D. E. Carter and Quintus Fernando

I Chemical Toxicology University of Arizona

Tucson. 85721 I Part I. Organic Compounds

There are a multitude of degrees of toxicity that range from mild irritation to death, all of which may be based on specific adverse reactions to chemicals.

I t is unfortunate that manv chemists are not familiar with the toxicity of common compounds that are used in the lab- oratorv. In the earlv nineteenth centurv newlv svnthesized - . compounds were tested by tasting the compound; since then chemists have made considerable progress in their apprecia- tion and understanding of chemical to;icology. Our objective in this article is to bring to the attention of chemists the tox- icological properties ofseveral important classes of organic and inorganic compounds. Even though the mechanisms of toxicity of the majority of compounds are not known and will probably not he determined for many years to come, the ex- perimental methodology and the probable mechanisms of toxic action that will he described should provide an increased awareness of the problems in chemical toxicology.

General Prlnclples

There are a multitude of degrees of toxicity that range from mild irritation to death, all of which may he based on specific adverse reactions to chemicals. Descriptions may include undesirable nhvsioloeical effects such as central nervous . . " system depression accompanied hy drowziness, confusion, and stunor. I t mav include descri~tions of specific orean damaee such as 1ive;cell death resilting in a chemically induced henatitis. The extent of eve or skin irritation as well as the extent of sensitization that results in an allergic reaction are additional indices of toxicity. Descriptions of toxicity may also include the ability of a chemical compound to cause damage to a fetus via the mother who has been exposed to the com- pound (teratogenesis), ahility to alter the inherited genetic material in spermatozoa and ova (mutagenesis), ahility to cause cancer (carcinogenesis), or damage t o the nervous sys- tem (neurotoxicity). The most commonly measured toxic re-

D. E. Carter, Associate Professor of Toxicology, has a joint appomtment in the Department of Pharmacology, College of Medicine, University of Arizona. He is also the Associate Director of the Toxi- cology Program. His research interests are primarily in the areas of pharmacokinet-

of drugs and toxins.

Quintus Fernando, Professor of CII. mo.lr\., h a - .? I 11111 appuintmtwl as I ' r ~ , t t - . ~ ~ r 01 ' I .,a~<s.l<.g> nnd Furensic 5, ikws t n ~ h d ~ x i < ~ h x ~ I'rarmn at the -. .. . . Universitv of Arizona. His main research . The Cover: James Gillray rendered this drawing in 1801. He titled

it, "Regone dull Care, I prithee hegone from Me!"The verse is wifered with apologies to Lord Bymn.

Some Guidelines on Toxicity

Chemical reaetivitv cannot be used as a euide to toxicity. Many chemicals are not directly toxic to cells but are activated by conversion in the body to reactive compounds such as free radicals, arene oxides, etc. . Structurally related chemicals may have widely different toxicities that result from differences in theability of the body to clear them from the circulation. . The most important single factor in toxicity is dose: alarge dose of a moderately toxic compound may he more dangerous than a small dose of a hiehlv toxic comoound.

larlv cffrrtlse in penetrating tlwsk~n. Theahility of chemicals to produce lissuc irritation or to induce cmritization rerulting in allergic rcaclions should be considered when designing student experiments. Sen- sitization can result in strong allergic reactions after repeated exposure tu minute quantities of the chemicals and these last for the lifetime of the individual. Some materials can readily cross the placental barrier and affect an unborn child without warning to the mother. Since very few chemical compounds have been tested for this form of toxicity, pregnant women should avoid exposure to labo- ratory chemicals. The chemistry teacher should learn about the toxicity of chemical compounds from standard texts; however, it must be recognized that there is a general lack of knowledge about chemical toxicity and care should he taken to minimize ex- posure.

sponse is the death of 50% of a population within 14 days of a single exposure (LDw); tables of these values can be found in the Toxic Substances List ( I ) .

