skin contact with acrylamide

Bryan L. Ford fordb at bcc.orst.edu
Thu Jul 23 02:44:07 EST 1998


Peter wrote:


> > Perhaps you
> > are neglecting to consider that these results fit very well with the
> > known damage to axoplasmic transport (or axonal if you prefer). Under
> > such a model the accumulation of moderate damage can be at least
> > partially repaired in the absence of the toxin, but longer term doses
> > cause accumulation of damage to levels that are substantially
> > irreversible.
> 
> Yes and look at the concentraqtion of acrylamide used.  Not exactly
> pysiological.  One would have to either breath the powder or eat the
> powder to get those concerntrations in vivo.  I have no doubt that If the
> acrylamide does enter into the neuron then these effects would be seen.
> Other agents that can react/crosslink with proteins can show similar
> effects.

"You" in this case being a rodent with very much shorter and smaller
diameter axons in sensory and other neuronal tracts!

> > Where is the article on your
> > "receptor crosslinking" idea, or supporting literature for the high
> > levels of sulphydryls in the plasma?
> 
> I said sulhydryls and Hydroxyls and yes they are in the serum.  For more
> reading, please look at the article:
> 
>        Blatt etal. The association of acrylamide with proteins. The
> interpretation of fluorescence quenching experiments.

Well now that is quite a citation, Peter.... I assume you left out
something here!

> What you fail to realize is that Acyrliamide is spontaneously reactive to
> these groups whether you want to believe it or not.  And there are a lot
> of these groups in the plasma.

Earlier I asked you to specify concentrations of sulphydrals in plasma.
I asked if it was anywhere near the intracellular concentration of
glutathione of 5 mM.  I have no doubt that acrylamide will react with
glutathione and other thiols. Your insistence that it will spontaneously
interact with free amines should be tempered by the relatively low level
of such materials in normal plasma and by the very low level of suitable
initiating radical oxygen species. You have not explained how it is that
pure acrylamide in aqueous solution can persist without polymerization
for years, and that it can be in the presence of TEMED for hours and
perhaps days without undergoing detectable polymerization. These are
things I cannot reconcile with your assertions about the reactivity of
acrylamide.

What I want to believe is *evidence*, especially for ideas that ask one
to be less concerned about a potential risk. Being cautious can cost a
bit of time and a small amount of money, erring in the other direction
can cost you your well-being for life.


> > > > However, I would not recommend using MSDS assertions to promote
> > > > dismissive claims about the harmlessness of contact with aqueous
> > > > solutions of potential toxins regardless of their modest solubility in
> > > > "oil". Lipophilic materials as a rule do not have the highest dermal
> > > > transport parameters, nor do strictly polar materials-- amphipathic
> > > > materials generally absorb better than either. The size of the
> > > > acrylamide molecule and perhaps its olefinic structure as well as its
> > > > amphipathic qualities make it remarkably mobile across skin, and then
> > > > well dispersed as a potential systemic toxin.
 
> Modest solubilities... Now the solubility is modest. 
 
Yes, and they are substantial, look it up, in say the Merck Index. 

>  Can you say
> "Partition coeffiecent? 

Not only can I say it, I was the first to mention it. Look at my post:

Quoting Ford's reply of July 20, '98:

"Such an argument, presumably rooted in thinking about partition
coefficients, is not correct even if acrylamide were a large and
non-amphipathic molecule. Acrylamide itself can partition into the skin
and widely distribute in tissues and into cellular compartments. The
aqueous solution is perhaps less dangerous than other conceivable
solutions with higher dermal transport rates, but even this is not
proven." 


> If the greater protion is partitioned into the
> Aqueous phase then it will react in the aqueous phase.  If you are able to
> swamp the aqueous system them some of the acrylamide(possibly a
> significant amt) will be able to pass through the lipid bilayer and react
> with the intracellular proteins  


If I am correctly interpreting the above, then my comment is that the
partition coefficient is a *constant* for any particular set of solvents
and solute at STP. Increasing the concentration of acrylamide in water
(up to saturation) will only *proportionally* increase that in the oil.
Above saturation the extra acrylamide is normally a solid so saturation
effectively eliminates any added acrylamide from participating in the
solvent system. 

