ELSEVIER-ENCYCLOPEDIA OF TOXICOLOGY- VOL 3 · seizures and uterine activity. Many antacids contain magnesium oxide or trisilicate as active ingredients. Background Information Magnesium

MMad Cow Disease See Bovine Spongiform Encephalopathy (Mad Cow Disease).

MagnesiumRussell Barbare

& 2005 Elsevier Inc. All rights reserved.

* REPRESENTATIVE CHEMICALS: Magnesium sulfate(Epsom salts); Magnesium hydroxide (in suspen-sion: milk of magnesia); Magnesium citrate

* CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER:CAS 7439-95-4

* CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Alkalineearth metal

* CHEMICAL FORMULA: Mg2þ

Uses

The elemental form of magnesium is used in lightmetal alloys, some aspects of metallurgy, and in theproduction of precision instruments and flares. Manyfoods contain magnesium and vitamins are oftensupplemented with it. Magnesium sulfate may beused topically as a soak, internally as a laxative, orintravenously during pregnancy to control eclampticseizures and uterine activity. Many antacids containmagnesium oxide or trisilicate as active ingredients.

Background Information

Magnesium is the most abundant divalent cation incells, where it is essential for a wide range of cellularfunctions. Magnesium is the sixth most abundantmetal on earth and dissolved magnesium constitutes0.13% of seawater. It is found naturally only in theform of its salts. First obtained in metallic form in1808, it is an essential nutrient necessary for human,animal, and plant health as it is an important com-ponent of red blood cells, a cofactor in over 300cellular processes, and central to the chlorophyllmolecule. The physiological role of magnesium was

essentially ignored until recently. With the develop-ment of new technologies to measure the intracellu-lar free concentration of magnesium ([Mg2þ ]i), thebiologically important fraction, there has been alarge increase of interest in the molecular, biochem-ical, physiological, and pharmacological functions ofmagnesium. Moreover, improved methods for asses-sing magnesium status in the clinic have contributedto the further understanding of magnesium regulat-ion in health and disease. Magnesium deficiency isnow considered to contribute to many diseases andthe role for magnesium as a therapeutic agent isbeing tested in numerous large clinical trials. Specificclinical conditions in which magnesium deficiencyhas been implicated to play a pathophysiological roleinclude hypertension, ischemic heart disease,arrhythmias, preeclampsia, asthma, and criticalillness. There are two conditions where magnesiumis now considered the therapeutic agent of choice,preeclampsia and torsades de pointes. Future researchat the fundamental and clinical levels will lead tofurther increases in the understanding of how magne-sium contributes to pathological processes and underwhat circumstances it should be used therapeutically.

Exposure Routes and Pathways

The primary route of exposure is ingestion. Secondaryroutes can include intravenous, ocular, or inhalation.

Toxicokinetics

Homeostasis of magnesium is tightly regulated anddepends on the balance between intestinal absorp-tion and renal excretion. Thirty-to-forty percent ofingested magnesium is absorbed from the gastroin-testinal system, mostly by the small bowel. Most ofthe magnesium in the body is stored intracellularly or

in the skeleton; o1% is extracellular. In plasma,B65% is in ionic form, with the rest being bound inproteins. The primary route of excretion is throughthe kidneys, but it is also excreted in sweat and breastmilk. Various hereditary disorders of magnesiumhandling have been clinically characterized, andgenetic studies in affected individuals have led tothe identification of some molecular components ofcellular magnesium transport.

Mechanism of Toxicity

Magnesium levels outside of the normal range altercellular ion balances and activity, especially Ca2þ

activity, which directly affects neural and muscularfunctions. One study found magnesium in relativelyhigh amounts in about half of human colon cancers,but the relationship is unknown and animal studieshave found that magnesium actually reduces sarco-ma incidence in some nickel- and cadmium-inducedtumors.

Acute and Short-Term Toxicity(or Exposure)

Animal

Acute animal toxicity resembles acute human toxicity.A unique effect of magnesium when introduced insmall amounts into the skin of animals has been called‘gas gangrene’ or ‘magnesiogenous pneumagran-uloma’. Necrosis and tumor-like formation are causedby the production of hydrogen and magnesium hy-droxide when metallic magnesium reacts with waterof body fluids.

Human

Magnesium is a skin, eye, and pulmonary irritant.Inhalation of fumes can cause metal fume fever.Acute systemic toxicity, defined as serum concentra-tions 42.8mEq l� 1, is almost always caused by bothoveringestion and reduced renal excretion together.Hypotension starts around 3mEq l� 1 and significantprolongation of cardiac intervals occurs between4 and 6mEq l�1. Higher serum levels lead to comaand paralysis and heart stoppage occurs around14–15mEq l� 1.

Chronic Toxicity (or Exposure)

Animal

Chronic animal toxicity resembles human toxicity.

Human

There is no hormonal regulation of systemic magne-sium levels, so toxic effects occur frequently withboth hypermagnesemia and hypomagnesemia butsystemic toxicity is rare in adults unless there isimpaired renal function. Hypomagnesemia is mostcommonly associated with alcoholism or small bow-el disease and is often accompanied by other elec-trolyte deficiencies, mostly hypokalemia (K deficit)and hypocalcemia (Ca shortage). The symptomsmost commonly include tremor, neuromuscular irri-tability, and widening of the QRS complex. Humanhypermagnesemia is generally caused by eitherincreased ingestion or renal impairment. The symp-toms of moderate increases include hypotension, se-dation, and somnolence. The possible associationbetween the risk of ovarian cancer and the levels ofcalcium and magnesium in drinking water frommunicipal supplies was investigated in a matchedcase–control study in Taiwan. The results of the studyshow that there may be a significant protective effectof magnesium intake from drinking water on the riskof ovarian cancer death. Another study has produceddata supporting a protective role of higher intake ofmagnesium in reducing the risk of developing type 2diabetes, especially in overweight women.

Clinical Management

Hypomagnesemia is treated initially with oral,intramuscular, or intravenous administration ofmagnesium salts. Immediate control of the symp-toms of acute hypermagnesemia is obtained withdoses of intravenous calcium repeated hourly butextreme toxicity may require cardiac support ormechanical ventilation. Calcium gluconate and cal-cium chloride can also be administered as antidotes.Serum levels are lowered by reducing intake and bynormal methods of excretion, with diuretics given topatients with normal renal function. Other accom-panying electrolyte imbalances should be treatedconcurrently, followed by treatment of the condi-tion(s) that lead to the imbalances.

Environmental Fate

Elemental magnesium oxidizes and joins the naturalenvironmental reserve.

Ecotoxicology

Magnesium and its compounds are not significantlyecotoxic.

2 Magnesium

Exposure Standards and Guidelines

The American Conference of Governmental Indus-trial Hygienists threshold limit value, 8 h time-weighted average, is 10mgm�3.

See also: Calcium Channel Blockers; Metals; Vitamin A;Vitamin D; Vitamin E.

Further Reading

Brophy DF and Gehr TWB (2002) Disorders of potassiumand magnesium homeostasis. In: DiPiro JT et al. (eds.)Pharmacotherapy: A Pathophysiologic Approach, 5thedn., pp. 989–993 New York: McGraw-Hill.

Chiu HF, Chang CC, and Yang CY (2004) Magnesium andcalcium in drinking water and risk of death from ovariancancer. Magnesium Research 17: 28–34.

Delva P (2003) Magnesium and cardiac arrhythmias.Molecular Aspects of Medicine 24: 53–62.

Genter MB (2001) Magnesium. In: Bingham E, CohrssenB, and Powell CH (eds.) Patty’s Toxicology, 5th edn., vol.2, pp. 221–226. New York: Wiley.

Lopez-Ridaura R, Willett WC, Rimm EB, et al. (2004)Magnesium intake and risk of type 2 diabetes in men andwomen. Diabetes Care 27: 270–271.

Schlingmann KP, Konrad M, and Seyberth HW (2003)Genetics of hereditary disorders of magnesium home-ostasis. Pediatric Nephrology 19: 13–25.

Song Y, Manson JE, Buring JE, and Liu S (2004) Dietarymagnesium intake in relation to plasma insulin levels andrisk of type 2 diabetes in women. Diabetes Care 27:270–271.

Touyz RM (2004) Magnesium in clinical medicine.Frontiers in Bioscience 9: 1278–1293.

Relevant Website

http://ods.od.nih.gov – US National Institutes of Health(NIH) Magnesium (from NIH’s Office of DietarySupplements).

MalathionKevin N Baer



* SYNONYMS: O,O-Dimethyl-S-(1,2-dicarbethox-yethyl)phosphorodithioate; Chemathion; Karbo-phos; Cythion; Malaspray; Malathiozol

* CHEMICAL CLASS: Organophosphorus insecticide* CHEMICAL STRUCTURE:

(CH3O)2P S CH C

H2C

S O

OC2H5

C

O

OC2H5

Uses

Malathion is an insecticide and acaricide for controlof mosquitoes, household insects, and human headand body lice.


Poisonings have occurred mainly from accidental orintentional ingestion, although dermal exposure hasresulted in systemic symptoms.

Toxicokinetics

Malathion is absorbed through the skin, lungs, andgastrointestinal tract. However, skin absorption isfairly low. Most organophosphate insecticides re-quire activation by oxidation of the P¼ S bond to themore toxic P¼O compound by microsomal enzymesof the liver and other organs, including the brain.However, the carboxyethyl ester groups in malathionare rapidly hydrolyzed by malathion esterases. Thisaction effectively detoxifies malathion and is thereason for the relatively low mammalian toxicitycompared with many other organophosphates. Theliver and kidney are primary sites of distribution andreflect the rapid detoxification and clearance ofmalathion. Malathion is rapidly excreted in the urine(Z90%) after 24 h. The half-life following intrave-nous administration in human volunteers wasapproximately 3 h.


Malathion is converted to the toxic oxygen analog(replacement of covalent sulfur with oxygen) bymicrosomal enzymes. The oxygen analog theninhibits acetylcholinesterase as do other organopho-sphates. As a result, acetylcholine accumulates atcholinergic nerve endings with subsequent hypersti-mulation of postsynaptic cells.

