Vaccari D.A., Strom P.F., Alleman J.E. Environmental Biology for Engineers and Scientists

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observed in the environment as well. Male ﬁsh living near municipal sewer outlets were

found to be producing a protein associated with females. Alligators hatched in Lake

Apopka, Florida, following a spill of organochlorine insecticides had altered hormone

levels and abnormally small penises.

Another type of epigenetic carcinogen is the cocarcinogens: These increase the

concentration of an initiator by affecting absorption, biotransformation, or detoxiﬁcation.

For example, they may decrease detoxiﬁcation by inhibiting enzymes or depleting

detoxiﬁcation substrates such as glutathione. Ferric oxide and asbestos may facilitate

cellular uptake of genotoxics.

The distinction betwee n genotoxic and epigenetic carcinogenesis may have signi-

ﬁcance in the risk assessment process. Speciﬁcally, the presence or absence of a toxic

threshold, a level of exposure below which essentially no effect is found, may depend

on the mechanism. This is discussed in Sect ion 19.4.1.

Genetic Basis of Cancer A fairly deta iled understanding of the causes of cancer pro-

gression is starting to emerge. Early in the twentieth century, the microscopic observation

that tumors tended to have damaged chromosomes, plus the fact that susceptibility to

some cancers could be inherited, led to the realization that genetic damage was the

root cause of all cancers. In addition, the fact that daughters of a cance rous cell would

continue to be cancerous if transplanted to another organism led to the one-hit hypo-

thesis: Malignant cancer was caused by a single mutation to a critical gene.

Eventually, the one-hit hypothesis gave way to other facts. If a single gene caused

cancer, and it was inherited, the cancer should develop immediately after birth. However,

even in cases of inherited susceptibility, inception of cancer still takes some years. This

implies that at least two changes are required, leading to the two-hit hypothesis. The fact

that some cancers go through a series of stages with increasing virulence, and daughter

cells from each stage maintain their characteristics when transplanted, imply that for such

cancers even more than two mutations occur.

In recent years, the tools of genetic engineering have revealed many of the detailed

steps involved for some cancers. The newer discoveries started with the examination of

viruses that cause cancer. It was found that the viruses carrie d a mut ated human gene that

they inserted into the infected cell. The normal human gene was called a proto-oncogene,

which is responsible for stimulating cell growth during gestation. Normally, this gene

is turned off in adults. The proto-oncogene can be mutated into a more active form, cal led

an oncogene. The oncogene sends growth sign als despite the presence of signals that

would tell other cells to stop. Thus, a single mutation is all that is necessary for the change

to be expressed. This is called a dominant mutation or an activated mutation. Recall that a

cell contains two copies of each gene. Only one mutation is necessary if the resulting

gene produces a protein that causes the disease. However, although the presence of one

or more oncoge nes facilitates a cell’s transformation into a cancer cell, by itself it is not

potent enough to produce a malignancy.

Other genes, called tumor suppressor genes, code for proteins that inhibit cell repli-

cation. To produce cancer by damaging these genes, it would be necessary to mutate or

delete both alleles, or else the undamaged copy would continue to produce the protein.

This supported the two-hit hypothesis.

The further progression of changes was found by examining tumors at different stages

and detecting genetic changes present. For example, colon tumors were studied because

the malignant tumor could sometimes be found next to the benign tumor, or polyp, from

718 THE SCIENCE OF POISONS

which it h ad developed. The malignant tumor would always have all the mutations found

in the benign tumor, plus additional ones. The results supported the theory of clonal

evolution of cancer, which states that cancer progresses from a single cell that receives

a single hit enabling it to replicate with less inhibition than normal cells; later, one of its

daughter cells receives a second hit, which makes it replicate faster; and so on until

enough hits occur to produce a malignant cell. Because each mutation causes the cells

to replicate faster, the chance of further mutations is enhanced. The more replications,

the greater the chance of an error.

In the case of colon cancer, the ﬁrst hit was to a gene called APC, whose function

is unknown. Then an oncoge ne called ras and two tumor suppressor genes, p53 and

DCC, are mutated. The order of the last three apparently does not matter, although the

ras mutation seems to occur ﬁrst most often.

The gene p53 seems to be responsible for slowing cell division when DNA damage has

occurred, presumably to allow time for DNA repair. Irradiation of a cell by ultraviolet

light increases the amount of protein coded for by p53 . It also may cause cell death

when damage is too great. This can prevent mutations from being passed on. As a result,

mutations to p53 can reduce these protective actions.

