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Toxicity of Heavy Metals and Biological Defense

Principles and Applications in Bioinorganic Chemistry-VII

Ei-lchiro Ochiai Department of Chemistry, Juniata College, Huntingdon, PA 16652

Some biologically essential elements have been discussed in the previous articles of this series (1-6). The
pre- sent article discusses some adverse effects of metallic elements, particularly those of the so-called
heavy metals. Heavy metals are ill-defined hut here are considered mainly cadmium, lead, and mercury.
Copper, zinc, and silver also will be mentioned.

Abundance and Toxicity

A certain degree of correlation was shown to exist be- tween the abundance in the environment and the
level of elements present in a biological tissue in a previous article (3). It is to be noted (see Figs. 2 and 3
of (3)) that the essential elements tend to be those that are relatively abundant in the environment. The
organisms must have tried to utilize the elements that they inadvertently ingested from the
environment. If the elements turned out to be useful to the organisms, they would have become
essential to the organ- isms. Therefore, there is a better chance for an element to become essential, if it
is present abundantly and in a readily accessible form in the environment (the first basic rule of
bioselection (1)).

It must he pointed out, though, that some elements such as Se and Co have become essential to
organisms in trace amounts despite their low abundances in the environment. No other more abundant
element could have substituted for these elements. On the contrary, an abundant element would not
become essential, if it is not useful to organisms. "Aluminum" may be such an element. Aluminum is
ubiquitous in the environment, though not necessarily in a readily accesible form.

How about the elements that organisms would encounter only rarely? They are the elements that are
present at low levels on the earth or in inaccessible forms. The heavy metals such as lead, mercury, and
cadmium belong to this group. Because most organisms have not had experience to deal with these
elements, the organisms could be subjected to their adverse effects, if they ingested them. Some organ-
isms, however, might have had enough experience to deal with the adverse effects of these elements
over the long history of their evolutions. If that is the case, those organ- isms must have developed
some defense mechanisms against the adverse effects of those elements. Otherwise they would not
have survived. In this sense, the elements that are rare on the earth tend to be toxic to the organisms in
general. This is only a rough generalization. There are many exceptions, as mentioned above. That is,
some elements that are rare can become essential to the organisms, if they are critical to the
functioning of the organisms.

Natural versus Anthropogenic Discharge of Elements into the Environment

Nature discharges a large quantity of a variety of the elements into the environment. The biosphere and
its in- habitants collectively and/or individually have managed to cope with the natural discharge of
elements. Otherwise the organisms would not have survived. Since mankind appeared, human activities
have interfered with the natural activities. We have collected, hunted, cultivated, and had the pastures
grazed by animals, and, as a result, ravaged our environments. Since the beginning of the civilization and
particularly since the industrial revolution we have been extracting the natural resources, utilizing them,
and discharging at least some portion of the utilized material into the environments, in such a way that
they might interfere with the activities of the nature.

Nature discharges elements through geological activities, weathering, and vulcanism. Their magnitude
has been estimated. It is more difficult to estimate the anthropogenic discharge level. One such estimate
has been made by Nriagu (7). The ratio of "the total discharge (natural and anthropogenic) over the
natural discharge" can then be computed. The ratio of "1.0" means no extraneous

anthropogenic discharge; i.e., it represents the background level. The ratio higher than "1.0" means
some extraneous discharge due to the mankind's activities and can be considered to be the "extra
burden" on the nature and the biosphere. The ratio or extra burden values are shown in Figure 1. The
figure suggests that we would have serious environmental problems not only with cadmium, lead, and
mercury, but also with tin, selenium, molybdenum, and, perhaps, copper, arsenic, chromium, and nickel.
Iron and zinc, though high in the ratio figure, may be tolerated better by the organisms, because they
are essential and used by organisms in substantial quantities and, as a result, the organisms have better
control mechanisms of the levels for these elements in their bodies.

The situation mentioned above is that of the average on the global scale. It is possible that the local
concentration of certain element; could be much higher than Figure 1 indicates. If so, the environmental
problem there could be much worse than the figure suggests.

Chemical and Physical Characteristics of Heavy Metal Cations

The ionic radii of some metal cations of interest are shown in Figure 2. The heavy metals are significantly
larger than the more common cations. An exception is Ca(II), whose size is similar to those of Cd(II),
Hg(II), and Pb(II). The variation in ionic radius among common transition metal cations is relatively small;
i.e., within 5- 10%.