Toxic responses are normally measured in laboratory ani- mals under carefully controlled conditions or in humans after exoosure. either hv studvine cases of accidental hieh acute . " exposure or by applying epidemiological techniques to isolate the effects caused hv exposure to s~eci f ic materials. Human data lacks experim&tai control and interpretation may he com~licated hv other factors; thus, we relv on animal experi- men&. The re&s of these experiments depend on a number of factors. Of prime importance in toxicity is the total dose, normally expressed as the amount of chemical compound administered per unit hody weight of the test species (for example, mg of compoundlkg hody weight). Also important are the frequency of dosing and the route of dosing-oral, intravenous injection, inhalation, or absorption through the skin. The same total dose given in divided amounts a t dif- ferent time intervals and by different routes can result in widely different intensities of response. The primary routes of exposure to chemicals in laboratory situations are ingestion, inhalation, and skin penetration. Using care, accidental in-

284 1 Journal of Chemical Education

gestion can be prevented, however, inhalation exposure occurs with volatile compounds and organic molecules are readily absorbed into the bloodstream throueh the lunes. Ahsomtion through the skin can be substantial ad the rate'bf penetiation is related directlv to lioid solubilitv and is related inverselv to molecular weight (i). The concentration of the admini;. tered compound in the bodv must attain a minimum level. called the threshuld level, before a toxic response can occur: When this lrvel is exceeded, a greater response in the exposed ~~(~pula t ion is achieved; this increase in dose with a concomi- tant increase in response is continued until all the animals testcd are responding. Theability r o reach rhe threshold level depends on the rate at which the annpound is absurhed into t h ~ hlog~d. the rate at whirh it is metabolized or altend hv the body to firm different chemical compounds and the ra"te a t which the comoound is eliminated throueh excreta (urine. feces, exhaled air, and sweat). ~ e t a b o l i s m occurs i n a n at: tempt by the body to increase the urinary excretion by in- creasing water solubility of the foreign molecule. For example, an organic molecule is oxidized, very often, to form hydroxy derivatives. This process may be followed by conjugation of these derivatives with polar endogenous materials such as elucuronic acid. sulfate. or amino acids. and results in a sie- ~" nifirnnt incrrase in water soluhility.

Transfer of the results ohtlined with exoerimental animals to humans is difficult because there are differences in ab- sorwtion, distribution. excretion. and metabolism between man and the test animals in addition to anatomical and physiological differences. Human limits of exposures to var- ious compounds are reached by making the best estimates of the effects of such differences, applying a safety factor and - - ~ - obtaining an exposure limit.

The toxicity of a chemical compound cannot always he adequately from its normal chemical reactivity because the body, in its attempt to metabolize the molecule to a more water soluble substance. mav svnthesize a hiehlv . " . - <

reactive material that is the ultimate toxic agent. This "bio- activation" is an area of intense investigation. If the hiehlv reactive species or activated species binds to DNA, it may cause a mutation and chemical carcinoaenesis mav be the result (3); if the activated species binds to essentiaicellular protein, cell death may occur (4.5). Manv agents may act more specifically and cauBe cell death by -converting lipids in membranes to peroxides and eventually destroying the membrane structure (6).

The toxicity of some selected materials from the general classes of oreanic and inoreanic comoounds will be described ~ ~ ~

and will ser;e as exampleiof groups of compounds that are potentially toxic. It must be kept in mind that these examples probably represent the best studied systems and that few chemicals have been studied extensivelv. Related chemical compounds may he more or less toxic haied on differences in metabolism and rate of clearance from the circulation al- though the structural features controlling these effects are still largely unknown.

Aliphatic Hydrocarbons Aliphatic hydrocarhons, when inhaled, cause central ner-

wus svslrm (CNSI de~ression resultinr in dizziness and in- coordkation. Aside frbm the CNS depression, any toxicity from gasoline and kerosene is probahlv due to aromatic hv- drocarhoo constitutents, which will bediscussed in the nekt section. The CNS depressant effects are general phenomena for all organic solvents that are sufficiently volatile and that are sufficiently lipophilic to pass into the brain. This de- pression is the same phenomenon that leads to anesthesia in high enough concentrations. I t will not be described in suh- sequent sections when describing toxicity of other materials, but CNS depression should be recognized as a general toxic property for all volatile organic solvents.

Since liquid hydrocarbons are fat solvents, excess skin ex- posure will remove its fat and result in dryness, scaling, and inflammation of the skin. Ingestion can lead to death from

pneumonia when it is induced chemically from the aspiration of the hydrocarbon into thelungs during vomiting (7).

An interesting exception to this general aliphatic hydro- carbon toxicity is hexane, which at high doses in rats and cats, causes neuroloeical chanees in the neri~heral nerves (those . . operating the arms, legs, etc.).'l'he nerves appear to "die hack" from the periphvry towards the spinal conl. These effects have been attributed to a mctat~dite oi hexane, 2,5-hexanedime. When this m~taholite (200 malkrlday~ was inierted intra- - - . peritoneally (into the peritoneal cavity containhg the intes- tines and other viscera) these peripheral ueuropathv effects were observed (8).

