EFFECTS OBSERVED IN THE WHOLE ANIMAL 955 



physiological metal ion. Might it not be assumed, with as little evidence, that 

 reduction of the free cysteine-cystine concentration by the formation of 

 Hg++ complexes would stimulate synthesis of these amino acids? 



Toxic and Lethal Doses 



A few of the results on different types of mercurial are summarized in 

 Table 7-22. The lethal dose will depend on the time interval chosen for de- 

 termination of the mortality, since death from mercurial poisoning may 

 occur several days following the administration, and this accounts for some 

 of the variability seen in the table. It is clear that the organic mercurials 

 are generally less toxic than HgCl,. It is difficult to estimate average doses, 

 but roughly the LD50 for HgClg is near 10 mg Hg/kg (0.05 millimole/kg) 

 and for the organic mercurials around 40 mg Hg/kg (0.2 millimole/kg); 

 there is so much species variation and differences between the organic mer- 

 curials that these figures are to be taken only as a crude basis for compari- 

 son. Differences between routes of administration are not as marked as one 

 might expect. One of the most important factors determining the toxicity of 

 mercurials given intravenously is the state of dissociation of the R — Hg — X 

 bond, where X represents any ion or thiol either introduced with the mer- 

 curial or present in the blood. In other words, the concentration of the free 

 R — Hg+ ion, which is able to react with the SH groups of the tissue cell 

 membranes, is a major toxicity determinant. If the mercurial is already 

 complexed with a thiol, as in mercaptomerin, the dissociation of the Hg — S 

 bond will be slow and little of the mercurial will be bound to SH groups, 

 in either the blood or the tissues. A second factor of undoubted significance 

 is the distribution of the mercurials, in both the R — Hg — X and R — Hg+ 

 forms. An R group or a slowly dissociating Hg — X bond will favor penetra- 

 tion into the central nervous system in some instances, and this may alter 

 the pattern of toxicity from a rapid cardiovascular death to a slowly de- 

 veloping degeneration of certain nervous pathways. 



Distribution, Metabolism, and Excretion of Mercurials 



Certain aspects of the fate of the mercurials in the body have been dis- 

 cussed relative to the diuretic action, and these will be briefly summarized. 

 (1) All mercurials are accumulated in the kidney and reach much higher 

 concentrations in this tissue than in others, although the rate and degree 

 of accumulation depend on the structure of the mercurial. (2) Mercurials 

 are to a great extent bound to the plasma proteins and erythrocytes so 

 that only a small fraction is free to enter the tissues or be filtered through 

 the glomeruli. (3) Some of the mercurials may be secreted by the renal 

 tubular cells. (4) Mercurials are excreted in the urine mainly complexed 

 with thiols such as cysteine. (5) Some organic mercurials are split to form 

 Hg++ in the body, but there is no agreement as to the degree to which this 