Malathion 3


Animal

The acute oral and dermal LD50 values in rats andmice range from 1 to 12 g kg� 1. Domestic animalsexhibit similar signs of cholinergic toxicity as seen inhumans. Chickens may be somewhat more sensitiveto acute toxicity from malathion exposure, butdelayed neurotoxicity is not caused by this agent.

Human

Malathion exhibits very low toxicity compared withother organophosphates. The lethal dose in a 70-kgman is estimated to be Z60 g. However, commercialpreparations of malathion may contain organopho-sphate impurities that can lead to increased toxicityby interference with the detoxification systems. Signsand symptoms of severe malathion poisonings aresimilar to those of parathion and other organopho-sphates. They include an increase in secretions,gastrointestinal cramps, diarrhea, urination, slowpulse, uncontrollable muscle twitches followed bymuscle weakness, paralysis, confusion, dizziness,ataxia, cyanosis, convulsions, and coma. However,life-threatening respiratory or cardiac involvementtypical in parathion poisoning is usually not asso-ciated with malathion.


Animal

As with most organophosphorus insecticides, acutetoxicity is predominant. However tolerance to re-peated exposures can occur. The no-observed-adverse-effect level (NOAEL) established from a rabbitdevelopmental toxicity study was 50mgkg� 1 day� 1

based on maternal toxicity (i.e., reduced body weightgain). Developmental toxicity studies were negative inrats and rabbits. A two-generation reproductivetoxicity study in rats showed no increased sensitivityin pups compared to dams. Repeated exposure tomalathion does not cause delayed neurotoxicity. TheNOAEL of 2.4mgkg� 1 day� 1 was established basedon plasma cholinesterase inhibition in a long-termdosing study in rats.

Human

Generally, the onset and course of toxicity israpid. However, a number of poisoning cases haveshown prolonged symptoms including weakness ofproximal limb muscles, cranial nerve palsies, andrespiratory depression. As with other organo-phosphorus anticholinesterases, it is possible to

accumulate acetylcholinesterase inhibition with re-peated exposures, leading to signs of acute cholinergictoxicity.

Clinical Management

For exposure to eyes, eyelids should be held open andthe eyes flushed with copious amounts of water for15min. For exposure to skin, affected areas shouldbe washed immediately with soap and water. Thevictim should receive medical attention if irritationdevelops and persists.

For exposure through inhalation, the victim shouldbe moved to fresh air and, if not breathing, givenartificial ventilation. The victim should receivemedical attention as soon as possible.

First aid for ingestion victims would be to inducevomiting, keeping in mind the possibility of aspira-tion of solvents. Gastric decontamination should beperformed within 30min of ingestion, to be the mosteffective. Initial management of acute toxicity is theestablishment and maintenance of adequate airwayand ventilation. Atropine sulfate in conjunction withpralidoxime chloride can be administered as anantidote. Atropine by intravenous injection is theprimary antidote in severe cases. Test injections ofatropine (1mg in adults and 0.15mgkg�1 inchildren) are initially administered, followed by 2–4mg (in adults) or 0.015–0.05mgkg� 1 (in children)every 10–15min until cholinergic signs (e.g., diar-rhea, salivation, and bronchial secretions) decrease.High doses of atropine over several injections may benecessary for effective control of cholinergic signs. Iflavage is performed, endotracheal and/or esophagealcontrol is suggested. At first signs of pulmonaryedema, the patient should be placed in an oxygentent and treated symptomatically.


The acute population adjusted dose is 0.5mg kg� 1

day� 1. The chronic population adjusted dose is0.024mg kg�1 day�1.

See also: Carboxylesterases; Cholinesterase Inhibition;Neurotoxicity; Organophosphates; Pesticides; VeterinaryToxicology.

Further Reading

Abdel-Rahman A, Dechkovskaia AM, Goldstein LB, et al.(2004) Neurological deficits induced by malathion,DEET, and permethrin, alone or in combination in adult

4 Malathion

rats. Journal of Toxicology and Environmental Health,Part A 67(4): 331–356.

Gallo MA and Lawryk NJ (1991) Organic phosphoruspesticides. In: Hayes WJ Jr. and Laws ER Jr. (eds.)Handbook of Pesticide Toxicology, vol. 3, pp. 976–985.San Diego: Academic Press.

Relevant Websites

http://www.atsdr.cdc.gov – Agency for Toxic Substancesand Disease Registry. Toxicological Profile for Ma-lathion.

http://www.epa.gov – United States Environmental Protec-tion Agency.

Male Reproductive System See Reproductive System, Male.

MancozebMona Thiruchelvam



* SYNONYMS: Manganese–zinc ethylenebis(dithiocar-bamate); Carbamic acid ethylenebis(dithio) man-ganese–zinc complex; Dithane; Manzeb; Manzate;Zimaneb

* CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Ethyle-ne(bis)dithiocarbamate

* CHEMICAL FORMULA: C4H6N2S4 �Mn �Zn* CHEMICAL STRUCTURE:

[–SCSNHCH2CH2NHCSSMn–]x(Zn)y

Uses

Mancozeb is an ethylene(bis)dithiocarbamate fungi-cide. Mancozeb is classified as a contact fungicidewith preventive activity. It is widely used to controlfungal diseases in conifer and fir trees. It is also usedto control blight in potatoes. It is also used to protectmany other fruit, vegetable, nut, and field cropsagainst a wide spectrum of fungal diseases. It is alsoused for seed treatment of cotton, potatoes, corn,safflower, and cereal grains.

Mancozeb is available as dusts, liquids, water-dispersible granules, wettable powders, and as ready-to-use formulations. It is commonly found incombination with maneb and zineb.


Exposure routes and pathways to mancozeb aresimilar to the other commonly used ethylene(bis)-dithiocarbamates, maneb. Mancozeb has beenshown to cross sensitize with zineb and maneb.

Inhalation exposure can lead to upper respiratorytract irritation. Ingestion of mancozeb can lead tonausea, dizziness, headache and diarrhea. Severeoverexposure can lead to convulsions and coma.

Toxicokinetics

The absorption and metabolism of mancozeb issimilar to maneb. Mancozeb does not accumulate athigh levels in most organs due to its rapid turnoverrate. In experiments where rats were dosed with 14C-mancozeb repeatedly for 7 days and sacrificed 1 dayafter the last dose, radioactivity was detected invarious organs, with highest levels found in the liver,followed by the kidney and thyroid glands, withtraces found in all other organs.


Mancozeb has been classified as a contact fungicidewith preventive activity. It inhibits enzyme activity infungi by forming a complex with metal-containingenzymes including those that are involved in theproduction of ATP.

Mancozeb has effects on various organ systems. Itsprimary mechanism of toxicity is via skin contact,leading to contact dermatitis and dermal sensitiza-tion. Mancozeb has also been shown to haveteratogenic and reproductive effects. Mancozebexposure also alters the reproductive and endocrinestructures, leading to decreased fertility. Animalsorally exposed to mancozeb showed thyroid hyper-plasia, probably via its ability to inhibit the synthesisof thyroxin. Additionally, mancozeb exposure pro-duces neurotoxicity via yet an unknown mechanism.

Similar to maneb, mancozeb also has chelatingproperties, allowing it to possibly interfere with anumber of enzyme systems that contain metals, suchas zinc, copper, and iron (e.g., dopamine b-hydro-xylase).

Mancozeb 5


The acute toxicity of mancozeb is rather low both inhumans and experimental animals. Thus acutepoisoning is highly unlikely unless large amountsare ingested. Mancozeb is slightly toxic via thedermal route. Contact with mancozeb leads toinflammation and/or irritation of the skin, eyes, andrespiratory tract. Acute exposure to mancozeb maylead to effects such as hyperactivity, incoordination,loss of muscular tone, nausea, vomiting, diarrhea,loss of appetite, weight loss, drowsiness, slowedreflexes, and respiratory paralysis.

Animal

In general, mancozeb is not very toxic acutely unlesshigh levels of exposure occur. The acute LD50 formancozeb is 4500mgkg� 1 in laboratory animals.The acute dermal LD50 is greater than 5000mgkg

� 1

in rodents. Dermal exposure to mancozeb leads tomild irritation to the skin. Exposure to the eye alsoleads to moderate irritation. Inhalation of mancozebleads to irritation of the respiratory tract, with LC50of greater than 5.14mg l� 1.

A single exposure to mancozeb to relatively highdoses at day 11 of gestation produced substantialmalformations in the surviving animals. The mal-formations observed were cleft palate, hydrocephaly,and other serious defects. There was also an increasein the rate of resorption.

Human

Since the acute toxicity of mancozeb is relativelylow as is with most dithiocarbamates, acuteintoxication in humans is unlikely to occur unlesslarge amounts are ingested. Mostly mancozeb isknown for its irritant and allergic potential inoccupational exposures. Skin irritation and sensiti-zation has been studied in humans and have shownmild erythema and itching.


Animal

There is limited information regarding the chronictoxicity of mancozeb. It has been indicated that man-cozeb has low toxicity in most experimental animals.Its major metabolite, ethylenethiourea (ETU), hasbeen shown to produce carcinogenic and teratogeniceffects in laboratory animals at high dose levels.

Studies in dogs and mice indicate that mancozebdoes not have carcinogenic effects; however, in ratsthere was an increase in thyroid tumors. The tumors as

well as the inhibition of thyroid function due to thesetumors are thought to be due to its metabolite, ETU.

Inhalation exposure of rats to mancozeb, exposedeveryday for 4 months indicated an increase inirritation of the mucous membrane of the upperrespiratory tract and concentration-related non-specific changes to the liver and kidneys. Exposurewas in the form of dispersed aerosols at concentra-tions ranging from 2 to 135mgm�3. At the lowerconcentrations, there were no observable effects. Inanimals exposed repeatedly to high doses of manco-zeb (dust) equivalent to 150–250 times the accep-table exposure limit (AEL), reduced body weight,inflammation of the lungs, and abnormal thyroidfunction were observed.