Aromatic Hydrocarbons Repeated exposure to benzene in man leads to a progressive

disease in which the ability of the bone marrow to make cir- culating blood cells is eventually destroyed and results in a condition called aplastic anemia. Benzene adversely affects the immunological mechanisms and may also lead to one of several types of leukemia (9). Cases of hematologic effects have been reported from repeated inhalation exposure to concentrations as low as60 ppm, nnd 105 ppm ( l i j , and the present limit for exposure is 1 ppm in alr fur a 40-hr work week 111 ,. There is, howevrr, no clet~r dose-response effecr, and the time ~rfexposure and the cuncenrration of benzene necessary to cause hone marrow dysfunction varies greatly among iri- dividuals (9).

I t is aereed eenerallv that a metabolite of benzene is re- sponsible for the toxicity although the exact mechanism is unknown. The intermediate in metabolism mav be benzene oxidp (I2,, although a dihydrodiol or a semiquinine must also he considered as possible candidates. Xonc of these inter- mediate compuunds huvr hwn isolated from the body. Only phenol, hydroquinone, p)rocatechul, trihvdroxy derivatives and mucnnic acid have been t'uund, and of these metahohtes, onlv caterhol administration caused hone marrow toxicity similar to that found after benzene administration 191. In view of the unpredictable toxicity of benzene, its use in the'teaching laboratory should he discontinued.

The bone marrow effects of benzene appear to be unique among the aromatic hydrocarbons and have not been found for simple alkyl derivatives of benzene (13). Toluene, for in- stance, does not show any toxic effects other than normal central nervous system depression (at exposures above 200 ppm) that were described earlier for all hvdrocarbons. The absence of toxicity is probably related to its metabolism as there are no producb found from hydroxylatiou of the ring; onlv benzoic acid and other derivatives iesultine from 0x7- dation of the merhyl substinlent are formed (101. k, however, rhe aromatic rinr iss~lhstituted onlv bs haloeens.sieniiicant toxicity has heen-found when testedinanim&. For example, bromobenzene and related compounds have shown liver toxicity. From the metabolite composition after bromohen- zene exposure, it was postulated that the reactive intermedi- ates were either the 3,4-epoxide or 2,3-epoxide derivatives (14). These reactive epoxides formed in liver hind to biologi- cally important macromolecules and through an unknown mechanism cause cell death. Such covalent binding has been found and does correlate with the degree of tissue damage (4).

Human toxicity from polychlorinated biphenyls (PCB) was found when an accident in Japan exposed a large number of people who showed skin eruptions, peripheral neuropathy, and serum indications of liver function disturbances (15). The same signs were seen in monkeys exposed to PCB's and di- etary levels of 100 and 300 ppm resulted in death of the monkeys within three months (16). It is thought that the metabolism of PCB's goes through an arene oxide interme- diate (17), and although it is improbable that the skin and neurological signs are related to the formation of a reactive intermediate, the liver effects may be related to such a mechanism.

Similar metabolic activation is involved in the carcinogenic

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Human data lacks experimental control and interpretation may be complicated by other factors. . .

toxicitv of oolvnuclear aromatic com~ounds, and these me- taholitks are postulated to hind to ~ f i ~ for cancer to occur. Polvnuclear aromatics such as 3-methylcholanthrene; 7,12- di~ethylt) i~w[a]anthrnrt~nt~ and henwlalpyrenr can pmduce cancer aiter skin apr>licatiw iniertion 11ndt.r theskin,or when given orally to ratsand mice. There appear to he molecular features that can he correlated with such activity (3). An- thracene is not carcinogenic, hut addition of another benzene ring to form benz[a]anthracene makes a weak carcinogen, and addition of vet another benzene ring to make dihenzlah- . . anthracene or henzopyrene makes a powerful carcinogen. Addition of methvl erouos in selected uositions to form ~,12-d:methslt~enz~[a]d~ith~act~nt; tnr ;I-methylrhulanfhrt~nr ran R I W iictiww the mc~ltwle. Theorefiral calvulations hased on electronic structure indicate that the K region of the mol- ecule (5 and 6 positions of henz[a]anthracene) is important to the carcinogenic potential as well as specific kinds of sub- stitution in the L region (7,12 carbons in henz[a]anthracene). This formalism works well in predicting carcinogeneity for small ring systems hut is less useful in larger ring systems (3). ,~ ,~

The active species in these molecules result from liver me- tabolism and are either specific epoxides or their derivatives. Using henzo[a]pyrene as an example, only the K region ep- oxide (4,5-oxide) and a diol-epoxide (7,8-diol-9,lO-epoxide) have strong carcinogenic activity whereas many other epoxides and hvdroxv derivatives which are metabolites or ~oss ih le intermediates show weak, if any, activity (18).