Some metallic elements also can exist often in the oxyanion forms. Figure 3 shows the ionic radio of
more common oxyanions. The variation in size among them is even smaller than that among cations.
The variation among similar oxyanions is less than 5%. Another important character relevant to the the
biological behaviors would be the binding to ligands. A metal cation prefers a type of ligand over
another. Figure 4 shows the stability constants or solubility products for several interesting ligands. The
solubility product may not necessarily reflect the binding strength, but it has a lot to do with it. Pb(I1)
forms a very insoluble phosphate salt. The major contributor to this fact is the size of Pb(I1). Its large size
matches that of PO4> better than the other cations (radius-ratio effect).

It is apparent that Hg(II) has an inordinately strong affinity toward (S2-). The heavy metal cations Hg(II)
and Pb(II) are considered to be "soft": whereas. most of the transition metal divalent cations listed (Fig.
2-4) are considered to be on the borderline between the. "hard" and the "soft". A "soft" acid prefers to
bind to a softer base such as (S2-). Hg(II) is one of the softest cations. The soft metal can also form a
stable sigma-bonded organometallic compounds. Typical examples are Hg(CH3)2, Hg(CH3)+ and
Pb(C2H5)4, Pb(C2H5)3+.

Selectivity in the Uptake of Elements

The environmental problem due to the extra burden on the biosphere would not arise, if the organisms
have efficient means to cope with the intrusion of excess quantities of the elements. There are two
levels in the coping mechanisms. The first level of protection is to ingest or take up the elements
discriminately, so as not to take up unnecessary elements and or unnecessary quantities. The second
level of protection or defense is to render the adverse effects of the elements minimal when the
organisms have ingested them. Some mechanisms of the latter type will be discussed later. In this
section we will look at the selectivity in the uptake mechanisms of elements.

Metallic elements can be taken up either as a cation or as an oxyanion. Exceptions for this general rule
include the absorption of a metal-chelate as a whole, as in the case of Fe(III)-siderophore (see below).
Cell membranes are virtually impermeable to metallic cations and oxyanions. Up- take of an element, or
any substance for that matter, ultimately depends on its binding to a biomolecule (acceptor, carrier
protein etc.).

Cations and oxyanions are rather featureless. The only distinguishing factors that organisms can take
advantage of are:

(a) the electric charge,

b) the size,

c) the preferred ligands,

d) the preferable coordination structure

In contrast, organic compounds may be easier to distinguish, as they have distinct structures, including
the chirality.

Because the variation in size among oxyanions is relatively small, anions of the same geometrical
structure and of the same electric charge are difficult to distinguish. It can be inferred that the
physiological receptor-absorption site for the essential ((SO4)2-) may take up such ions as ((SeO4)2-) and
((MoO4)2-) (8) and also that the regular uptake mechanisms for (PO4)3-) could absorb ((VO4)3-) and
((AsO4)3-), too (9). If an absorption mechanism depends on a chemical reaction, rather than a mere
binding, a more effective discrimination may be accomplished. But no such mechanism is known except
for B02-, which can be bound to a carbohydrate moiety; then the ((BO)2-) sugar moiety is taken up.

The variation among typical divalent cations is not very large either. Thus, the selectivity in uptake
cannot be expected very high, if it is based on the size and the electric charge alone. In fact, not many
efficient systems have been developed in the organisms to discriminate many of the common divalent
cations through the size difference. This does not necessarily mean that ions of different sizes do not
behave differently. They do, but the difference may not be sufficiently large to be utilized for
discrimination in up- take.

It needs to be pointed out, however, that organisms do have a developed group of compounds that
discriminate cations such as Na(I), K(I), Ca(II), and Mg(II) according to size and electric charge. These
compounds called "ionophores" (10) have, in general, cyclic structures, which have holes that match
closely with the sizes of cations. Some organisms, fungi and bacteria, produce and secrete Fe(III) specific
chelating agents called "siderophores" (11). The entire chelates, rather than Fe(III) ion, are then taken
up by the organisms. There are also ion-specific channels that discriminate ions by their sizes. For
example, a Na(I) channel hardly allows K(I) ions to go through. These are exceptional and very selective
There are at least two different iron-uptake mechanisms in the human intestine. One of them absorbs
Fe(II) actively. It has been demonstrated that Co(II) or Mn(II) competes for this Fe(II)-absorption site
(12). The selectivity of this site is not very great, most likely because Co(II) and Mn(II) have sizes similar
to that of Fe(II), and thus can bind the Fe(II)-binding site, though with different affinities. That is, this
uptake mechanism cannot discriminate Fe(II) against Co(II) and Mn(II) very effectively. This situation
appears to be quite general as far as cation absorptions are concerned.

