Found where? Good question. If it is not "commonly available"
the manufacturer does not need to dig to find it. They certainly do not need
to do any testing. Since this is a labor regulation, there is no need to put
anything about its environmental effects into the MSDS, although most do.
*Q. Is it required (by law!), to provide the MSDS and the proper training in
an understandable language for the employee?
A. Very important point. I teach more about worker protection in ENVE 649, Hazardous
and Toxic Waste Management. Briefly, it is the employer's obligation to sure
each employee understands the hazards. The problem is that the employees will
insist they understand English, when they may not. Also, without proper training,
how will an English-speaking employee know who IARC is? Or what "hepatotoxic"
means?
*Q. I have seen too many MSDS that were so vague and incomplete that they created more risks than they mitigated. Frequently the omitted information is readily available or easily measured. In fact, the companies usually need it to run their production operations. The most egregious area seems to be in the recommendation of proper personal protective equipment standards. They also seem to avoid discussing the context in which the chemical will be used and what the ramifications are for a particular use and setting. There is a very big difference between limited amounts in a lab hood and chemical production. Yet the MSDS’s rarely address these different scenarios. Using information that is already available it would seem that the quality of MSDS sheets could be greatly improved. Why is it that OSHA and NIOSH have not been as diligent as the FDA in developing regulations and pushing legislation for the MSDS data standards? To take it beyond government regulation, why haven’t customers been more demanding of the suppliers in this regard? If a pharmaceutical company’s labeling is lacking, the company and the FDA will hear about it from the medical community. It would seem that there is a market mechanism to improve the MSDS. Yet it does not appear to be happening.
A. The MSDS program was not a law itself, but rather a regulation promulgated by OSHA as part of its hazardous communications standard. It was designed to give workers some information about the chemicals they are exposed to. Since the employer often knows nothing about the chemicals, OSHA requires the manufacture or importers to supply this data. OSHA has no authority or power over manufactures. Their authority is limited to the employers responsibly for the health and safety of workers in the workplace. It would take a new, separate federal law, which is not likely. We won’t do TSCA in this course, but it is headed in the direction you suggest. http://www.epa.gov/regulations/laws/tsca.html
*Q. What criteria from a toxicological report does the government use to determine how closely a toxic chemical should be regulated in the environment? Also, like you mentioned in the module, cheeseburgers and cigarette smoke could be considered toxic, where is the line drawn between taking personal responsibility and having the government intervene?
A. These are among the most profound questions in regulatory toxicology. The EPA has board authority to regulate chemicals in the air and water, but must promulgate a regulation or amend one. These are always resisted by the affected industries, which provide some check on EPA enthusiasm. Generally, the EPA will commission a study by an outside consultant that summarizes the problem and the available literature. Drawing the line is 99% political and depends on one’s view of the proper level of governmental authority. One group believes that unless industry can prove a thing is not harmful, it must be eliminated or regulated below harmful level. The other group believes that unless the anti-industry groups can prove something is harmful, it should not be regulated at all. The truth is that for both sides, there usually is not enough scientific data to prove or disprove anything. We’ll do a module on regulatory toxicology later.
*Q. What is the big deal with companies not listing specific PPE on the MSDS sheets? Is it too much work to look up whether the user should wear a nitrile or a butyl glove? Or does glove technology, respirator cartridge type, etc change so quickly that the MSDS writers have decided to avoid the issue? Or are the companies who put out the MSDSs just trying to avoid liability issues?
A. A good point. Often a company that supplies chemicals, like Baker, is responsible for hundred or thousands of MSDS. For less profitable chemicals, they do not have the resources to do any original research, and thus use standards data bases. If these don’t have details, they are under no obligation to push any further. Liability is a tricky issue. Often the standard data bases are not correct. For example, for glove material, the standard is many years old. Many chemicals are not listed. Many glove materials are not listed either. So saying less is often more prudent.
*Q. According to US law: do scientific research or medical institutions have
to report the newly obtained data on chemical's toxicity? If yes, where? To
whom? Or is it a requirement for manufacturers to carry such research?
A. No they don't. When a manufacturer markets a new chemical they must prepare
an MSDS sheet, but they do not need to do any research on it. They have a legal
liability if anyone gets hurt; so most manufacturers do some investigation.
Many new products are mixtures of several chemicals, and the properties of these
constituents are known. These will be on the MSDS sheet. Medical or scientific
labs might discover something but they are not required to report their discoveries.