Halogenated Hydrocarbons Chlorinated hvdrocarhons have been the most extensively

studied of the halogenated hydrocarbons and many members have been found to seriously damage the liver (CCld, CHC13, etc.) with some being potentially carcinogenic (vinyl chloride, vinylidene chloride and perhaps trichloroethylene) (19). Carbon tetrachloride and chloroform first cause fatty infil- tration into the liver eventually leading to liver cell death. The mechanism is related to metabolic reductive dehalogenation resulting in CCI bond fission with formation of free radicals (trichloromethyl and chlorine radicals for CCld. The radicals probably react with unsaturated fatty acid chains, forming further radicals which react with oxygen to form peroxides and hydroperoxides. These peroxides induce decomposition of the fatty acid chains destroying membranes and other essential macromolecules (6, 19). The hepatotoxicity of hromotrich- loromethane is greater than either carbon tetrachloride or rhlorofurm suggesting t h ~ t u~xicity is related inversely to the I)t,ntl diss(~1~11(111 ener~ies. 'l'hat is. a low dissaciatiun enerm would correspond to an increased tendency for homolytic fission to the trichloromethyl radical.

Many other chlorinated alkanes have been studied; those compounds with high rates of metaholic dechlorination like 1,2-dichloroethane, 1,1,2-trichloroethane and 1,1,2,2-tetra- chloroethane have high liver toxicity, and those compounds with low metaholic rates like ethanes with a trichloromethvl substituent have low liver toxicity. Other metaholic steps to eliminate C17 and HCI are ~ossihle; however, the reductive dehalogenat~n to form frek radicals appears to he the im- portant step in toxicity (19).

The potential carcinogens belong to the chloroalkene family and the metaholic activation is thought to involve oxidation to an oxirane (an epoxide) which can then alkylate cellular components. The detoxifying component of this metaholism is rearraneement to chlorinated aldehvdes or acvlchlorides u

which can he further oxidized or hydrolyzed to acids or re- duced to alcohols. The common molecular feature in the three

carcinogenic materials is the formation of an unsymmetric oxirane. Comnounds which would form a svmmetric oxirane do not appear to exert these effects (19):The determining factors probably involve the rate of formation of the inter- mediate, the stability of the intermediate towards re-ar- rangement, the reactivity of the intermediate towards cellular macromolecules, and the rate of further metaholism to non- toxic metaholites. Until quantitative measures can be applied to these processes, no further interpretation can be given to the value of common structural features between toxins.

The anesthetic, halothane, (l,l,l-trifluoro-2-hromo-2- chloroethane) has shown a severe liver toxicity in a small percentage of people given anesthesia and has been studied extensively. Although the active intermediate has not been identified. the toxicitv reauires a low oxveen concentration . . and is probably the result of reductive mkcaholism. Spectral evidence has led to the ~ostulation of a carhene intermediate (20), and this may repiesent a third type of reactive inter- mediate for halogenated hydrocarbons.

Fluorocarbons have achieved notoriety in propellant sniffing deaths among teenagers and have heen found to cause heart arrhythmias by changing the sensitivity of the heart to an endogenous material, epinephrine (21 ). Whether this effect is caused hv the narent. some metabolite. or a reactive inter- . . mediate, is unknown. I t is interesting that certain chlorinated hvdrocarhons also cause cardiac effects a t hieh concentrations, ~~* ~~ ~ ~~

so it is possible that this is a general effect for most halogen- ated hydrocarbons(22).

Alcohols Ethanol, the most commonly used and widely studied of the

alcohols. is metaholicallv converted first to acetaldehvde and then to acetate ion where it enters the body's acetate pool formed from sugar metaholism. In addition to its well-known effects on the nervous system, it causes liver toxicity starting with accumulation of fat and ending with cell death. The ef- fects of excessive alcohol exposure are profound and varied with all three soecies (alcohol, aldehyde, and acid) being im- plicated in its ioxic actions (10).