Toxic effects in animals from repeated ingestion ofhigh doses include reduced body weight and thyroideffects. Increased incidences of thyroid tumors andocular lesions (retinopathy) were observed in ratsadministered 750 ppm (equivalent to B35mgkg� 1

day� 1) of mancozeb in their diet for 2 years. Thiscompound is considered to show weak carcinogenicactivity. Tests in some animals indicate that thecompound may produce embryo and fetal toxicity,but only at maternally toxic doses. Multigenerationstudies in animals demonstrate no reproductivetoxicity. Although there have been isolated reportsin the scientific literature of mutagenic activity ofmancozeb, in general mancozeb is not genotoxic inanimals or in cell cultures. Mancozeb has not beentested for heritable gene mutation. It has been shownto exert a dose-dependent adverse effect to gonads ofmale and female rats, with reproductive and endo-crine structures being affected leading to decreasedfertility. The exposure paradigm utilized here wastwice a week for 4.5 months. Mancozeb also hasbeen shown to produce teratogenic effects, withgross malformations observed in surviving rats ofexposed dams.

ETU, a breakdown product and a minor metabo-lite of mancozeb, was shown to induce liver tumorsin mice but not in rats or hamsters, and causedthyroid tumors in rats. ETU is not genotoxic. ETUhas been categorized as a probable human carcino-gen by the International Agency for Research onCancer and as group B carcinogen by the NationalToxicology Program. At sufficiently high doses, ETUalso causes birth defects in laboratory animals.

Human

Exposure of mancozeb to humans can occur viaabsorption through the gastrointestinal tract, absorp-tion through the skin or lungs. Human exposure tomancozeb, similar to maneb, has been calculated for

6 Mancozeb

the population of the United States on the basis ofestimated consumption of dietary residues of ETU intreated crops. Please refer to the maneb entry formore specifics on mancozeb human toxicity.

Most human exposure to mancozeb is via occupa-tional exposure. Cases of diffuse erythema andeczematoid dermatitis have been observed amongagricultural workers. Overexposure to mancozeb byskin contact may initially include skin irritation withdiscomfort or rash. The compound has been infre-quently associated with skin sensitization in humans.Significant skin permeation and systemic toxicityafter contact appears unlikely. Eye contact mayinitially include eye irritation with discomfort, tear-ing, or blurring of vision. Based on animal studies,long-term exposure to high levels of mancozeb maycause abnormal thyroid function. Individuals withpreexisting diseases of the thyroid may have increasedsusceptibility to the toxicity of excessive exposures.

In Vitro Toxicity Data

In vitro systems have been developed to try andunderstand the mechanism of action of mancozeb,similar to other dithiocarbamates. The genotoxic,cytotoxic, and neurotoxic effects of mancozeb havebeen studied using a variety of primary cultures aswell as cell-lines.

Clinical Management

Mancozeb can be absorbed into the body byinhalation, though the skin, and by ingestion.

If swallowed, large amounts of water should beingested, only if person is conscious, to dilute theconcentration of the compound and a physicianshould be called immediately. Vomiting can also beinduced. Upon inhalation exposure, the exposedindividual should be removed to fresh air, awayfrom the contamination site. If skin contact occurs,all contaminated clothing should be removed and thearea exposed should be washed with copiousamounts of water and soap. If the product is presentin the eyes, large amounts of water should be used toflush the eye for at least 15min.

Environmental Fate

Mancozeb is generally not active in the soil. Itrapidly degrades in the soil into numerous secondaryproducts, principally ETU and eventually CO2.Plants however can absorb ETU. Because it degradesso quickly, very little mancozeb gets adsorbed by thesoil and its breakdown products are highly solubleand do not get adsorbed to soil particles.

Its persistence is very low in soil. One studyrecovered only 1.16% of mancozeb 7 days afterapplication to silt loam soils, while the half-life wasmeasured as only 3 days in fine sand. Lots of soilmicroorganisms readily break down mancozeb.

Ecotoxicology

Mancozeb is generally of low toxicity to mostwildlife. It is practically nontoxic to birds and honeybees. It has a relatively high toxicity to fish. The 48 hLC50 for goldfish is 9mg kg

� 1, and for rainbowtrout it is 2.2mg kg�1.

Mancozeb has been shown to reduce the popula-tion of soil organisms, and in soil nitrification hasbeen reported at concentrations ranging from normalto 10 times the normal field application rates. Thesechanges have tended to be temporary and reversedwithin 3 months.

Mancozeb is toxic to some plants such as marigoldat normal field application rates. Some genetic effectswere seen in onion cells exposed to mancozeb.


* Occupational Safety and Health Administration:5mgm�3 ceiling.

* American Conference of Governmental IndustrialHygienists: 5mgm� 3 time-weighted average(TWA).

* National Institute for Occupational Safety andHealth: 1mgm� 3 recommended TWA; 3mgm� 3

recommended short-term exposure limit.* Threshold limit value: 5mg (Mn) m� 3.

Miscellaneous

Mancozeb is a grayish-yellow powder with a mustyodor, which is practically insoluble in water as wellas most organic solvents. It is a polymer of manebcombined with zinc. While it is relatively stable andnoncorrosive under normal, dry storage conditions,it is decomposed at high temperatures by moistureand by acid. Mancozeb may produce flammableproducts upon decomposition. It is also unstable inacidic conditions.

See also: Dithiocarbamates; Maneb; Pesticides.

Further Reading

Belpoggi F, Soffritti M, Guarino M, Lambertini L, CevolaniD, and Maltoni C (2002) Results of long-term experi-mental studies on the carcinogenicity of ethylene-bis-dithiocarbamate (Mancozeb) in rats. Annals of NewYork Academy of Sciences 982: 123–136.

Mancozeb 7

Extoxnet Extension Toxicology Network (1993) Manco-zeb. Pesticide Management Education Program. Ithaca,NY: Cornell University.

Shukla Y, Taneja P, Arora A, and Sinha N (2004)Mutagenic potential of Mancozeb in Salmonella typhi-murium. Journal of Environmental Pathology, Toxicol-ogy and Oncology 23(4): 297–302.

US Environmental Protection Agency (1988) Pesticide FactSheet: Mancozeb, No. 125. Washington, DC: Office of

Pesticides and Toxic Substances, Office of PesticidePrograms, US EPA.

US Environmental Protection Agency (1992) SubstanceRegistry System – Mancozeb. Washington, DC: US EPA.

World Health Organization, International Program onChemical Safety (1988). Dithiocarbamate Pesticides,Ethylenethiurea, and Propylenethiourea: A GeneralIntroduction. Environmental Health Criteria No. 78.Geneva, Switzerland: World Health Organization.

ManebMona Thiruchelvam



* SYNONYMS: Manganese ethylenebis(dithiocarba-mate); Ethylene bis(dithiocarbamic acid)-manga-nese salt; Farmaneb; Manesan; Manex; Manzate;Nereb; Newspor

* CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Ethyle-ne(bis)dithiocarbamate

* CHEMICAL FORMULA: C4H6N2S4 �Mn* CHEMICAL STRUCTURE: [–SCSNHCH2CH2NHCSS-

Mn–]x

Uses

Maneb is an ethylene(bis)dithiocarbamate fungicideused in the control of early and late blights onpotatoes, tomatoes and many other diseases onvarious fruits, vegetables, field crops, and ornamen-tals. Maneb has been shown to be effective on awider spectrum of fruit, vegetable, and turf diseasescaused by fungi compared to other fungicides. It isavailable as granular, wettable powder, flowableconcentrate, and ready-to-use formulations.

Maneb is also used for the protection of wheatbecause of its growth inhibition properties and in theplastics and rubber industries as accelerators andcatalysts.


Exposure to maneb can occur via several routes,including dermal, oral, and inhalation. Skin contactwith maneb can result in contact dermatitis and insome cases lead to sensitization. Besides dermalexposure, maneb can also be absorbed when inhaledor ingested.

Occupational exposure during manufacturing,mixing/loading, spraying, and harvesting to thiscompound can occur via dermal deposition andinhalation. Numerous studies have examined theeffects of long-term occupational exposure to manebat various steps in the manufacturing and applicationprocess of maneb. These studies have led to theimplementation of preventive measures to reduceoccupational exposure to maneb. Human exposurecan also occur via consumption of treated crops.Residues of maneb and its metabolites have beenfound in and/or on treated crops. The residue levelschange during storage, processing, and cooking dueto environmental factors and during these processesthe parent compound may be transformed.

Toxicokinetics

Maneb is absorbed via the skin, mucous membrane,respiratory, and gastrointestinal tracts. Its absorptionthrough the skin and the gastrointestinal tract arepoor due to its metal-complexed state. Maneb ismetabolized to ethylene thiourea (ETU), ethylene-diamine, ethylenebisisothiocyanate sulfide (EBIS),and carbon disulfide. ETU is further broken downto molecules that can be incorporated into com-pounds such as oxalic acid, glycine, urea, andlactose. Due to its rapid metabolism, maneb doesnot accumulate at high levels in most organs. Most ofwhat is excreted in the urine and feces is in the formof the metabolite, ETU, with very little of the parentcompound being eliminated unchanged.


Maneb has effects on various organ systems. Itsprimary mechanism of toxicity is via skin contact,leading to contact dermatitis, erythema, and evendermal sensitization. Maneb has also been shown tohave teratogenic and reproductive effects. Exposureto pregnant animals has been shown to have adverseeffects on the fetus. Maneb exposure has also been

8 Maneb

shown to alter the reproductive and endocrinestructures, leading to decreased fertility. Animalsorally exposed to maneb showed thyroid hyperpla-sia, probably via its ability to inhibit the synthesis ofthyroxin. Additionally, maneb exposure producesneurotoxicity via yet unknown mechanism. Humansexposed to maneb show signs of parkinsonism withtremors and slowed movement and gait, developingafter years of unprotected handling of exceptionallylarge amounts of this compound.