*Q. In general words, how will I, common person, know how toxic might be a
simple household chemical, if a manufacturer provides old data?
Consumer products, those that you buy in a supermarket, come under the Consumer
Product Safety Commission regulations. These require labeling of toxicity, but
only in the very general way. You will see most labels have an 800 number or
address for more information, but I have not had any luck getting real toxicity
information by this route. Most commercial products by major manufactures have
been tested pretty well. The chemicals you use in the laboratory are not consumer
products and do not need to be labeled.
*Q. I finally went to the department homepage that states that MSDS sheets
should be obtained from the manufacturer for any chemical used in the lab. Based
on the limited information in the database, this is a great idea, but they should
not represent their database as containing MSDS info.
A. There is worker-OSHA issue in that statment. In the US you are allowed to
use CD's and MSDS's from the web to inform your employees, but they have to
be trained in this and the system must be readily available. You can't just
tell employees, "you can find it on the web."
*Q. In addition to same MSDS sheets the companies or manufacturers mention
about the purity of the chemical they are selling.
A. Because they don't have to. But that brings up an important point, often
a minor impurity from a chemical standpoint, might be the major factor from
a toxicological standpoint. 2,3,7,8 TCDD is a minor impurity of "agent
orange" but was allegedly responsible for many effects.
Q: Are the rate of organic reactions generally faster or slower compared to
the rate of inorganic reactions and why?
A. They are so variable that you could not categorize reaction rate by organic
vs. inorganic. Most reactions rates are temperature dependent and biological
reactions are limited to a narrow range of temperatures.
Q. Why don't companies and manufacturers follow one particular guideline for
MSDS sheets for their products ?
A. They do, but the guideline, the OSHA regulation, is very broad.
Q. Do the majority of toxics affect tissue and organs or the CNS?
A. The CNS, central nervous system, is a branch or department of the organ system
known as Nervous System. Most such branches of other organ systems are separate
organs. For example the pancreas and liver are separate organs in the GI system.
The CNS is really just one organ and the "system" part of the name
is somewhat a misnomer. Almost all toxics that are interested do their damage
at the cellular and biochemical level of organization. The "clinical significance"
on the other hand, comes when this damage to individual cells becomes significant
to an organ or organ system.
Q. That Tissues, Organs, Systems, Signals and Receptors Submodule seems like
it could have been a whole lesson in and of itself. Do you have a eukaryote
point of view on organelles?
A. Only eukaryotes have "membrane bound" organelles. Prokaryotes do
have ribosomes.
Q. Also, are unsaturated oils better for you because of the physical properties
(ie the slipperiness and shape) or because of the chemical properties (the double
bond that may allow something)?
A. Both, but many of the details are beyond me. Note the location of the double
bonds is apparently very important.
Q. In light of these different styles and qualities, was there a regulatory
change at some point in the 1990s that dictated a uniform style to MSDS's.?
A. No. The ANSI standard is still voluntary. The ANSI standard was developed
in 1993, long after the HAZ COM law, so some major players did not have theirs
in ANSI format. They would also object to a change in the standard.
Q. Finally, have there been any proposals to establish regulatory oversight
and review of MSDS quality, such that an incomplete MSDS would require rewriting
if a review deemed it inadequate?
A. Not as far as I know. It takes a major push and about 10 years to change
an OSHA regulation.
Q. I am very disturbed by the story of Dr. Wetterhahn. If DMM is that lethal,
it seems to me that there should have been some very extensive training for
not only Dr. W., but for everyone who worked in that lab and may have had the
opportunity to come in contact with DMMe~. If the chemical was so dangerous,
why didn't anyone know or tell Dr. W. about the latex gloves? Dr. W. was experiencing
symptoms- shouldn't she have been under a special medical surveillance program?
If she were working with radioactive isotopes, she would have been forced to
wear film badges, protective clothing and get her thyroid checked twice a year.
Was this just a fluke incident of compounding errors, or is there potential
for similar incidences that we are not aware of?
A. Her employer, Dartmouth, was fined by OSHA. Training is a difficult issue
in this case because Dr. W probably was the local expert on DMMe. Gloves and
other backup systems are not tested until there is a mistake. She may simply
have not spilled any on herself in the past. Her symptoms did not occur until
several weeks after the exposure. This is an extreme case. In this tox class
we have to break off learning about worker protection at some point, in the
Hazardous and Toxic Waste course (ENVE 649) we spend much more time on those
topics.