The most toxic of the alcohols is methanol which forms ti~rmaldehyde and fvrrnnte ion when metaholizt~d. In addition tn the effects oi ethanol, m1.t hand cause3 selerfivr dt!structi~m of the optic nerve resulting in hlindness and more dissemi- nated organ damage (lung hemorrhage, fatty kidney and heart, and degeneration of nerves). The retinal damage is the only toxic action that has been related to a particular species, the formaldehvde metabolite.

The other afcohols show similar types of toxicity to ethanol hut with different ootencies. Thev all appear to use the same . . enzyme system in their metaholism.

The alcohol metaholism system is also postulated to he responsible for the toxicity of the diol, ethylene glycol (10). The oxalate bladder stones, liver degeneration, and injury to the kidney tubules appear to be related to the metaholic for- mation of oxalic acid from the ethylene glycol. The oxalic acid complexes with calcium and can form crystals that will dam- age the organs although some organ toxicity has been observed in the absence of crvstalline oxalate as determined hv mi- croscopy. I t is interesting that propylene glycol has a lower toxicity while the ethers of ethylene glycol (for example, di- ethylene glycol, dipropylene glycol, monomethyl-, ethyl-, and butyl ethers of diethylene glycol) have a higher toxicity and show lung, liver, and kidney damage. The reason for the more uronounced renal damage in the presence of the ether linkage is unknown (23).

.

The aromatic alcohols, phenol and cresols, are recognized

286 / Journal of Chemical Education

Human limits of exposure to various compounds are reached by making the best estimates of the effects of such differences [between experimental animals and humans], applying a safety factor, and obtaining an exposure limit.

as general protoplasmic poisons which are toxic to all cells (23). They are corrosive when applied locally to tissues but are also systemic poisons as a result of their surprisingly rapid skin absorption. The main effect after a large single exposure is damage to the central nervous system although it has been shown that these compounds can destroy many types of nerve fibers. With prolonged exposure, damage to the kidneys, liver, pancreas, and spleen, and fluid accumulation in the lungs may result (24). This toxicity probably results from the parent molecule. Aldehydes, Esters, Ethers, Ketones

Aldehydes are highly reactive chemicals that can combine with many functional groups to form addition products or to initiate polymerization processes. In a homologous series of aliphatic aldehydes, the toxicity appears to decrease with increasine molecular weight. and unsaturated aldehvdes are more toxL than their saGrated homologues (23).

- Generally, esters are hydrolyzed rapidly by enzymes found

in the blood and most tissues. A rough guide to the toxicity of an ester is the sum of the toxicities of the acid and alcohol hydrolysis products (23).

Simple ethers like ethyl ether are powerful central nervous system depr<:ss:tnls whirh in large dosei can cause death. The (.'NS synlpttm.; i,,r ethvl ether arr similar to ethanol except that the mser is more ranid and the duration is shorter. The dangers from ethers are usually associated with single high exnosures and rarelv from small repeated ones (24). Dioxane has been implicated in five human deaths aft& inhalation exposure and causes CNS depression perhaps followed by fluid accumulation in the lung and eventually by death. Re- peated exposure causes liver and kidney damage (24). The toxicity ofbioxane occurs when doses are sufficient to saturate metabolic pathways which suggests that dioxane, and not a metabolite, is the toxic species (25).

None of the ketones have shown systemic toxicity except for the neurotoxin 2.6-hexanedione described ~reviouslv in the aliphatic hydrocerbin section (24). Sulfides, Mercaptans, Carbon Disulfide

Of all the possible organic compounds containing sulfur, the only compound that has been studied to any extent is carbon disulfide. The primary toxic effect is on the central nervous svstem. and industrial workers have shown a wide variety of neurological signs after exposure. The signs range from irritabilitv to manic-depressive ~svchosis. Both central . . and sensory peripheral nerve damage can occur. Carbon di- sulfide can react with many nucleophilic functional groups found in the body including (1) amino acids to form dithio- carhamates, (2) mercapto groups to form trithiocarbamates, . .. . (31 hydroxyl g n t ~ p s t u form xanthugrnic acids, and (4) cum- poundi a,ith twt, such g r ~ ~ p s to firm heteroc\dt~s. The thio- carbamates are good ligands for binding me& ions and can change the metal content in body organs (23). The toxic sig- nificance of some of these reactions is unknown. Nitrogen-Containing Compounds