Maneb possesses chelating properties, allowing it topossibly interfere with a number of enzyme systemsthat contain metals such as zinc, copper, and iron(e.g., dopamine b-hydroxylase). It is also capable ofinhibiting sulfhydryl-containing enzymes and someother enzyme systems involved in glucose metabolism.


The acute toxicity of maneb is rather low, and thusacute intoxication is unlikely to occur.

Maneb is practically nontoxic by ingestion. Via thedermal route, it is slightly toxic. Contact with manebleads to inflammation and/or irritation of the skin,eyes, and respiratory tract. Acute exposure to manebmay lead to effects such as hyperactivity, incoordina-tion, loss of muscular tone, nausea, vomiting,diarrhea, loss of appetite, weight loss, drowsiness,slowed reflexes, and respiratory paralysis.

Animal

In general the acute oral and dermal toxicity ofmaneb for most mammals is relatively low. The acuteoral LD50 for rats is 45000mgkg

� 1. The acutedermal LD50 for rabbits is 45000mg kg

�1 and forrats is 410 000mgkg� 1. It is a moderate skin andeye irritant.

Rats exposed to maneb produced dose-dependentsigns of decreased movement, disturbances of coordi-nation, lack of appetite, and general weakness.Teratogenic and embryogenic toxicity has beenobserved with single exposures to maneb. In ratsgiven a single dose of 770mgkg�1 maneb on the 11thday of gestation, early fetal deaths occurred. Fetalabnormalities of the eye, ear, body, central nervoussystem, and musculoskeletal system were seen in ratsgiven this single dose. In mice a single oral toxic doseof 1420mgkg�1 during gestation caused toxicity tothe fetus. Relatively high acute doses of maneb arerequired to observe adverse consequences.

Human

Since the acute toxicity of maneb is relatively low asis with most dithiocarbamates, acute intoxication in

humans is unlikely to occur. A case was reportedwhere a 62-year-old man suffered acute kidneyinsufficiency following maneb application; however,the precise contribution of maneb exposure wasunclear as the patient had other health complications.

Maneb is primarily known for its irritant andallergic potential in occupational exposures. Skinirritation and sensitization has been studied inhumans: mild erythema and itching are common.


Animal

Chronic exposure to maneb has been related toreproductive, embryotoxic teratogenic, and neurotoxiceffects. Although the toxicity associated with manebexposure is low, it has been shown that in combinationwith other toxicants such as metals, other fungicidesand herbicides the effects of maneb may be morepronounced, leading to more severe deficits.

Rats fed maneb for 2 years at a dose of12.5mgkg� 1 showed no adverse effects; however,when fed with 67.5mgkg� 1 maneb for only 97days,rats showed reduced growth rate and increasedthyroid weight. Dogs treated orally with 200mgkg� 1

day� 1 maneb for 3 or more months developedtremors, lack of energy, gastrointestinal disturbances,and incoordination. Additionally, spinal cord damagewas observed. Rats exposed to 1500mgkg� 1 day� 1

for 10 days showed evidence of weight loss, weaknessof hind legs, and increased mortality.

Inhalation exposure to maneb in rats producedirritation to the upper respiratory tract, and led tononspecific changes to the liver and kidneys.

Chronic exposure to maneb also affects reproduc-tive abilities. Rats fed maneb for 3 months beforemating showed decreased fertility, and changes toreproductive and endocrine structures.

Teratogenic effects of maneb are observed atrelatively high levels of exposure. Progeny of albinorats treated with either 700 or 1400mgkg� 1 manebtwice a week for 4.5 months showed congenitaldeformities in the caudal vertebrae, palates, limbs,and tail. However, in the mouse the teratogeniceffects of maneb exposure were much milder, withalmost no deformities observed.

Little or no mutagenic potential has been detectedin any assays with maneb.

Most dithiocarbamates have neurotoxic effects,including maneb. Rats exposed orally to manebtwice a week for 4 months at doses of 350 and1750mg kg�1 produced high mortality and paresisin the hind limb progressing to complete paralysis.Exposure to maneb in combination with some

Maneb 9

known dopaminergic neurotoxicants (e.g., MPTPand paraquat) has been shown to potentiate changesto the dopaminergic system even though exposureto maneb alone showed no significant alterations.In combination with these other toxicants, signsreminiscent of Parkinson’s disease have been observed.

Human

Exposure of maneb to humans can occur viaabsorption through the gastrointestinal tract, andthrough the skin or lungs. Human exposure tomaneb (and other ethylenebisdithiocarbamates) hasbeen calculated for the population of the USA on thebasis of estimated consumption of dietary residues ofETU in treated crops. Upper and lower limits ofexposure have been assigned by the US EPA. Foodresidues have been detected and usually are analyzedas a collective level because analysis is accomplishedby measuring carbon disulfide levels. Residues areregularly detected in fruit and vegetables, but mostlyat levels below the maximum residue level. However,repeated exposure via ingestion can lead to a chronicexposure state, potentially leading to cumulativetoxic effects.

Most human exposure to maneb is via occupa-tional exposure. Cases of diffuse erythema andeczematoid dermatitis have been observed amongagricultural workers. Studies on maneb productionworkers showed elevated levels of ETU in the urineand high blood levels of manganese. Very slightalterations to thyroid function were observed.


In vitro systems have been developed to try andunderstand the mechanism of action of maneb. Inparticular, the mechanism of toxicity of maneb onthe central nervous system using synaptosomal andmitochondrial preparations from brain tissue hasbeen utilized. These studies have shown that manebhas adverse effects on the dopaminergic system, viamechanisms that relate to mitochondrial inhibitionand altered neurotransmitter uptake. The genotoxic,cytotoxic, and neurotoxic effects of maneb have beenstudied using a variety of primary cultures as well ascell lines, including human lymphocytes. As notedabove, maneb has little mutagenic potential.

Clinical Management

The extent of exposure will determine the initialtreatment. On skin contact, contaminated clothingshould be removed immediately followed by washingcontaminated skin with soap and water to remove

the chemical from the body. Similarly, if exposure toeyes occurs, large amounts of water or isotonic salinefor at least 15min should be used to flush the eye,occasionally lifting upper and lower lids.

If inhalation exposure occurs, the person shouldbe removed from the exposure area to an areawith fresh air. If needed, rescue breathing shouldbe administered and medical attention sought im-mediately.

Upon ingestion, vomiting should be induced in theconscious patient. Activated charcoal should beadministered to adsorb the remaining fungicide,followed by a sodium or magnesium cathartic.

Environmental Fate

Maneb has low persistence, with a reported fieldhalf-life of 12–36 days. It is readily transformed toETU, which is much more persistent. Maneb stronglybinds to most soils and is not highly soluble in water;therefore, it is not very mobile. It therefore does notrepresent a significant threat to groundwater. How-ever, its breakdown product, ETU, may be moremobile. Maneb breaks down under both aerobic andanaerobic soil conditions. In one particular study, itwas shown that maneb does not leach below the top5 in. of soil.

Maneb degrades very quickly in water, with a half-life less than 1 h. Its main breakdown product isETU. Significant amounts of ETU have been found invegetables treated with maneb. Vegetables such asspinach, carrots, and potatoes that are treated withmaneb after harvest produce a significant amount ofETU in the cooking process. Washing the vegetablesor fruits before cooking or eating eliminated amajority of the residues.

Ecotoxicology

Maneb is practically nontoxic to birds. A 5 daydietary LC50 for maneb in bobwhite quails andmallard ducklings is greater than 10 000 ppm.

Maneb is however highly toxic to fish and otheraquatic species. The 96 h LC50 for maneb is 1mg l

� 1

in bluegill sunfish. The reported 48 h LC50 is1.9mg l�1 in rainbow trout and 1.8mg l� 1 in carp.Maneb-treated crop foliage may also be toxic tolivestock.


* OSHA ceiling limit is 5mgm� 3.* ACGIH TWA is 1mgm� 3 (NIOSH recommended

TWA).* NIOSH recommended STEL is 3mgm� 3.

10 Maneb

* Mine Safety and Health Administration (MSHA)Standard air ceiling concentration is 5mg (Mn)m� 3.

* Occupational Safety and Health Administration(OSHA) permissible exposure limit (general in-dustry, construction, shipyards, federal contrac-tors) ceiling concentration is 5mg (Mn) m� 3.

Miscellaneous

Maneb is a yellow powder with a faint odor. It is apolymer of ethylenebisdithiocarbamate units linkedwith manganese. It is highly insoluble. Its watersolubility is 6mg l� 1 and is practically insoluble incommon inorganic solvents.

See also: Dithiocarbamates; Manganese.

Further Reading

Berg GL (1986) Farm Chemicals Handbook. Willoughby,OH: Meister Publishing Company.

DuPont de Nemours and Company (1983) TechnicalData Sheet for Maneb. Wilmington, DE: AgriculturalChemicals Department, DuPont.

Extoxnet Extension Toxicology Network (1993) Maneb.Ithaca, NY: Pesticide Management Education Program,Cornell University.

US Environmental Protection Agency (1988) Pesticide FactSheetManeb. Washington, DC: Office of Pesticides andToxic Substances, Office of Pesticide Programs, US EPA.

US Environmental Protection Agency (1992) IntegratedRisk Information System – Maneb (CASRN 12427-38-2). Washington, DC: US EPA.

World Health Organization, International Program onChemical Safety (1988) Dithiocarbamate Pesticides,Ethylenethiourea, and PropylenethioureaA General In-troduction. Geneva, Switzerland: Environmental HealthCriteria No. 78.

ManganeseShayne C Gad


This article is a revision of the previous print edition

article by Arthur Furst and Shirley B Radding, volume 2,

pp. 271–272, & 1998, Elsevier Inc.


* CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Metals* CHEMICAL FORMULA: Mn2þ

Uses

Manganese is used in ceramics, glass, dyes, dry-cellbatteries, and special high-carbon steels. It is alsoadded to fertilizers and animal food. Potassiumpermanganate is used as an oxidizing agent, andseveral antioxidant drugs now under developmentincorporate manganese in an organic matrix. Manga-nese is an essential trace element, and its concentra-tions are highest in tissues rich in mitochondria, whereit forms stable complexes with ATP and inorganicphosphate. Manganese functions as a constituent ofmetalloenzymes and an activator of enzymes.


