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SOT Highlights -- methylene chloride and nitrogen dioxide

Chuck Miller rellim at MAILHOST.TCS.TULANE.EDU
Mon May 6 16:04:54 EST 1996


More "Highlights" from the 35th annual Soc. of Toxicology Meeting appear in
the April 12 issue of Science, on p. 200. The mechanistic aspects of
methylene chloride genotoxicity/carcinogenesis (those following the animal
models discussion may want to note the species specific effects) and
nitrogen dioxide's effect on immunity and challenge to infectious agents
are discussed.

Those of you who attended the SOT meeting are encouraged to post your own
favorite "highlights" to this news group for discussion (post your e-mail
to toxicol at net.bio.net or toxicol at daresbury.ac.uk, depending on your
location).

An anonymous participant in this news group e-mailed me asking:

>In a recent Science article and discussion in San Francisco the carcinogenic
>effects of methylene chloride in rats versus humans was discussed.  
>The consensus was that methylene chloride is conjugated in the rat nucleus
>leading to the carcinogenic metabolite while in humans this is not the case.
>Certainly the metabolic pleimorphisms that exist in nature are a big discussion
>among toxicologists now and the feeling I get is that they want to now
>reevaluate  their thinking on >what is considered human toxicants.  However if
>someone could explain this mechanism of methylene >chloride being GSH
>CONJUGATED to a
>CARCINOGENIC metabolite I would be more than appreciative.

A considerable amount of work in this area has been done by Trevor Green
and coworkers (see Carcinogenesis vol. 16:1919-26, 1995 and references
therein.) When using an agent to deplete glutathione, they observed a
REDUCTION in the CH2Cl2-induced DNA damage detected as strand breaks via
alkaline elution.

In the review in Science, Green and colleagues postulate that mice have a
more active GSH system than rats or humans. Furthermore, they note that the
murine GSH-S-transferases are located in the nucleus, and may be a factor
contributing to the species specific effects. As further evidence for a
GSH-mediated mechanism, R. Thier, et al. (Proc. Natl. Acad. Sci. USA
90:8576-80, 1993) have isolated an S-[1-(N2-deoxyguanosinyl)methyl]GSH
adduct and have shown that expression of recombinant human
GSH-S-transferase 5-5 in Salmonella contributed to the genotoxicity of
CH2Cl2 in the Ames test. 

(Any more info. or comments from others?) 

While this research may not constitute direct proof of a CARCINOGENIC
metabolite, it does correlate with the observed carcinogenesis data. 

The upshot of this recent research is that the murine cancer data for
CH2Cl2 may not be so relevant to human carcinogenesis--the possibility of
reducing the carcinogen status of CH2Cl2 is discussed. 


Virtually yours,

Chuck

Dr. Charles A. Miller,  rellim at mailhost.tcs.tulane.edu 
Bionet.toxicology Discussion Leader
Dept. Environmental Health Sciences 
Rm. 374, Center for Bioenvironmental Research
School of Public Health and Tropical Medicine
Tulane University Medical Center  
1430 Tulane Ave. Box SL29                 
New Orleans, LA 70112               
Ph. 504-585-6942, Fx. 504-585-6939              

                                                                        
                   






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