in the Chemical Laboratory Edifed b y NORMAN V. STEERE,
140 Melbourne Ave., S.E. Minneopolis. Minn., 55414
XLIII. Mode of Action of Toxic Substances HERBERT E. STOKINGER, Ph.D. Occupofionol Health Rereorch and Troining Facility, Cincinnati, Ohio
Toxic substances exert their elkcts by physical, or by chemical or physiologic (enzymatic) means, or by a comhirmtiun of both. The classification as presented here of the toxie mechanisms in the mammalian host has no precedent or any accepted basis other than that it appeals to be inclusive, reasonable, and pract,icable. The classiiication has been developed to delineate two basic actions: the action of the toxicsubstance on the host, and the action of the host a n the toxic wbstitnce. For it is the interplay of these two aclions, together with the rate a t which t,he body excretes the toxic substance, t,hat determines what is called the toxicit,y of a snbstance. The full toxic potential of mosl. s i b stances is not usually asserted because of destructive actions by the body and its mechanisms of elimination by urine, sweat, feces, and exhalations, or because of sequestration in inactive forms at. certain tissue sites such as hone, skin, hair, and nails. If this were not so, synergistic or enhanced toxicities would never be manifest. Synergistic or enhanced toxicities arise from the development of n m ~ s or d enhanced concentrations of the toxic substance. This occurs when one or more of the usual means of elimination or redoct,ion of the toxie substance are blocked. The following elassiiierttion of toxic mechanisms must necessarily be based on prevailing knowledge, which varies greatly from discipline to discipline. I n enzymology, for example, the stat,e of knowledge is a t the molecular and in some instances, a t the submolecular level. Such a situation obviously permits more exact definition of the governing mechanisms than is afforded by a discipline in which knowledge is st 8. cellular or organ level. Thus, a mechanism regarded a t present as physical might be later labeled chemical or enzymatic to reflect the a c q ~ k i t i o nof new knowledge a t a more int,imnte level. Indeed, when all mechanisms can be explained a t the submolecular level, an entirely different classification will result,. It is hoped that the present classification, believed appropriate within the limit,s of present knowledge, may not only provide greater insight into how chemicals act in the body but also point to possibly um suspected relationships among t,he actions of diverse ohemicals.
Physical Modes of Action Harmful aubstanrss that have a solvent or emulsifying action can produce aft,er prolonged or repented eon1,aeta dry, scaly, and fissured dermatitis. This effect is commonly attribnlod to tbe physical removal of surface lipid, hnt may also be caused by denaturst,ion of the keratin or injury t,o the water bart.ier layer of the skin. Acidic or alkaline solnble gases, vapors, and liquids, may dissolve in the aqueous protective film of the eye and m i ~ o u membrsnes s of the nose and throat,, and in sweat,, cansing irrit,ation a t these sites. hloreover, sueh insults may erode teeth and produce changes in hair structure. On the inner srwfl~cesof t,hc hudy-lhe lungs and gxstroint,est,inaltract-physical eonlael of unphysiologic xmonnts of substances causes irritation. This may lead to inflammation or produce contraction, sa in the reflex constriction of the respirat,ory vassapes . . upon inhalation of an irritant pas wi1.h resufiant coughing, choking, or i s phyxiation. I n the upper gastrointest,inal tract. the effect mev include vomitine and further down in the tract the irritation may result in peristalfiis and defecation. Inert gases can exert serious and often fatal effects simply by physical displaeement of oxygen, leading t,o asphyxia. Under presswe, inert gases snch as nitrogen can produce compressed sir illness by dissolving in unphysiologic amounts in the blood, lymph, and intereellulnr spaces, or may ntptore delicate membranes such as the enrdnm. Suddeu decrease in pressure will result in decompression siokness. Less inert gases such as carhon dioxide and oxygen under greater thsu atmospheric pressure can lead to rrarrosis and olher more serious efioct,~,such as nerve and brain damage. Physical adsosptiun of gases or vapors on solid or liquid pwrl.iculstes (aerosols), may, upon inhitlabion. lead to physiologic etkcts out of pmportion to that antioip x k d from their inhaled concentration prior to adsorption. The action is kmwn as synergism when the effect of gas and particulate exweds the sum of the elreeta expected from either alone, or antagonism when (,he erect is less than expected. A physical theo1.y has been developed to explain these abnormal aotians. It is based on molecular properties
feature
of gases xrrd araolmts for the synergism by posl~dnting"adsorbed" layers of the gas O N the particulate that, upon inhalation, r a n y to t,he sensitive lung tissue e n o c m