Cd(II), Hg(II), and Ph(II) could very likely enter a cell through the mechanisms to absorb the essential
cations such as Ca(II), because of their similarity in size and electric charge. These heavy metal cations,
however, may not be able to enter efficiently through the Fe(II) or other essential smaller cation-
absorption sites, for their sizes are sufficiently different.

Other factors, i.e., "preferred coordination structure" and "preferred coordinating ligand atom", may be
utilized to enhance selectivity in the cation binding. For example, the earlier transition metal ions prefer
"O-atom" over "N- atom" as the ligand, while the later transition metal ions tend to bind "N-atom''
ligands better, and the heavy metal cations bind with sulfur strongly. Unfortunately, these fac- tors are
rather subtle and have not been utilized fully by organims to enhance the selectivity. It might be pointed
out, though, that the strong affinity toward sulfhydryl groups is employed by a special protein,
metallothionein, to store or control the level of heavy metals including cadmium, mercury, copper, and
zinc (see below).

Another important factor is a kinetic one. A substitution inert ion such as Cr(III), once bound to a
biomolecule, cannot be displaced readily by another ion. This not only would lead to a high selectivity,
but also it hinders the subsequent reaction. which may require release of the ion from the biomolecule.
Substitution cations, Cr(III), Co(III) (in low-spin), Ru(II) and Rh(III) are not used widely in biological
systems. Exceptions, however, include low- spin Fe(II) complexes, vitamin B12 coenzyme (Co(III)), and,
perhaps, Cr(III) used to maintain a specific structure of DNA.

The selectivity in cation-uptake, thus, is not very great in general, as far as a single step-uptake is
concerned. The cation uptake in single-celled organisms, therefore, may not be very discriminatory. The
selectivity can be improved in multicellular organisms. because a metal ion must go through several
barriers before it reaches a target cell. Suppose that two metal ions M1 and M2 compete for the same
binding site at each step, and that the discrimination factor (K1/K2) is 10-to-one at each step and that
there are three barriers to go through. Then the overall discrimination factor would have become 1000-
to-one at the target cells.

A step or two in the process, however, often utilizes factors other than thermodynamic ones. For
example, a chemical reaction may be used, which enhances the selectivity enormously. For example,
Fe(II) and Co(II) can be absorbed by an active transport mechanism in the intestine. When they come
out to the portal vein side, they need to be oxidized in order to be bound to the transport protein,
transferrin. This process is catalyzed by a copper-enzyme, ferroxidase; Co(II) cannot be oxidized to Co(III)
and hence, cannot be bound to transferrin. Thus, at this stage, the cobalt would be left behind and
would not be carried to the bone marrow or the liver. Therefore, the overall iron selectivity over cobalt
would be enhanced greatly. There is a very specific mechanism for the transport of cobalt-containing
vitamin B12 (cobalamins).
The discussion above apply to the cases of metallic ions (aquo species). Some elements, particularly the
heavy metals. can readily form stable organometallic compounds. For example, mercury can form
dimethyl mercury or monomethyl mercury, (CH3)2Hg or CH3Hg(OOCCH3). These compounds can go
through cell membranes more readily than divalent aquo-cations, because of their affinity to the
membrane. Such a compound can be taken up almost indiscriminately.

Toxicities of Heavy Metals

The symptoms of the toxic effects of heavy metals may vary widely at the physiological level, but the
basic toxicity mechanisms at the molecular level may be limited. The toxicities of heavy metals may be
caused by the following mechanisms:

