D. E. Carter and Quintus Fernando University of Arizona Tucson, AZ 85721
Evolutionarv- nrocesses have selected certain elements. . known as essential elements, to perform one or more physioloeical functions and have reiected the other elements. Of the twenty six elements that are Eonsidered to be essential for life, the eleven elements, H, C, N, 0 , Na, Mg, S, C1, K, Ca, and P are major elements and the remaining fifteen, B, F, Si, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Se, Mu, Sn, and I are trace elements. Boron is essential for plant life, and recently the trace elements F, Si, V, Ni, and Sn have been shown to be essential or a t least heneficial when included in the diets of lahoratorv. animals. I t is possible that some of these trace elements m& prove to be essential or beneficial to man. In addition to the essential elements, there are about thirty elements that are found in low concentrations in living systems. These are the inert elements for which no essential physiological functions have been found, and their presence in the living organisms is probably caused by contact with the environment. The toxicitv of the elements roughlv their abun- . varallels dance in the earth's crust and in sea water. Elements that are present in low concentrations in nature are normally toxic. The metals Ph, Cd, and Hg are not very abundant in nature and have prominent toxic properties. The concentration of Ph is less than 10 nnm in the earth's crust and less than 0.03 pph in sea water; tieconcentrations of Cd and Hg are less than 0.2 oom in the earth's crust and less than 0.1 . nnb . in sea water ~~~
~~~~~~
~
~
~~
~~~
~
~
Chemical Toxicology Part 11. Metal Toxicity
~
b
B
w
A/
I
C
D
Concentratron ol Essentlal Trace Metal
F
*
Figure 1. Illushationof the effect of the concentrationof a trace metal on gmwm Concentration: A, no growth; C, maximum biaiogical activity: D.toxicity: F. lethality.
~~
(3oj.'
The known essential trace metals in man are arouved together from vanadium through zinc in the first transition series in the periodic table. Molybdenum and selenium should be included in this group of essential metals although selenium is a non-metal rather than a metal. The concentrations of the essential metals as well as many of the inert metals in the human body are maintained at levels that are approximately constant by homeostatic mechanisms (Fig. 1). The concentration of the essential trace metal has to be Rreater than the value a t A for any effect, such as growth, to b e manifest. At concentrations less than C, there is a deficiency of theessential trace metal and toxic symptoms may become evident. The measured effect shows a continuous increase with concentration until the plateau RE is reached. It is at this plateau that the homeostatic mechanism operates fully. When the
e km 3
D. E. Carter, Associate Professor of Toxicology, has a joint appointmentin the Department of Pharmacology, College of Medicine, University of Arizona. He is also the Associate Director of the Toxicology Program. His research interests are primarily in the areas of pharmacokinetics and metabolism of drugs and taxins.
Quintus Fernando. Professor of Chemistry, has a joint appointment as Professor of Toxicology and Forensic Sciences in theToxicology Program at the .e'~ University of Arizona. His main research < interests are in the general area of metal complexation and trace metal analysis. 490 1 Journal of Chemical Education
I Concenlratlon ol Trace Metal I with No Known I I Blolog#cal~unctmn+ Figure 2. Illustration of the effect of the concentration of a trace metal with no known biological function A , Very toxic metals (Cd, Hg. Pb); 8,mcderately toxic metals (As, Sb): and C. slightly toxic metals (All.
concentration of the essential trace metal is increased from C to D, there is no increase in the measured effect and the excess metal is excreted. If the metal concentration is increased beyond D, the metal becomes toxic as shown by a decrease in the measured effect, and a t the concentration F where there is a vertical drop in the effect, the concentration of the metal has reached its lethal value. The curve, which is applicable to all living things, is quite wide for mammals but .very narrow for certain bacteria and marine organisms (31, 32). I t is evident, therefore, that exposures to low levels of essential metals will not result in toxicity because there is no accumulation of these metals with age: On the other hand, exposure to very low levels of Cd, Hg, Pb, Sh, and Sn may have a cumulative effect and the human body burdens of these elements that have no apparent biological function will increase since there are no homeostatic mechanisms that can operate to regulate the levels of these toxic metals (Fig. 2). More than half the elements in the periodic table are metals that have some degree of economic importance and are processed industrially in quantities varying from many millions of tons to a few ounces per year. The use of metals in modern
The toxicity of the elementsroughly parallels theirabundance in the earth's crust andin sea water. Elements that are present in low concentrations in nature are normally toxic.