Ingestion is the primary exposure pathway for thegeneral population; sources of exposure includegrains, nuts, fruits, and tea. Inhalation is a significant

exposure pathway in industrial settings. Air andwater pollution are minor sources in most areas.Manganese is a ubiquitous constituent in theenvironment, occurring in soil, air, water, and food.Thus, all humans are exposed to manganese, andmanganese is a normal component of the humanbody. Food is usually the most important route ofexposure for people, with typical daily intakes of2.5–5mgday� 1.

Toxicokinetics

Less than 5% of ingested manganese is absorbedfrom the gastrointestinal tract. Manganese is carriedin blood serum by a b-globulin, which may bespecific for this metal. Manganese is a cofactor forenzymes related to synthesis of cholesterol and alsofatty acids. It is necessary for phosphorylationreactions. In some cases it can substitute formagnesium. Manganese is excreted in the bile, butsystematic loads are slowly cleared.


Brain extracellular concentrations of amino acids anddivalent metals (e.g., manganese) are primarilyregulated by astrocytes. Adequate glutamate home-ostasis is essential for the normal functioning of thecentral nervous system (CNS), for example, glutamateis important for nitrogen metabolism and, along withaspartate, is the primary mediator of the excitatory

Manganese 11

pathways in the brain. Similarly, the maintenance ofproper manganese levels is important for normal brainfunctioning. In vivo and in vitro studies have linkedincreased manganese concentrations with alterationsin the content and metabolism of neurotransmitters,for example, dopamine, g-aminobutyric acid, andglutamate. Rat primary astrocytes exposed to man-ganese display decreased glutamate uptake, therebyincreasing the excitotoxic potential of glutamate.Furthermore, decreased uptake of glutamate has beenassociated with decreased gene expression of gluta-mate–aspartate transporter in manganese-exposedastroctyes. Other studies suggest that attenuation ofastrocytic glutamate uptake by manganese may be aconsequence of reactive oxygen species generation.These data suggest that excitotoxicity may occur dueto manganese-induced altered glutamate metabolism,representing a proximate mechanism for manganese-induced neurotoxicity.

Acute and Short-Time Toxicity(or Exposure)

Human

Available human toxicity data are limited to theindustrial setting, where adverse health effects haveresulted from inhalation of manganese (primarily asmanganese dioxide). Inhalation of particulate man-ganese compounds such as manganese dioxide(MnO2) or manganese tetroxide (Mn3O4) can leadto an inflammatory response in the lung.

Acute inhalation exposure produces manganesepneumonitis; the incidence of respiratory diseaseamong exposed workers is higher than that of thegeneral population.


Human

In workers with chronic inhalation exposure, irondeficiency and liver cirrhosis are commonlyobserved. Chronic inhalation exposure also affectsthe CNS, resulting in Parkinsonian-like symptoms.Mental aberrations are also observed. The psychia-tric disturbance has been called ‘manganesemadness’. Symptoms include confusion, unusualbehavior, and sometimes hallucinations. Apathy,difficulty with speech, and loss of balance are mostcommon. Other symptoms include difficultywith fine motor movement, anxiety, and pain.Manganese intoxication can result in a syndrome ofparkinsonism and dystonia. If these extrapyramidalfindings are present, they are likely to be irreversible

and may even progress after termination of theexposure to manganese. Clinical features are usuallysufficient to distinguish these patients from thosewith Parkinson’s disease. The neurological syndromedoes not respond to levodopa. Imaging of the brainmay reveal magnetic resonance imaging signalchanges in the globus pallidus, striatum, andmidbrain. Positron emission tomography revealsnormal presynaptic and postsynaptic nigrostriataldopaminergic function. The primary site of neurolo-gical damage has been shown by pathological studiesto be the globus pallidus. The mechanism of toxicityis not clear. The US Environmental ProtectionAgency (EPA) lists manganese as category D, thatis, it is not classifiable as to human carcinogenicity.While rare in occurrence, manganese deficiency inhumans has been reported. It is characterized byskeletal abnormalities and seizure activity, probablydue to decreased MnSOD and glutamine synthetaseactivities.

Clinical Management

Many symptoms of manganese toxicity disappearafter the victim is removed from the source ofexposure. L-Dopa (levodopa) can reverse somesymptoms, but complete recovery is not expected.Calcium-EDTA (the calcium disodium salt ofethylenediaminetetraacetic acid) will help improvean acute manganese-induced psychosis.

Environmental Fate

Higher levels of environmental exposures to manga-nese are most likely to occur in or near a factory or awaste site that releases manganese dust into air.Manganese is also released into air by combustion ofunleaded gasoline that contains manganese as anantiknock ingredient. Some manganese compoundsare readily soluble, so significant exposures can alsooccur by ingestion of contaminated drinking water.However, manganese in surface water may oxidize oradsorb to sediment particles and settle out. Manga-nese in soil can migrate as particulate matter in air orwater, or soluble compounds may be dissolved bywater and leach from the soil. Elemental manganeseand inorganic manganese compounds have negligiblevapor pressures, but may exist in air as suspendedparticulate matter derived from industrial emissionsor the erosion of soils. The half-life of airborneparticles is usually on the order of days, depending onthe size of the particle and atmospheric conditions.

The transport and partitioning of manganese inwater is controlled by the solubility of the specificchemical form present, which in turn is determined

12 Manganese

by pH, Eh (oxidation–reduction potential), and thecharacteristics of available anions. The metal may existin water in any of four oxidation states (2þ , 3þ ,4þ , or 7þ ). Divalent manganese (Mn2þ ) predomi-nates in most waters (pH 4–7), but may becomeoxidized at pH greater than 8 or 9. The principal anionassociated with Mn2þ in water is usually carbonate(CO3

2� ), and the concentration of manganese islimited by the relatively low solubility (65mg l�1) ofMnCO2. In relatively oxidized water, the solubilityof Mn2þ may be controlled by manganese oxideequilibria, with manganese being converted to the(3þ ) or (4þ ) valence states. In extremely reducedwater, the fate of manganese tends to be controlled bythe formation of the poorly soluble sulfide.

Manganese in water may be significantly biocon-centrated at lower trophic levels.

Manganese is a natural component of most foods.The highest manganese concentrations (up to40 ppm) are found in nuts and grains, with lowerlevels (up to 4 ppm) found in milk products, meats,fish, and eggs. Concentrations of manganese in infantformulas range from 34 to 1000 ppb, compared toconcentrations of 10 ppb in human milk and 30 ppbin cow’s milk.


The American Conference of Governmental IndustrialHygienists threshold limit value, 8 h time-weighted

average (TWA), is 0.2mgm� 3 for elemental manga-nese and inorganic compounds. The (US) Occupa-tional Safety and Health Administration permissibleexposure limit, 8 h TWA, is 5mgm�3 for manganeseas a fume and 0.2mgm� 3 for manganese asparticulate matter. The US EPA recommends aconcentration of manganese in drinking water not inexcess of 0.05 ppm. The US Food and Drug Admin-istration has set the same level for bottled water.

See also: Metals.

Further Reading

Erikson KM and Aschner M (2003) Manganese neuro-toxicity and glutamate-GABA interaction. Neurochem-istry International 43: 475–480.

Goyer RA, Klaassen CD, and Waalkes MP (1995) MetalToxicology. San Diego, CA: Academic Press.

Pal PK, Samii A, and Calne DB (1999) Manganeseneurotoxicity: A review of clinical features, imagingand pathology. Neurotoxicology 20: 227–238.

Relevant Websites

http://www.atsdr.cdc.gov – Agency for Toxic Substances andDisease Registry. Toxicological Profile for Manganese.

http://www.inchem.org – International Programme on Che-mical Safety. Manganese (Environmental Health Criteria17). See also: Manganese and its Compounds (ConciseInternational Chemical Assessment Document, CICAD).

Margin of Exposure (MOE)Udayan M Apte and Harihara M Mehendale


Definition

Margin of exposure (MOE) is defined as the ratio ofthe no-observed-adverse-effect level (NOEAL) to theestimated exposure dose:

MOE ¼ NOEALEstimated exposure dose

Introduction

The determination of MOE is a part of the riskcharacterization process of a compound. MOE is away to express the risk of noncarcinogenic effects of

a compound. It utilizes the NOEAL determined inanimals and estimated exposure dose to humanpopulation. NOEAL is the highest dose level of achemical that does not produce a significantlyelevated increase in an adverse response. NOEAL isdetermined in test animals such as rats and isexpressed in milligram per kilogram per day. Theestimated exposure dose is determined by estimatingamounts of the chemical in the sources of contam-ination (e.g., water supply) and is expressed inmilligram per kilogram per day. MOE indicateshow close the estimated exposure of the toxicant is tothe dose, which produces no observable adverseeffect in a test animal. Low values of MOE indicatethat the human exposure of the chemical in the targetpopulation is close to the NOEAL in the animals.MOE values below 100 are considered unacceptableand generally demand further investigation. Higher

Margin of Exposure (MOE) 13

values of MOE indicate that the exposure of thechemical is much lower than the NOEAL in animals.It should be noted that the MOE calculation does nottake into account the differences in animal-to-humansusceptibility and/or the extrapolation of dose fromanimals to humans.

Example of MOE

Consider that the human exposure of a chemicalX calculated via drinking water supply is 2 ppp, thatis, 2mg l� 1 day� 1. Suppose a 70 kg man consumes2 l of drinking water per day then the estimatedexposure dose would be 2mgkg� 1 day� 1�

2 l day� 1 divided by 70 kg (body weight), which isequal to 0.057mgkg�1 day�1. Suppose that theNOEAL of chemical X is 150mgkg�1 day�1, thenthe MOE would be more than 2600. This indicatesthat the exposure of chemical X is much below itsNOEAL and the risk to public health is very low.