1. Blocking the essential functional groups of biomolecules such as enzymes: Specific amino acid
residues, such as serine-OH, cysteine-SH and histidine-N often constitute the active sites of
enzymes. Hg(II), for example, binds strongly cysteine-SH's, blocking an enzymatic activity.
2. Displacing essential metal ions from biomolecules: A metal ion may displace a native ion. if its
affinity to the binding site is stronger than that of the native one. Often a biomolecule with a
foreing metal ion loses its activity.
3. Modifying the active conformation of biomolecules: especially enzymes and perhaps
polynucleotides: A coordination of a cation may change the conformation of a protein ,
rendering it non-functional.
4. Disrupting the integrity of biomembranes: A metal cation may bind the negatively-charged
head(s) of phospholipids and the integral protein residues of the membrane.
5. Modifying some other biologically active agents: For ex- ample Cd(II) and Pb(II) appear to
potentiate the endotoxins produced by bacteria (13). This might be due to their effect. to block
some enzymes which degrade the endotoxin, as in (1).
6. Binding with bioanions, resulting in a decreased level of essential bioanions, especially ((PO4)3-)
or a displacement of an essential from biominerals: For example, P(II), having a size similar to
that of Ca(II), could replace Ca(II) in a bone mineral. AS a result, the mechanical strength of the
hone may be affected. The size and the electric charge would be an important factor in these
effects. One of the basic toxic effects of Pb( II), is considered to binding of ((PO4)3-), rendering
its cytoplasmic level very low.

These toxicity mechanisms are all based on the strong binding abilities of these metallic ions. And a s in
the case of selectivity in uptake mechanism, substitution of a me-tallic ion by another is relatively
simple. This is so except for substitution-inert metals. In practice, however, any metal cation bound to a
large, somewhat rigid hiomolecule is kinetically difficult to displace, though not necessarily substitution-
inert. This does not necessarily apply to the cases of proteins of a rather flexible conformation, as in the
case of metallothionein discussed later on. What happens

often is that a replacement takes place an k i n hinds a cation. A wrong cation can he
incorporated in this stem.,if .vresent there.
Cd(I1) and Hg(II), for example, can replace the native Zn(I1) ion from many proteins and enzymes to a degree
that depends on their affinities. Cu(I), M I ) and Au(I) also have similar characters to Zn(II1, Cd(II), and Hg(I1) be-
cause of their iso-electronicity. I t would he needless to point out that other cations such a s Cu(II), Ni(II), etc. also
may displace a native cation such a s Zn(I1) from enzymes and proteins. For example, the carcinogenicity of Ni(I1)
is considered to he due to its replacement of Zn(I1) and/or
Me(I1)".. the essential cations in DNA oolvmerase. Because

., "

of its different size, Ni(I1) seems to increase the chance of binding wrong nucleotides, thus resulting in the
formation of DNA of a wrong sequence (15).

Many symptons of Cd(II) toxicity are believed to arise from the displacement of Zn(II) by Cd(I1). An
example is the testicular necrosis by Cd(I1). Testes produce sperms. Hence, the DNA polymerase activity
is quite high. DNA polymerase is a Zn(I1) enzyme, whose activity can be jeop-ardized by substitution by
Cd(I1). (See ref. (14) for a list of enzymes affected by Cd(I1)).

H d I I ) shows a n enormous affinity toward sulfide a s seenrn Figure 4. Because the cystei&c sulfhydryl
group play a rntulytic role in a number of mzymvs, their eruy-matic actlvltles are susceptihlr to IlgrII,. Or
the binding of Hg\Il, to amino acid residurs can change a protein contbr-mation sufficiently to render it
inactive. Kxamples of en-zvmes suscc:ptible to Hg 11, include NR/K-A'~I'as(: (the 50-called s o d i i m
pump); alkaline phosphatase, lactate dehydrogenase, and glucose-6-phosphatase (14).

Ph(I1) also inhibits a variety of enzymes. However, the most interesting is its inactivating effects on
the enzymes involved in the heme synthesis (16). Particularly impor-tant are ALA dehydratase (ALA-
D) and ferrochelatase (FC). [ALA= baminolewlinic acid]. ALA-D, also called "porphohilinogen
synthase", is a pivotal enzyme in the heme synthesis, and FC catalyzes the insertion of Fe(I1) into
protoporpyrin. The inhibition of ALA-D results in a n increased level of ALA in urine, which is
considered to be a sensitive measure of lead poisoning. The level of the non-fuctioning metal-free or
Zn(I1)-porphyrin will increase when FC is inhibited. I t also has been reported that the glohin protein
synthesis is affected by lead (17).

The toxicities of h e a w metals have been reviewed ex-tensively in references 14 and 18.

Biological Defenses against Heavy Metals

When confronted with the toxic effects of heavv metals. the organisms had had to develop some means
to defend themselves against them, As mentioned earlier, not all or-ganisms have encountered all the
heavy metals equally.