technology will continue to increase and, as a consequence, their concentrations in the environment will also increase. In the course of industrial activity, metals are released into the environment in several forms: water soluble species or insoluble precipitates that contaminate the rivers and lakes, metal-containing particulates and volatile metal compounds that contaminate the atmosphere. The total population is exposed to varying levels of these metal-containing contaminants. Industrial workers are e x ~ o s e dto metal fumes. metal oxide particulates, and volatile metal compounds on a daily hasis a t much higher levels than the urban population which is exposed to lower levels of toxic metal compounds, hut on a continuing basis. Common methods of entry of these toxic metals into the human system is by inhalation or ingestion. Entry of toxic metal compounds into the hody via skin exposure is relatively commonplace for workers in many typei of industry. From the results that have been accumulated over many years, a list of "safe or acceptable" levels of occupational exposure to toxic metals has been published in the Federal Register (33). . . These levels are assumed to he safe for exDosures ofeight hours duration that a worker may he s ~ ~ l ~ j e c t r d T O everv wmkinr dav. compuunds - The volatile orrtanom~~t;tllic are much more toxic than the relatively nonvolatile inorganic compounds or the metal itself, and quite often the route of entry of volatile compounds is via the skin in addition to the more obvious route of entry via the lung. It is difficult to assess the effects of continuous rather than intermittent exposure to metals or metal compounds that are present in the environment a t lower levels than the "safe or acceptable" levels published in the Federal Register (33). After much debate the standard for airborne lead has been finally set by the Environmental Protection Agency a t a quarterly average of 1.5 pg/m3. Careful, long-term epidemiological studies can help elucidate the health hazards that are associated with exposure to mercury from the combustion of coal, or lead halides that are produced in automobile exhaust gases. It is unfortunate that the results of many epidemiological studies cannot he interpreted unequivocally. Evidence from such studies has indicated that industrial workers who are exposed to arsenic have a high incidence of skin cancer and cancer of the respiratory tract. This conclusion could not be substantiated by the results that were obtained with experimental animals (34). Metals are not biodegradable; the non-essential metals react to varying extents and tend to concentrate in the hody thus increasing the total body burden. Exposures to extremely low levels of environmental metal contaminants over long periods can, therefore, cause subtle health effects, which in some instances mimic chronic diseases. Little is known ahout this form of metal toxicity and the adverse health effects that are caused are almost impossible to predict (31).
-
The Essential Trace Metals All the trace metals that are considered to be essential belong to the first transition series, except selenium and mo-
lybdenum. There are some indications that vanadiurn is ail essential element in certain biological systems (Xi, 36). Chromium (111) is essential for glucose and lipid metabulisni (37). Manganese (11) is a cofactor in a number ot'enrymntic reactions. Althowh enzvmes such as cvtochrume and xiu~thine essential for the nrevention oianernia. Nickel~,(1l)~huwt:vcr. , , ~~. ~ is probably an essential element for mam~nals,but no bio logical function has been demonstrated for this metal. Cupper and zinc are both essential metals and play an important rule in enzyme activity. Copper is required by oxidative enzymes such ascatalaseand peroxidase and zinc is a constituent ut'a variety of enzymes including carbonic anhydrase, car bury^ peptidase, and alkaline phosphatase. Molybdenum is an cssential element that is widely distributed in nature and may he found in a number of oxidation states. It is a cofactor hir xanthine oxidase and aldehyde oxidase. 'The biochemical rulc of selenium is not well understood although it is considered to he an essential element. The normal levels of all the essential elements in the humnu body are maintained by homeostatic mechanisms. 'The esti mated dailv intake of these elements via food or d r i ~ ~ k i n e water togeiher with their human body burdens are given i;; the table (38). The toxic action of most of these elements is. therefore,largely confined to the respiratory tract as a result of chronic or acute occupational exposures, unless, of course. a large quantity of one of the compounds of these elrmenta is ingested accidentally. ~
~
~
Vanadium and Chromium Vanadium exists in a number of oxidation states the cutltmonest of which are the +I11 and +V states. It is uhiquitouj in nature and is found in many foods, particularly fats and oils. When any vanadium-containing compounds are ingested, they are absorbed only moderately; the total body burden is maintained a t an approximately constant value by home+ stasis, the principal route of excretion being via the kidney. Onlv a small nercentaee. - . however. of anv inhaled vanadium compound is kxcreted in the urine', and ;here fore, vanadium compounds tend to accumulate in the lune. 'The occurrence of h k c h i t i s and hronchopneulnurlia is inure frequent in workers who have been exposed to dusts cuntaining vauadium pentoxide. Vanadium occurs widely in fuel oil especially ii it is of South American origin. The con~hustionof fuel oil in power plants and other industrial operations releases v a n a ~ dium oxides into the atmosphere and can cause an environmental hazard. The seriousness of this hazard may be gauged from the following observatiuns: vanadium pentoxide is recovered from flue dusts; urban air contains 0.05 fig V/m3 (39); vanadium may exert a synergistic effect un cadmium in causing heart disease (40). The essential role of chromium, unlike that of vanadium, has been established. Although all the oxidation states 01' chromium between +I1 and +VI are known, the stable uxi-
Estimated Daily Intake and Human Body Burden of the Essential Trace Elements
--
Element Va
Daily intake (mg) Human body burden (mg170 kg: Probably an
2.5 30
Cr
0.06