See also: Risk Assessment, Human Health.

Further Reading

Klasssen CD (ed.) (2001) Casarett & Doull’s Toxicology:The Basic Science of Poisons. New York: McGraw-Hill.

MarijuanaChristopher P Holstege


This article is a revision of the previous print edition article

by William A Watson, volume 2, pp. 272–273, & 1998,

Elsevier Inc.


* SYNONYMS: Tetrahydrocannabinol (THC); Bhang;Dronabinol; Cannabis; Ganja; Grass; Hashish;Hemp; Honey oil; Marihuana; Marinol; MaryJane; Pot; Refeer; Weed

* CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Psy-choactive substance

* CHEMICAL STRUCTURE:

O C5H11

OH

Uses

Dronabinol is prescribed for its antiemetic andappetite stimulant properties. Marijuana is primarilya drug of abuse, although it is currently used bypatients for the same purposes as dronabinol.


Inhalation of marijuana smoke is the most commonmethod of use followed by ingestion. Parenteral useis uncommon. Dronabinol is an oral capsule.

Toxicokinetics

After smoking, 18–50% of the available THC isabsorbed, the onset of clinical effects occurs within10min, and effects continue for 2–4 h. Peak plasmalevels occur within 5–12min of smoking with peakclinical effects noted at 20–30min later, afterdistribution into brain and other tissues. Followingingestion, only 5–20% of THC is bioavailable, theonset of effects begins within 30–60min, and effectspersist for 4–6 h. Gastrointestinal absorption isincreased by fatty foods or a lipid vehicle. Peakplasma levels occur 2–3 h after THC ingestion. THCis 97–99% protein bound with a volume of distribu-tion of B10 l kg� 1. THC undergoes substantial first-pass metabolism by the liver. THC is metabolizedprimarily to 11-hydroxy-delta-9-THC. The 11-hy-droxy-delta-9-THC is pharmacologically active, butis further metabolized to inactive metabolites,primarily 11-nor-delta-9-THC carboxylic acid. Lessthan 1% of THC is excreted unchanged in the urine.The high lipid solubility results in an initial shortplasma half-life, but this adipose storage produces abiologic half-life of 25–30 h. THC may be detectablein plasma for up to 15 days. With chronic high-doseuse of marijuana, the presence of metabolites of THCin the urine can be detected for 6–8 weeks.


The mechanisms involved in THC’s central nervoussystem (CNS) and cardiovascular effects have notbeen well delineated. Specific cannabinoid receptorsin the cerebral cortex may be responsible for thepharmacologic effects of THC. THC also hasimmunosuppressive effects and results in depression

14 Marijuana

of both B- and T-cell activity and depression of tumornecrosis factor levels by macrophages. The antie-metic effect appears to involve the CNS vomitingcontrol center.


Animal

The clinical effects of marijuana in animals aresimilar to those observed in humans. Clinical effectsmay be more pronounced after ingestion of marijua-na than those seen with inhalation exposure.

Human

Toxicity primarily involves the CNS and cardiovas-cular system. Euphoria, increased apparent visualand auditory sensory perception, and altered percep-tions of time and space are common with mildintoxication. Larger doses can impair memory,decrease attention and cognition, and result inlethargy. Impaired sensory interpretation and perfor-mance of complicated mental tasks increases the riskof trauma with activities such as operating a motorvehicle. Decreased balance, ataxia, and muscleincoordination can occur. Anxiety, panic attacks,paranoia, depression, confusion, and hallucinationscan occur with high doses; these effects are morecommon in less experienced, younger users. Cardi-ovascular effects include increased heart rate andcardiac output and decreased exercise tolerance.Bronchodilation and, less frequently, bronchocon-striction may be seen. The pupils will constrictslightly and the conjunctiva will become red second-ary to congestion of the blood vessels. A dry mouth iscommon. The intravenous administration of mar-ijuana has been associated with severe multiple organsystem failure, including renal failure, rhabdomyo-lysis, increased hepatic enzymes, shortness of breath,headaches, and hypotension.


Animal

Nonhuman primates have displayed behavioral signsof withdrawal after chronic administration of THC.Chronic administration of THC via gavage over 2years found no evidence of carcinogenic effect in ratsand equivocal findings in mice at higher doses.Chronic use of THC has been shown to inducetumor regression in rodents.

Human

Chronic use can result in an amotivational state,paranoid behavior, worsening muscle incoordina-tion, slurred speech, and delusions. Smoking mar-ijuana is implicated in both chronic lung disease andthe development of lung cancer. Fertility canbe impaired in both males (decreased sperm countand activity) and females (decreased ovulationand abnormal menses). Prenatal marijuana use bythe mother correlates with increased hyperactivity,impulsivity, and delinquency in the child. Toleranceto some CNS effects may develop with chronic use,and a withdrawal syndrome is possible after chronichigh-dose use.


The active moieties of marijuana have been studiedfor medicinal purposes in a variety of models. Somecanabinoids have displayed effects on neuronaltransmission and alterations of calcium homeostasis.Other cannabinoids have been shown to stimulatecell death (apoptosis), which may help explainobserved antitumor effects in some animal models.

Clinical Management

Clinical management is primarily supportive.Reassurance is generally effective in treating altera-tions in thought process, although benzodiazepinesmay be necessary in uncommon, severe toxicity.If large amounts of marijuana are ingested, activatedcharcoal administration may be considered for recentexposures.

See also: Drugs of Abuse.

Further Reading

Johnson BA (1990) Psychopharmacological effects ofcannabis. British Journal of Hospital Pharmacy 43:114–122.

Macnab A, Anderson E, and Susak L (1989) Ingestion ofcannabis: A cause of coma in children. PediatricEmergency Care 5: 238–239.

Onaivi ES (ed.) (2002) Biology of marijuana: From Gene toBehavior. London: Taylor and Francis.

Schwartz RH (2002) Marijuana: a decade and a half later,still a crude drug with underappreciated toxicity.Pediatrics 109(2): 284–289.

Selden BS, Clark RF, and Curry SC (1990) Marijuana.Emergency Medicine Clinics of North America 8:527–539.

Marijuana 15

Marine OrganismsWilliam R Kem


A wide variety of natural toxins, from smallheterocyclic molecules to large proteins, occurs inmarine organisms. The phyletic diversity of plants inthe ocean is far less than on land, while the numberof marine animal phyla significantly exceeds that onland. Thus, it is not surprising that many of theknown marine toxins are of animal origin. In thisarticle, we will not only focus upon the toxins ofunicellular organisms and marine animals, but alsoconsider a few seaweed toxins.

What is a toxin? First, the word denotes a singlechemical entity or compound which possesses adefined chemical composition and covalent structure.Generally, this word is reserved for molecules thatoccur naturally within an organism. Vertebrate (andhuman) toxins include the complement system anddefensin peptides which serve as one of our chemicaldefenses against infectious bacteria. Toxic substancesmade with human hands (and minds) are generallyreferred to as poisons. A venom is a mixture ofsubstances secreted together by an animal to eitherdefend itself and/or capture prey. Animal venomsusually are mixtures of enzymes and toxins that,acting together, are more effective than when actingseparately. For instance, phospholipases are com-monly present in venoms because they facilitate thedistribution of the toxins in the venom by digestinglipids in lipid membranes which act as barriers to thedistribution of toxins throughout the body. Con-versely, some membrane-disrupting toxins also en-hance lipid digestion by phospholipases. Enzymes,hyaluronidase and collagenase, break down macro-molecules responsible for holding cells together, alsoenhance the distribution of venoms in the body.

Many toxins act rapidly on their victims. Thiscertainly makes sense if the toxin is being used toimmobilize prey or to escape from predators. Rapidlyacting toxins generally affect excitable cells such asnerves and muscles (including the heart myocardium)which allow movement. Their targets (receptors)include voltage-gated ion channels involved in thegeneration of nerve and muscle action potentials,which share many of the same characteristics. Theseion channels are membrane-penetrating proteinswhich open in response to a change in the electricalpotential across the membrane, allowing sodium orcalcium ions to diffuse inwards, causing a rapid(millisecond timescale) depolarization of the mem-brane sufficient to serve as an electrical stimulus for

the adjacent membrane and thereby causing theconduction of an electrical signal called an actionpotential. This depolarizing wave rapidly propagatesdown the length of the cell, ultimately causingcontraction (muscle) or release of a neurotransmitter(nerve). Either process activated by an actionpotential involves the opening of calcium-selectiveion channels, which allows calcium ions to rush intothe cell and trigger either contractile proteins orrelease of packets of neurotransmitter at the nerveterminal. Many toxins, aquatic and terrestrial, attackthe sodium or calcium channels involved in theseprocesses, since their alteration usually causes paraly-sis and possibly death of the affected organism.

A neurotransmitter diffuses a very short distance toreach its receptor on a nearby cell which has formed asynapse with it; there the neurotransmitter activateswhat is called a ligand-gated ion channel which alsousually generates a smaller electrical signal which canbe excitatory (depolarizing, causing another actionpotential to be generated on the other side of thesynapse) or inhibitory (suppressing action potentialgeneration in the postsynaptic cell). There are manytoxins which affect the release of neurotransmittersfrom their presynaptic sites or the subsequent effectof the neurotransmitter on its receptor. These effectsalso can cause a very rapid paralytic effect on avictim. In the following discussion of marine toxinswe will at least briefly consider what is known aboutthe sites and modes of action of a toxin.