The that were the metals did have developed mechanisms to combat them. 0 t h organ-

isms mav not have had enoueh.. deal with the heavy metal.;, and thus have only relatively

mtt:tns to cornhat them. The extraneous anthro~ogen~cdls-charge of the heavy metals into the
environment a s out-

lined above thus poses a serious problem. We will briefly

explore some of the biological defense mechanims against heavy metals. m i s is not meant to be an
exhaustive sur-vey, but i t is given to illustrate some chemical p,.inciples behind the biological defense
General Tolerance

Most elements seem to he tolerated by organisms to cer-tain limited degrees. The degree of tolerance is highly de-
pendent on the organisms, their life stages, a s well as on the elements. This is rather non-specific. Metal ions are
to be confined to locales that have little influence on the gen-era1 biological activities. Such places include cell
wall, some noncritical portions of the cell membranes, vacuoles, lysosomes (191, hard tissues such as bone, and
extra body tissues such a s hark and hair. As long as the metallic ions are confined in these non-critical places, they
may not ex-hibit their toxic effects. Obviously the extent of tolerance by these means is limited and highly
dependent on the structures of the organsims. The toxic symptoms will manifest when a metal ion level exceeds a
certain thresh-old level, unless other more specific defense mechanisms are available.

secretion of mucus Material

This is found especially in fish. Mucus consists of anionic polysaccharides, such as chondroitin sulfate,
ascophyllan and fucoidan. These contain carhoxylate and/or sulfate groups, and they bind cations, It has
been that fish killed by a high level of Pb(I1) or Zn(I1) were found to have high levels of mucus around
their gills (20). It has been suggested that mucus may function as a defense mechanism against cations.


Metallothioneins (MT) are low molecular weight (6- 7000), cysteine-rich proteins that bind metals such
as Zn(II), Cd(II), and Hg(II) (23). MT and its analogues are widely distributed among organisms, from
bacteria and fungi to plants and mammals. A typical mammalian (Zn, Cd) MT is folded into two domains
that form separate polynuclear metal cysteine thiolate clusters; Cd4-Cys11 cluster in the C-terminal
domain and Zn3-Cys9 cluster in the N-terminal domain. This structure has been determined by X-ray
crystallography (21). and appears to be common to most MTS which bind seven metallic ions. Metallic
ions that form M7-MT include Co(II). Ni(II). Hg(II). Pb(II), and Bi(III) in addition to Zn(II) and Cd(II)(22):
Ag(I) and Cu(I) can displace Zn(II) or Cd(II) from a MT and bind in the form of M12-MT (22). Hg(II) then
displaces 12 Ag(I) or Cu(I) ions and form Hg7-MT (22).

It has been demonstrated that synthesis of MT can be induced by Cd(II), Zn(II), Hg(II), and Ag(I) (23). This
fact indicates, as suggested hy many researchers, that MT could function as a protective means against
toxic elements such as Cd(II), Hg(II), and Ag(I). Zn(II) is an essential element (3). and MT also is involved
in the control of Zn-metabolism. The chemical basis of these functions is obviously the strong affinity of
these ions toward thiolate. Toxic metals, thus, bound to MT cannot exhibit their adverse effects.
However, lowering pH of the medium or other yet-to-be-identified mechanisms can release the metal
ions from MT, and hence, MT may control their cytosolic levels, and also may function as a temporary
storage for certain elements such as Zn(II).
The metabolism of MT is not very well understood. How- ever, it has been reported that Cd-MT is
degraded rapidly in kidney cells, releasing Cd(II), which is considered to be the cause of the proximal
tubular damage (24). The situation in liver seems to be different. For example. the presence of MT
decreases significantly the release of metals (Cu and Zn) into bile. suggesting that the metals remain
chelated to MT.

Metallothioneinlike Compounds

The descriptions above apply to the mammalian type of MTs. Other organisms produce MT-like proteins
that are not exactlv the same as the mammalian MT. For example. a yeast copperthionein can be
induced by Cu(II), but not by Zn(II) or Hg(II). It is distinct from the mammalian MT. but the 12 cysteine
residues are conserved. The protein protects cells against copper poisoning. but is apparently
dispensable for normal cellular growth (25).