Permit me to give my lecture on the deficiencies of a simple
partitioning model and to provide a more comprehensive model in its
place: 

If the body were simply a blob of oil and it were floating in a solution
containing acrylamide, what would happen? You know the answer, but I
will say it here anyway, the concentration in the aqueous phase and in
the oil phase will eventually reach an equilibrium ratio. That ratio of
the two concentrations we call the partition coefficient for this
particular ternary system. Peter correctly recognizes that the partition
coefficient (that is a measure of competing solubilities) is somehow
related to the dermal transport rate of acrylamide. Peter is also aware
that the *model* partition coefficient for many investigations involving
potential toxicants in environmental situations is an oil/water or
octanol/water number that is experimentally derived for each potential
solute or toxicant. We both know this number is useful.

However, Peter appears to be misapplying the partition coefficient it in
this situation. The body is not much like a blob of oil that is
potentially in contact with some aqueous solute. If one thinks about it,
the issue is not a about an immiscible solvent pair (oil/water) but
instead is two aqueous "solutions" one with acrylamide and the other
with plasma (or possibly cytoplasm) separated from each other by a thin
membrane (the skin, or cell membrane and/or even a barrier such as a
glove). The transport rate across the barrier is going to be a complex
process, reflecting the heterogeneous and composite nature of the
barrier, the relative mobilities of solute and solvent molecules across
the barrier, and the solubility of the solute in the fluids on each side
of the barrier. The membrane has some finite thickness,and for our
purposes it generally has both lipophilic and hydrophilic components, it
may have pores or other forms of passage, the membrane may be damaged in
various ways. In an exposure to a water borne penetrant/toxicant the
membrane acts as a *rate* limiting barrier. The resulting overall
transport rate is related to thickness of the membrane, to the molecular
size, shape and electronic and charge properties of the
penetrant/toxicant, to temperature and pressure, to the presence of
co-solvents, and even to the partition coefficient. The diffusion of
toxicant across the membrane is related to the membrane's ability to
accomodate or dissolve the toxicant to be sure, but with essentially
identical solvents (water) on both sides of the membrane (skin) the
ultimate equilibrium concentrations of the solute will approach the same
value. The rate of transport for acrylamide across such a membrane is
high (as I have repeated several times in past posts) because it is
amphipathic (having both hydrophilic and lipophilic properties) and
because it is of small size. A word I have used here that encompasses
this is "mobility".

(Note for the News reader interested in acrylamide toxicity: From here
down there is only personal motives, commentary, history, no science or
would-be science)

Peter wrote:

> I am currently working in liver
> regeneration/cancer. 

Interesting, much of my dissertation deals with liver tumors. It would
have been interesting to be able to look at my model with regeneration
as a variable. Maybe the next grad or post-doc here will come with some
expertise in this area.

> > Some areas of interest/expertise:
> >
> > Molecular biology
> > Molecular oncology
> > Molecular evolution
> > Subnanosecond fluorescence phenomena
> > Nutritional biochemistry

> Expertise impies that you have published in these feilds.  Just out of
> curiousity have you? 

Interest/expertise was intended to imply for me that I have one or the
other, or some combination of both. Here is a bit of detail, at the risk
of boring all who read:

Molecular biology and molecular oncology (or molecular carcinogenesis)
papers published number two (search Bryan Ford for the other one).

Molecular evolution is a long standing interest, and there is a bit of
that in the comparative oncogene work I've been fortunate enough to
collaborate on in the above publications. I have developed a technique
for obtaining strong PCR signals from wax-embedded Bouin's fixed tissues
that is very promising. I hope someday to try some variations of this on
ancient DNA-- since in some ways Bouin's is a model of very aged DNA.

Subnanosecond optics are the subject of a submitted patent application
with a co-inventor. At least one other patent application is expected
fairly soon in this area. My interests in this area go back many years,
and are likely to continue due in part to the great patience and
expertise of my collaborator.

Nutritional biochemistry is a long time interest and hobby. No
peer-reviewed publications, yet. Some years ago I wrote some extended
critiques in a rather obscure newletter relating to the biochemistry of
aging, and nutritional variables modifying this-- more info available on
request.

> I feel that WE are beginning to
> waste space on this Newsgroup.

I tend to agree. Patrick F.H. Lai politely wrote as much. However I
notice Susan Hogarth, whose opinions always seem quite sensible, is very
entertained by the "pissing contest". My primary motive for entering
this fray was to dissuade lab workers from adopting a lax attitude
toward the potential dangers of acrylamide. I am not interested in
argument for its own sake. I wish to encourage fellow workers to be safe
rather than sorry. I hope that no one has gone the other direction
because of my style. A neuroscientist warned me about the dangers of
acrylamide early in my lab career, and subsequent seminars, posters and
articles have regularly confirmed his warnings. I am trying to pass on
this concern.

--Bryan



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