-
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
& 2005 Elsevier Inc. All rights reserved.
* CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER:CAS 121-75-5
* 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.
Exposure Routes and Pathways
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.
Mechanism of Toxicity
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
-
Acute and Short-Term Toxicity(or Exposure)
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.
Chronic Toxicity (or Exposure)
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.
Exposure Standards and Guidelines
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
& 2005 Elsevier Inc. All rights reserved.
* CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER:CAS 8018-01-7
* 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
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.
Mechanism of Toxicity
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
-
Acute and Short-Term Toxicity(or Exposure)
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.
Chronic Toxicity (or Exposure)
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.
Exposure Standards and Guidelines
* 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
& 2005 Elsevier Inc. All rights reserved.
* CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER:CAS 12427-38-2
* 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 Routes and Pathways
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.
Mechanism of Toxicity
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.
Acute and Short-Term Toxicity(or Exposure)
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.
Chronic Toxicity (or Exposure)
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 Toxicity Data
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.
Exposure Standards and Guidelines
* 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
& 2005 Elsevier Inc. All rights reserved.
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 ABSTRACTS SERVICE REGISTRY NUMBER:CAS 7439-96-5
* 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.
Exposure Routes and Pathways
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.
Mechanism of Toxicity
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.
Chronic Toxicity (or Exposure)
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.
Exposure Standards and Guidelines
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
& 2005 Elsevier Inc. All rights reserved.
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
& 2005 Elsevier Inc. All rights reserved.
This article is a revision of the previous print edition
article
by William A Watson, volume 2, pp. 272–273, & 1998,
Elsevier Inc.
* CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER:CAS 7663-50-5
* 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.
Exposure Routes and Pathways
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.
Mechanism of Toxicity
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.
Acute and Short-Term Toxicity(or Exposure)
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.
Chronic Toxicity (or Exposure)
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.
In Vitro Toxicity Data
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
& 2005 Elsevier Inc. All rights reserved.
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
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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
& 2005 Elsevier Inc. All rights reserved.
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