Many authors had reported that Pb(I1) did not induce MT, but Ikebuchi et 1986 reported that a MT-
like protein containing Pb(II) was induced along with a Zn(II)- MT in the rat liver when lead acetate was
administered (26). It appeared to be very similar to the Zn-MT(II), but distinct in electrophoresis. It still is
not clear whether the Pb-MT was induced by Pb(II) rather than Zn(II) which may have contaminated the
lead acetate sample, though its zinc content was reported to be less than 0.05%. The importance of a
MT-like rote in in detoxifying Pb(I1) has not been well established, though Pb(II), does bind to a
preformed MT as mentioned above Pb(II), may not induce the synthesis of MT, not because it cannot
bind to MT or a fac- tor to induce its synthesis, but rather because Pb(II) may be trapped by phosphate
entities present in vivo before it reaches the MT synthetic apparatus.

Cadmium-resistant Pseudomonas putida produces three Cd(II),-binding proteins: 3815,7216, and 7239 in
molecular weight (27).They contain six to eight cysteine residues and bind cadmium, zinc, and copper.
Coordinating ligands seem to be cysteine residues,histidine nitrogen, and, perhaps, glutamate

Suspension cultures of Rauvolfia serpentina (a higher plant) produced heavy-metal complexing peptides
when grown in a medium containing (CdSO4) (28). The peptides were identified to be (y-glutamate-
cysteine)n,glycine (n=2 to 11). The composition suggests that the peptides are the derivatives of
glutathione. The peptides, called "phytochelatins". were shown to be induced also by Cu(II). Hg(II).
Pb(II), and Zn(II). The induction of the peptides bi Cd(II) also was observed in cell cultures of other plants
including - Bereris stolonifera, Fumaria palviflora, and Galium mollugo.

Sulfide and Selenide

One copper-detoxifying mechanim found in many fungal species is the excessive production of HzS. For
example, certain strains of yeast acquire a brown color when cul- tured in the presence of copper, due
to the formation of in- soluble and hence inactive CuS/Cu2S (29). Microscopic studies have shown that
the copper sulfides were located mainly in and around the cell wall. An antagonism between selenium
and heavy metals has long been known. For example, selenite has a protective property against Cd-
toxicity in testis necrosis, has been shown to inhibit Cd-induced destruction of nonovulating ovaries and
placenta, and has protected against the terato- genic effects of cadmium (30). It is interesting to note
that the retention of Cd by tissues actually is increased in the presence of selenium. A similar effect has
been observed in regard to selenium versus mercury (30). Tuna and bonito tend to accumulate mercury
to a high level: yet the fish themselves are healthy. The tuna was found to contain also a high level of
selenium, and the Hg/Se mole ratio was close to one-to-one (31). Subsequently. a linear relationship
also was reported for Hg versus se contents in seals and other marine mammals (32) as well as mercury-
mine workers (33).

Lead Inclusion Body

A dense granular structure (lead inclusion body=LIB) was first discovered in the nuclei of renal tubular
lining cells and hepatic cells of children dying of acute lead poisoning (34). LIB is observed at smaller lead
dosages, even before an increased excretion of ALA ensues (see above). Similar inclusion bodies have
since been reported in other animals (34) and also a moss (35). The LIB isolated from the kidneys of
poisoned rats contained an average of 57 mm (fresh basis) of lead. The whole kidneys of the poisoned
rats contained 0.8 ppm, while the level of Pb in A the control kidneys was 0.009 mm. The LIB consists of
a dense central core and an outer fibrillar zone . The protein of the LIB has a high content of aspartic
acid, glutamic acid, glycine, cysteine, and tryptophan. The lead in LIB can be removed readily in vitro by
EDTA. It has been suggested that the formation of LIB serves as a protective mechanism against lead
poisoning (34).

Conversion to Readily Excretable Forms

A single-celled organism is small in size, and hence, if a chemical entity can be changed to a volatile
form, it can readily diffuse out of the cell. Hg(II) can be converted into Hg(0) (36) or (CH3)2Hg (37) in
some bacteria. Both of these forms of mercury are much less toxic than Hg(II) or CH3Hg (+), as well as
they have significant vapor pressures. Methylcobalamin has been demonstrated to effect the
methylation of Sn(II y IV) and Pb(II y IV) as well as Hg(II)(37). Methylation of arsenic compounds to
(CH3)4As(+) ( very likely through S- adenosylmethionine) may serve as a defense mechanism , as
(CH3)4AS(+) is readily excretable through the kidneys(9).

Concluding Remarks

It has been shown that the toxic effects of and the bio- logical defenses against heavy metals can be
understood basically in terms of the fundamental chemical principles and the basic properties of these
elements. It also has been armed that the toxicities of rare elements are caused partially by the fact that
the organisms rarely have encountered and, thus, have not developed effective means to combat with