Q. In chemical engineering, the term kinetics is associated with how fast reactions
occur and is invariably tied up with differential equations. I recall that this
is also the case in biological reactions e.g. the Michaelis-Menten equation.
Does toxicokinetics also rely on this mathematical approach?
A. Yes, We assume each compartment is a well-stirred continuous flow reactor.
Elimination goes on in one or two selected compartments; this may be first order,
M-M, or whatever. The compartments are linked by first order differential equations.
Chemical engineers make good toxicokineticists.
Q. Just as an interesting note: Secondary and tertiary amines can also act
as weak acids because the N-H proton can be removed by a strong base. For example
the production of Lithium diisiopropylamide from Butyllithium and diisopropylamine
(Organic Chemistry, McMurry).
A. McMurry is my textbook too. The key is "strong base," most biological
bases and acids are weak. But thanks for the fine point.
Q. What is special about the composition of nerve tissue that makes it a good
conductor of electrical impulses - at least more so than other tissues?
Q. It's specialized for that, and only that. Nerve cells (which are called neurons)
that are designed to transmit long distances have insulating cells around them,
called Schwann cells. We'll talk a little more about that in a few weeks.
Q. I was wondering if the [p] designation in the chemical name dibenzo[p]dioxin
signifies the "para" orientation of the oxygen molecules to the chlorine
atoms on the benzyl rings of the compound. In dibenzo[b,e][1,4]dioxin, what
does the [b,e][1,4] indicate?
A. Go here: http://www.chem.qmw.ac.uk/iupac/fusedring/app2.html
and look at item 63 and note l. [p] for para would take care of one of the para
connections, but not the second.http://www.chem.qmw.ac.uk/iupac/fusedring/app2.html.
Q. What are/is the chemical receptors on the cell that the dibenzo[p]dioxins
target?
A. We will do a little more on that, but it's called the Ah receptor, it seems
to affect DNA quite a bit in some species, but no one is quite sure what the
"natural" function of the Ah receptor was or why there is such an
enormous species difference in it.
Q. All chlorinated dioxins and furans are so toxic they are not usually distinguished.
I think it is un-correct. Because their molecular formulas are different. But
yesterday I visit the web of http://www.foxriverwatch.com/dioxins_pcb_pcbs_1.html,
and I was told:" all three compounds (dioxins, furans and PCBs) are often
referred to collectively as "dioxin." So, I do not know which one
is correct or they are all correct.
A. This is a good example of the hazards of Internet searching. The Fox River
Watch is an environmental special interest group, not a scientific or educational
entity. I use their site for some things, but would not rely on them for a technical
matter. While dioxins, furans and PCBs are all chemicals that are frequently
cited as "environmental toxins," PCB's are almost never referred to
as a dioxin. All three have many "congeners" that vary tremendously
in toxicity, and we will talk about that in a later module.
Q. Why are the MSDS minimum requirements for safety information so lax? It
appears to me that toxicology is very young scientifically. Do we really understand
the dangers of the chemicals that we are coexisting with?
A. Yes and no. We don't do much with OSHA here in ENVE 652; we spend more time
in ENVE 649. On the negative side, there are about 3 million chemicals around
(and that's not counting the nearly infinite number of mixtures) and about chemicals
30,000 in "common use." Of these, we have significant toxicological
information about less than 3,000. On the positive side, those chemicals tested
are the ones most likely to cause problems or that have some history of problems.
American workplaces are generally safe and workers who follow the MSDS sheets
and various well-know health and safety standard have a low risk to their health.
We'll talk more about the effects at low concentrations in the general environment
later in this class.
Q. In module 2B, you say that TCDD's toxicity results from its fitting into
a special chemical receptor in the cell. Why would the cell have a receptor
that is such a good fit for TCDD? TCDD is generally the result of man-made chemicals,
is it not? Is there a beneficial substance that would more typically attach
to that receptor?
A. Great question and the topic of lots of big research projects. You would
assume that the receptor has some "natural" use and the TCDD fit is
an accident. The receptor was identified as the "Ah" receptor, or
Arylhydrocarbon receptor. I don't know what the "natural" function
of this receptor is. It would make a good term paper for you.
Q. What if Karen Wetterhahn contacted physician at once after the accident?
Would she stay healthy?
A. Probably not. The effects seem powerful and irreversible.