Dinoflagellate Toxins

Single-celled organisms (formerly referred to asprotozoans but more recently as prokaryotes)abound in aquatic environments including the seasand oceans. Much is known about their biology asthey can often be cultured in the laboratory and theirunicellular nature makes them excellent subjects formany cell biology studies. While most prokaryotesdo not contain toxins, some marine dinoflagellatescan secrete or release upon death very potent toxinscapable of causing harm to a variety of animalsincluding humans. The most cosmopolitan type oftoxic dinoflagellate (genus Gonyaulax) contains atoxin called saxitoxin which blocks voltage-gatedsodium channels in nerve and skeletal muscle andthereby inhibits excitability. Saxitoxin is concen-trated by clams and mussels as well as other filter-feeding animals which feed upon Gonyaulax.Although these animals are relatively insensitive tothis toxin (otherwise they could not feed upon this

16 Marine Organisms

dinoflagellate!), animals which feed upon bivalvescontaining sufficient amounts of this or closelyrelated saxitoxin analogs can be paralyzed by sodiumchannel blockade caused by this toxin. In many wayssaxitoxin acts like a local anesthetic (e.g., lidocaine)on the nerve impulse, blocking the sodium channelsand causing paralysis. However, there are twoobvious differences. First, saxitoxin much moreselectively blocks the sodium channels and at over1000-fold lower concentrations. Second, since sax-itoxin is a much more polar molecule, it does notenter the brain readily from the systemic circulation,and thus acts primarily on the peripheral neuromus-cular system causing relaxation of skeletal muscles.Depression of breathing by inhibiting the intercostalsand diaphragm skeletal muscles can be fatal!Fortunately, our myocardial sodium channel is lesssensitive to saxitoxin and thus cardiac depression israre. Shellfish beds which are harvested for humanconsumption are monitored by federal agencies fordinoflagellate toxin levels to assure their safeconsumption. When saxitoxin or related intoxicationoccurs, symptomatic treatment in a hospital setting isused to get the patient through the critical period ofrespiratory weakness.

Besides paralytic shellfish poisoning (PSP) there isalso neurotoxic (NSP) and diarrhetic (DSP) shellfishpoisoning due to other dinoflagellates in the marineenvironment. NSP is relatively rare, but in 1987received considerable attention when there was anoccurrence of this type of poisoning in Nova Scotia.NSP victims showed central nervous system cognitivedeficits such as amnesia. The causative agent waslater found to be domoic acid, which is known to betoxic to excitatory synapses in the brain whichinvolve the neurotransmitter glutamic acid. Thistoxin is a chemical analog of glutamic acid, whichis not readily removed from the nervous system andthus causes persistent stimulation of such synapses,which results in a massive calcium elevation whichproves lethal to neurons expressing glutamatereceptors. Again, this dinoflagellate toxin was onlyretained and concentrated by the bivalve.

DSP is not as life-threatening as PSP and NSP. Themain toxin, called ciguatera toxin, is actually a groupof very similar polyether molecules which, like PSP,also affects voltage-gated sodium channels. However,ciguatoxin stimulates the opening of a small fractionof sodium channels and this causes an increase innerve excitability in contrast with saxitoxin’s depres-sant action on excitability. Gastrointestinal crampsand diarrhea are the major effects. Ciguatoxin ismade by a bacterium but because it is very lipophilicit is concentrated as it is passed up the food chain.Another chemically related marine bacterial toxin,

maitotoxin, also causes ciguatera symptoms but actsby a different mechanism, enhancement of restingmembrane calcium ion permeability. Thus predatoryanimals at the very top of the chain can accumulatethe highest toxin concentrations. These include fishlike barracuda. The highly lipophilic ciguatera toxinsleave the victims very slowly, sometimes over monthsor a year, thus prolonging the misery.

There are several other marine dinoflagellateswhich secrete toxins into the sea water primarilywhen their high concentrations (blooms) cause apopulation crash, and the dead cells then release theirtoxins. In the United States, a very commonorganism causing massive fish mortalities is Karenia(formerly Gymodinium) breve. The so-called breve-toxins, like ciguatoxin, are large polyether moleculeswhich tightly bind to voltage-gated sodium channelsin excitatory cells and enhance their excitability.Because fish sodium channels are very sensitive tothese toxins, they usually die before they are caughtand consumed by humans. Thus this toxin isprimarily injurious to marine ecosystems due tomassive mortalities of fish and other animals. Theonly common human effect is bronchoconstriction ofthe airways resulting from inhalation of brevetoxinswhich can be airborne in coastal regions experien-cing this red tide.

Although red tides occurred before human popula-tion density became high, the frequency and wide-spread occurrence of particular red tides is oftenattributed to eutrophic conditions along coastscaused by runoff of agricultural fertilizers and animalwastes. Unfortunately, the spores of these organismsare readily transported from one sea to another in theballast waters of ships. It is thought that red tidedinoflagellates are now widely distributed around theoceans of our planet because of these humaninfluences.

Increases in environmental pollution or nutrientlevels, reduced oxygen levels, and other factors canchange conditions significantly in marine environ-ments, especially in protected coastal areas wheretidal flushing currents may be slow. Sometimes whenthis occurs, different organisms that thrive underthese altered conditions begin to emerge as do healthconcerns for both people and other species coming incontact with these species and the toxins theyproduce. One fairly recent example of this is a majoroutbreak of finfish kills and some human healthproblems (respiratory and eye irritation, skin rashes,gastrointestinal and neurological symptoms) reportedalong the middle Atlantic seaboard of the UnitedStates in the early 1990s. The cause of this appears tobe exposure to dinoflagellate Pfiesteria sp. (includingPfiesteria piscicida and Pfiesteria shumwayae) and to

Marine Organisms 17

the yet unidentified substances that they produce.Such toxicity had not previously been detected in thisregion. This is just one illustration of how importantit is to be aware of the impact of human activity onmarine environments and the unintended changes ourspecies may be bringing about.

Invertebrate Toxins

Sessile marine animals such as encrusting sponges,bryozoans, and tunicates are known to harbor avariety of toxins which may serve as chemicaldefenses against predators. These are filter feedinganimals and thus many of the toxins and repellantsubstances obtained from these organisms mayoriginally have been made by bacteria or otherplanktonic organisms which are concentrated by theseanimals. Certain sponges (the genus was originallyHaliclona, but has been changed to Amphimedon)make pyridinium polymers called halitoxins whichlyse blood and other cells which have been tested.Sponges containing high concentrations of this poly-meric toxin are generally avoided by most predatoryfish. The Carribbean Fire Sponge (Tedania sp.)possesses toxins which cause a delayed hypersensitiv-ity as well as acute inflammatory reaction whoseunpleasant nature the author has experienced. Theactive constituents of this and other inflammatorysponges have not yet been characterized.

Bryozoans look more like plants than animals andare common coastal animals growing on docks andboats in addition to the natural surfaces. A family ofheterocyclic molecules aptly called bryostatins hasbeen identified and is being tested as potentialtreatments for certain cancers. Similarly, tunicates,representing some of our most primitive chordate(backbone) ancestors, produce cyclic peptides whichpreferentially kill certain types of cancer cells.Vast numbers of sponge, bryozoan, and tunicateand other encrusting marine species are beingextracted and tested for antineoplastic activity by ascreening program sponsored by the National CancerInstitute and many lead compounds have alreadybeen identified.

The phylum Cnidaria consists of hydrozoans(including Portuguese Man O’War medusae and firecorals), scyphozoans (jellyfish), and anthozoans (softcorals, hard corals, and sea anemones). All of theseanimals are covered with stinging capsules (thecnidae) which are used to paralyze prey and defendagainst predators. The cnidae are located in cnido-cytes, the epidermal cells which make the stingingcapsules and eventually control their discharge. Thewall of the stinging capsule has been shown to beimpermeant to molecules larger than about 800. Since

all of the known cnidocyst toxins are peptides orproteins exceeding this mass, they can be kept withinthe capsule without expenditure of energy. Jellyfishand hydrozoan toxins are relatively large, unstableproteins which form large pores in cell membranes,which cause their cells to swell up and burst due to theosmotic imbalance. The toxins of sea anemones aresmaller and generally stable after isolation. The aminoacid sequences of several sea anemone toxins areknown. The toxins which affect excitable membranesare generally called neurotoxins, although they maybe even more potent on heart sodium channels. Thesepeptides of about 50–55 amino acid residues areknown to prolong the repolarization phase of theaction potential by delaying the process of sodiumchannel inactivation which is important for returningthe nerve membrane to its resting state. This leads toan abnormally large release of neurotransmitters atnerve endings, and results in spastic paralysis of thevictim. The other sea anemone toxins are largerpeptides which form large ion channels pores in cellmembranes, causing depolarization, loss of osmoticbalance, and cell death (cytolysis). Particularly com-mon are the ‘actinoporins’, which are B20000 Daproteins, which, like the bacterial porins, possess largeamounts of B-pleated sheet structures. A third, morerecently discovered group of sea anemone peptidetoxins block voltage-gated potassium channels atextremely low concentrations. One can imagine thatwhen these three toxins act together on a nervemembrane that it will be depolarized much of thetime! Soft corals, in contrast to the above-mentionedcnidarians, seem to rely upon small, repellant terpenemolecules to deter predators.

Of the 25 animal phyla, almost half are worms.Thus, it is not at all surprising that some wormscontain toxins. The nemertines are a phylum of over800 known species which resemble flatworms but areactive predators on crustaceans and other worms.This phylum is exceptionally toxic among thevarious worm phyla. The Heteronemertine sidepossesses peptide toxins which appear to be onlydefensive, as these animals have no means ofinjecting a venom. The peptides include neurotoxins,which enhance excitability of nerve membranes, andcytolysins, which permeabilize and destroy cellmembranes. Members of the Hoplonemertine classinject a venom into their prey using a mineralizedstylet located in their proboscis, which is also used toimmobilize the prey. Their toxins are alkaloidssimilar to nicotine which in minute amounts paralyzecrustaceans and annelid worms and primarilyactivate nicotinic acetylcholine receptors. Anotherwell-known worm toxin is nereistoxin, a disulfide-containing alkaloid which also binds to nicotinic

18 Marine Organisms

receptors but is largely inhibitory to their normalfunctioning. This toxin was isolated after fishermannoticed that flies which ate the flesh of the deadworms were paralyzed. It later became an importantagricultural insecticide because it is particularlyeffective on rice-stem boring insects.

