968 7. MERCURIALS 



there has been no work on the relative inherent or direct toxicities to cel- 

 lular processes, metabolic or functional, or adequate comparison of their 

 abilities to react with relevant SH groups, it is impossible to be certain 

 that the differences are due solely to variation in the penetration. Indeed, 

 one is not sure that the mercurials all act by the same mechanism. One 

 factor which is often ignored is the role of the size of the side chain in 

 membrane processes, assuming that they all react with identical SH groups 

 in the membrane. Nevertheless, such quantitative studies are valuable in 

 establishing a necessary basis for understanding the mechanisms by which 

 the mercurials act; further work will undoubtedly allow these results to 

 be interpreted more readily. 



Mammalian Cells and Tissue Cultures 



We must note that growth, in common with many other processes, may 

 be accelerated by low concentrations of the mercurials, as noted by Hira- 

 shima (1934) in chick fibroblast cultures, and by others. This has also been 

 reported for plant tissues, p-MB at 0.001-0.005 mM stimulating the growth 

 oi Arena coleoptiles some 20-25% (Thimann and Bonner, 1949). It is inter- 

 esting to recall that Mallus (1931) gave HgClg at 0.25-0.3 mg/kg to atrophic 

 but otherwise healthy children and observed certain changes — increased 

 chest measurements, rise in erythrocyte count and hemoglobin, and eleva- 

 tion of urinary nitrogen — indicating a stimulation of growth and metabo- 

 lism. The mechanisms by which mercurials can stimulate growth are un- 

 known, but it is possibly not a specific action since many types of cells ex- 

 hibit an increased proliferative activity when disturbed slightly by irritant 

 substances (our terminology in this field is admittedly inadequate). 



Inhibition of growth is invariable when the mercurial concentration is 

 increased beyond a certain level, which is frequently quite low. Many of 

 the experiments with tissue cultures have been done of necessity in complex 

 media (e.g., embryo extract) which must bind a large fraction of the mer- 

 curial, so the true inhibitory potency must be much greater than is indi- 

 cated by the concentrations used. Fibroblastic and leucocytic migration is 

 depressed 50% by Hg++ at concentrations near 0.08 mM, and growth is 

 somewhat modified even at 0.0037 mM (Meier, 1933). Chick embryo heart 

 cultures fail to grow in 0.08 mM Hg++ (Salle and Lazarus, 1936) and here 

 the organic mercurials are less toxic (Salle, 1943). Pulsations of the cardiac 

 cells are stopped by Hg++ before growth is affected, but the organic mer- 

 curials (thimerosal and nitromersol) stop growth and cause cytolysis with- 

 out previously interfering with the contractile activity. The concentration 

 of Hg++ for 50% inhibition of Eagle's KB strain of human carcinoma cells 

 is 0.037 mM (Smith et al., 1959), and 75% reduction in the mitoses of mouse 

 ear epidermis requires 0.01 mM p-MB (Gelfant, 1960). We may thus con- 

 clude that mercurials at concentrations around 0.005-0.05 mM seriously 