Nitrogen-containing compounds can cause a wide variety of effects which are difficult to predict. One only needs to be reminded that the most commonly used drugs, (amphet- amines, antihypertensives, barbiturates, tranqiilizers,~anti- histamines, opiates, anticonvulsives, etc.) and the transmitters necessarv for nerve conduction (catecholamines. acetvlcholine. , . serotonin, etc.) all contain nitrogen atoms as an important part of their structure. Hence. all free amines should he considered

Manv of the aromatic amines and nitrobenzenes show the ability i o oxidize the iron in hemoglobin to form methemo- elobin. This oxidation reduces the ahilitv of the blood to carrv oxygen and can result in damage to the central nervous syi- tem. The compounds can he absorbed through the skin or absorbed after inhalation and are sufficiently potent that the maximum allowable concentrations for an 8-hr work exposure are 1 ppm for the nitrobenzenes and 5 ppm for aniline (26). Some aliphatic amine and nitro compounds including nitro- methane. nitrooro~ane. amvl nitrite. dicvclohexvl amine and . . . . , . hydroxylamine can also cause methemoglobin formation. The toxicity of some of the arylamines has been related to their N-hydroxy metabolites (27), and it is possible that even the nitro compounds form hvdroxvlamines after being metabol- ically rediced to amines.

.

The same type of activation to hydroxylamines has been postulated fo r the carcinogenic activity -of some aromatic amines and amides (28). Most of the carcinogenic aromatic amines are derived from a polycyclic hydrocarbon containing a t least two rings, however, both 2,4,6-trimethylaniline and toluene-2.4-diamine are carcinoeens in rats. Some of the carcinogenic amines include 2-naphthvlami~~e: 4-ammoli oht!n\.l hut not 2-aminot~iohenvl: 4.nminoter~hensk Iwnzidine and i"ts derivatives; 2-a&noflu&ene; 2-anihramine but not l-anthramine: and 2-~henanthreneamine hut not l-phe- nanthreneamine (3). .

Nitro derivatives of carcino~enic amines also have been found to cauie tumors since nitro cumpounds can he reduced to amines. It is ioteresting, howe\w, that J-nitroquitloline N-oxidt: is nctivated by rrductinn to J-hydroxylaminoqui- nolint. N-oxide, but thr corresponding nminuquindinc N- uxide derivative is inactive. Since the 4-nitrop!~idine rop!l.illine.oxides require 3-alkyl whstiturion to be carcinogenic, this s~tggt!its that a stabili7ed (ntinuid s r r ~ t c t ~ ~ r e of an intermrdiate h\.- droxylamino compound is necessary for activity. In addition some nitrofuran derivatives have been shown to be potent carcinogens, and their potency depends on their structures (3).

Another group of carcinogenic compounds are the nitro- samines. More than 100 nitroso compounds have been tested and about 80% have induced tumors. The carbon atomsalpha to the nitroso group are the most sensitive to substituent ef- fects which chanee notencv. Several secondarv amines have been given to racaiong with sodium nitrite aLd tumors have been produced characteristic of the tumors produced by the corresponding nitrosamine. These amines include methyl- benzamine, mor~holine, be~tamethvleneimine, ethvlurea. and met hvluren. It is po.;rulilteh that the iwmdary aminrs react with sodium n~tr i tear the acidic pH found in tht:itomach to form a nitrosamine and thus induce cancer (29).

Carcinogens Although chemical carcinogens have been described above,

wherever appropriate in the different sections, a separate section is devoted to these com~ounds because they are so important. 'l'heir muit important property is 3 certain level of chemical nbactivity. They must be electrophilic reactants which are nut 51, reactivt! that they react with wsrrr or tissue ctmstituents and are not so itnreactive that rh6.y can be me- tabolired by the hlody prtor to their reaction. The prol~lem with trying to pretliur their structural rrquirements i i that the active s p r ~ k is a prcduct of thr lrdy's action on the molecule and thcsc rcoctions nrr poorly undrrsrmd.

There are s:me com~ounds thnt nre thoucht to be direct- potentially toxic. acting carcinogens and they include alkylrmines, alkylene

Volume 56. Number 5. May 1979 1 287