Starfishes and sea urchins usually contain toxinsserving as a chemical defense against predators andpotential settling animals. Starfishes make saponins(diterpene glycosides) that are chemically similar tothe saponins found in unripe tomatoes and in potatospuds. These enter the lipid bilayer part of the cellmembrane and form complexes with cholesterol, amembrane-stabilizing lipid. This makes the mem-brane leaky to ions and water, causing cyolysis.Among the spines of sea urchins are found smallflower-like appendages, pedicellariae, some of whichare venomous. Their toxins are peptides and nonehave yet been characterized chemically. They canparalyze small animals which might otherwise attach(settle) to the surface of the urchin.

While most mollusks possess a protective shell,some also possess powerful venoms which can be usedas a further defense against predators and also forparalysis of their prey. Undoubtedly, the best knowngroup is one of marine snails known as ‘cone’ snailsbecause their shells are often nearly perfectly conical.The genus Conus actually contains more than 300species, and it is likely that all possess a venomharmful to some animal. Only B10% of the speciesare thought to be harmful to vertebrates and these arespecies that usually prey upon fish. Venoms of theothers may also contain peptide toxins affectingvertebrates but are unlikely to be lethal. Most conesactually prey upon annelid worms or nonpoisonoussnails (sometimes the cones battle as well, in achemical warfare without backbones). Their venomstend to be specialized for their molluscan orvermiferous prey rather than us vertebrates. Never-theless, when scuba diving or snorkeling, it is best notto handle cones unless your skin is protected by glovesand wet suit. Since the venom is emitted from a tinyharpoon shot out with considerable force, it is alsoadvised not to place the snail in a pocket! Octopusesare also venomous. Although the Australian blue-ringed octopus uses tetrodotoxin (TTX, see nextsection), most octopuses inject a salivary gland venomcontaining a protein (cephalotoxin) which paralyzescrabs in very small amounts. This toxin does not seemvery potent when injected into vertebrates.

Vertebrate Toxins

Sea snakes (family Hydrophiidae) are close relativesof the cobra, coral, and other snakes belonging to the

family Elapidae. While these snakes are usually notvery aggressive, they are potentially dangerous,possessing venoms that on a unit weight basis areamongst the most potent of all snakes. Sea snakes areconfined to the Pacific Ocean and contiguous tropicalseas including the Red Sea. They use their venom toparalyze prey, primarily fish. Two peptide toxins andphospholipase A2 are generally present in thesesnake venoms. The most life-threatening toxin isthe so-called a-neurotoxin, a peptide composed ofB60 amino acid residues that is held together in athree-fingered loop structure by three disulfidebonds; the longer, middle loop binds to the nicotinicacetylcholine receptor on neuromuscular synapsesand blocks the ability of the neurotransmitteracetylcholine to activate skeletal muscle. This seasnake toxin acts essentially like curare alkaloids andmodern nondepolarizing muscle relaxants, but itbinds more tightly to the receptor and thus theneuromuscular block takes more time to be reversedas the toxin disappears from the systemic circulation.

The second sea snake peptide toxin, cardiotoxin,is homologous (common ancestral gene) with thea-neurotoxin, but lacks the particular amino acidresidues favorable for binding of the latter peptide tothe nicotinic receptor. Cardiotoxin binds ratherindiscriminantly to cell membranes including thoseof the heart and disrupts their normal structure suchthat they become more permeable to sodium,calcium, and other ions, which depolarizes thenormal resting membrane sufficient to cause systolicarrest of the heart. It acts synergistically withphospholipase since it makes the membrane phos-pholipids more accessible to attack by the phospho-lipase A2 which is also a major enzymatic constituentof this venom. The most common means of treat-ment of sea snake envenomation involves intrave-nous injection of sea snake antivenin containingantibodies directed toward the various toxic consti-tuents. When antivenin is unavailable cholinesteraseinhibitors might be useful therapy when muscularparalysis is not complete. Artificial ventilation mustbe maintained until the victim is able to breathespontaneously.

There are many poisonous fishes in the oceans ofthe world. Perhaps the most notorious is the pufferfish (family Tetrodontidae). Besides being able toinflate itself, thereby directing the spines on its skintoward a potential predator and becoming a largeoval shape, this fish contains a heterocyclic toxinwhich, like saxitoxin, blocks some voltage-gatedsodium channels at very low (nanomolar) concentra-tions. TTX was initially purified from a puffer fishprized as food in Japan, where chefs must pass arigorous test demonstrating their ability to remove

Marine Organisms 19

the poisonous viscera and skin from the edible flesh.Puffers apparently use TTX only as a chemicaldefense against predators. TTX has been demon-strated to be produced by a bacterium which liveswithin the poisonous tissues of the fish. This may alsoexplain why it also occurs in a wide variety of otheranimals including the California newt (an amphi-bian), the blue-ringed octopus, marine crabs, andworms. Fortunately, our myocardial (heart) sodiumchannels are relatively resistant to this toxin, as arethe nerves of the puffer fish. Also, being ionized andvery polar, the toxin does not readily penetrate acrossthe blood brain barrier into the brain.

There are many fishes with poisonous spines, mostnotably the stone fishes and scorpion fishes occurringin Pacific and contiguous seas. The stone fish is anugly fish that quietly sits upon the rocky substrate ofshallow coastal waters waiting for its prey. Unlikeother species it does not move when a humanintruder appears, but rather holds its ‘ground’. Thus,people who are wading in shallow waters sometimesstep on these fishes with their upright dorsal finspines which can puncture the skin readily andproduce extremely painful stings that are usually notlife threatening. Recent research has yielded severalprotein toxins which are currently being investigated.Scorpion fish have large pectoral and dorsal finswhich have numerous poisonous spines also posses-sing protein toxins which depress neurotransmitterrelease from nerve terminals. Small scorpion fish aresometimes found in marine aquarium shops. Perhapsthe most commonly encountered fishes with poiso-nous spines are sting rays. Unlike stone fish, stingrays usually swim away when disturbed. Waders inwaters infested with these bottom dwelling fishes areadvised to walk in a shuffling gait to provide the rayswith enough advance notice of their presence and towear boots when possible, to avoid being stuck bythe ‘whiplashing’ tail spine. Some species of catfishalso have stinging spines containing a venom whichhas not yet been characterized. Therapeutic treat-ments of individuals envenomated by poisonous fishspines are still largely symptomatic since antiveninsare not usually available.

Treatment of Marine Envenomationsand Intoxications

Relative to treatment of snake, spider, scorpion, andother terrestrial animal envenomations, the treat-ment of most envenomations due to marine animalsis rather primitive. This is primarily due to ourknowledge of these venoms being less complete.The incidence of jellyfish envenomation amongst

swimmers is undoubtedly much higher than forstings of some of the above mentioned terrestrialserpents, but rarely are jellyfish stings life threateningunless the swimmer is stung over a large surface areaby the Australian box jellyfish (Chironex fleckeri)or the hydrozoan Portuguese Man O’War (genusPhysalia). However, marine ‘toxinology’ has madesteady progress in the past two decades and one canexpect antivenins for common marine envenoma-tions to eventually become available. Antivenins areprimarily useful for neutralizing proteinaceous ve-nom constituents. If the effect of a venom is largelydue to a single type of toxin, one can anticipatefuture treatments to be based on counteracting theeffects of the toxin on its receptor target.

Toxins as Molecular Modelsfor Development of New Drugs

Centuries ago the Swiss physician Paracelsus statedthat all drugs are poisons and all poisons are drugs.While the first portion of this statement is generallyconsidered valid, not all poisons are drugs. Never-theless, there is a long tradition of developingmateria medica from natural sources, generally plantextracts, which were used to treat a variety of diseaseconditions. An example would use of powderedleaves of the foxglove plant (and later purifieddigitalis alkaloids) to treat congestive heart failure.Toxins and other substances, because they often arepotent modulators of particular ion channels orreceptors, also can serve as ‘lead’ compounds fordesigning new drugs. Manipulation of the molecularstructure frequently improves selectivity for a parti-cular target (receptor) and thereby reduces thelikelihood of adverse effects in therapeutic use. Toxicnatural products isolated from several phyla ofmarine organisms have led to new drug candidatesin recent years and there will likely be more in thenot too distant future.

See also: Algae; Animals, Poisonous and Venomous;Saxitoxin; Shellfish Poisoning, Paralytic; Tetrodotoxin.

Further Reading

Halstead BW (1988) Poisonous and Venomous MarineAnimals of the World. Princeton, NJ: Darwin Press.

Kem WR (2000) Natural toxins and venoms. In: Roberts S(ed.) The Principles of Toxicology: Environmental andIndustrial Applications, ch. 17, pp. 409–433. New York:Van Nostrand.

Kem WR (2000) The brain alpha7 nicotinic receptor maybe an important therapeutic target for the treatment of

20 Marine Organisms

Alzheimer’s disease: Studies with DMXBA (GTS-21).Behavioural Brain Research 113: 169–183.

Samet J, Birnami G, et al. (2001) Pfiesteria: Review of thescience and identification of research gaps. Environmen-tal Health Perspectives 109(5): 639–658.

Yasumoto T and Yotsu M (1992) Biogenetic origin andnatural analogs of tetrodotoxin. In: Keeler RF, MandavaNB, and Tu AT (eds.) Natural Toxins: Toxicology,

Chemistry and Safety, pp. 226–233. Washington, DC:American Chemical Society Press.

Relevant Website

http://www.marine-medic.com.au – Marine-medic.com

Material Safety Data Sheets See Chemical Hazard Communication and Material Safety Data Sheets.

Maximum Allowable Concentration (MAC)Shayne C Gad


Maximum allowable concentrations (MACs) are themaximum airborne concentrations that can be justi-fied consistent with the objective of maintaining un-impaired health or comfort of workers or both. Thecriteria on which the standard is established are theavoidance of (1) undesirable changes in body struc-tures or biochemistry, (2) undesirable functionalreactions that may have no di

Documents

ELSEVIER-ENCYCLOPEDIA OF TOXICOLOGY- VOL 3 · seizures and uterine activity. Many antacids contain magnesium oxide or trisilicate as active ingredients. Background Information Magnesium