It may not be evident from this discussion that mutations and transcription errors are

rare events. Cancer is common in humans only because cell growth and occasions for

DNA repair occur with high frequency. Even without genotoxic chemicals in the environ-

ment, natural or not, radiation from cosmic rays and natural radionuclides in the body is

probably responsible for the great majority of human cancers. It is estimated that each

cell in our bodies must make tens of thousands of DNA repairs per day as a result of

this radiation. Each human has up to 10

cells. About 25% of all humans contract cancer

in their lifetimes. Even if we assume that all of these cancers are caused by radiation

damage and a 70-year lifetime, this would indicate that the probability of a single DNA

repair resulting in cancer is about 10

25

! This provides no consolation since the great

number of repair events produces such a high risk at the individual level.

Several other factors at the genetic level reduce the risk of cancer. One is that the number

of our 25,000 genes that are proto-oncogenes or tumor suppressor genes is very small. Also,

many of the cellular mutations probably result in the death of the cell. Finally, a large

portion of the DNA actually consists of introns, which are apparently not expressed.

Classiﬁcation of Carcinogens Several U.S. federal agencies have developed classi-

ﬁcation systems for carcinogens based on the strength of the supporting evidence. For

example, the U.S. EPA adopted the following classiﬁcation system in 1986:

Group A: Human Carcinogen: Chemicals are placed in this group only if there is

sufﬁcient evidence from epidemiological studies to support a causal relationship

between exposure to the chemical and cancer in humans.

Group B: Probable Human Carcinogen: This includes two subgroups:

Group B1: Agents for which there is ‘‘limited’’ epidemiological evidence for

carcinogenicity in humans.

Group B2: Agents for which there is ’sufﬁcient‘ evidence of carcinogenicity in animals

but ‘‘inadequate evidence’’ or ‘‘no data’’ from epidemiological studies.

Group C: Possible Human Carcinogen: Includes agents with ‘‘limited’’ evidence of

carcinogenicity in animals. Such limited evidence would include marginally

TOXIC EFFECTS 719

statistically signiﬁcant ﬁndings or ﬁnding of benign tumors caused by substances

that are not mutagenic.

Group D: Not Classiﬁable as to Human Carcinogenicity: Includes agents for which

there is inadequate evidence for human or animal carcinogenicity.

Group E : Evidence of Noncarcinogenicity for Humans: No evidence of carcinogeni-

city was found in at least two adequate animal tests in difference species or in both

one animal test and one epidemiological study.

The International Agency for Research on Cancer (IARC) has a similar classiﬁcation

scheme used by many countries. Appendix C lists some substances classiﬁed as carcino-

gens by the U.S. EPA, along with their classiﬁcation and levels of evidence. Group A

is often called known human carcinogens. Only about 50 chemicals or substances have

sufﬁcient evidence associated with them to be placed in this classiﬁcation. About 13 of

these are of signiﬁcant environmental concern:

Arsenic Hexavalent chromium Plutonium-239

Asbestos Diethylstilbestrol Radium-226

Benzene 2-Naphthylamine Radon-222

Benzidine Nickel Vinyl chloride

Bis(chloromethyl) ether

In 1996 the U.S. EPA proposed a new set of guidelines for carcinogenic risk assess-

ment in which they propose replacing the foregoing categories by three descriptors:

known/likely, cannot be determined, and not likely.

17.4.6 Histological Effects

Histological effects are those observable in st ructures and functions at t he cell and

tissue level by microscopic examination. The gross effe cts of toxicity observable

at the individual level are almost always preceded by histological or biochemical

effects. Thus, these effects are more sensitive indicators of toxicity than mortality or

behavioral changes. Table 17.3 lists some histological changes that can be caused by

toxic substances.

Inﬂammation is a response of connective tissues to repair and isolate, or ‘‘wall off,’’

damage. Special cells release histamine, heparin, potassium, and prostaglandins. These

cause nearby blood vessles to dilate, making the area appear reddened and to feel warm.

Phagocytes and macrophages are attracted to remove pathogens and cell debris. The out-

come of inﬂamed tissues may be repair, chronic inﬂammation, or necrosis, depending on

how successful the organism is in repairing the damage. Chronic inﬂammation results

from the spread of whatever caused the original damage. Fibrosis often results as the

organism attempts to isolate the irritant and replace lost cells. An organism can die from

excessive inﬂammatory reponse. For example, damage to lungs or gills from ﬁbrosis

can reduce oxygen transport in those organs.

Necrosis results at a sufﬁcient level of cellular damage. Degenerative changes leading

to necrosis are often the result of the inability of the cell to maintain ionic balance across

intracellular and extracellular membranes. This, in turn, can be caused by loss of ATP

production. Direct damage to intracellular membranes can result in their rupture. Rupture

720 THE SCIENCE OF POISONS

of lysosomes releases hydrolytic enzymes to the cytoplasm, resulting in further damage.

Unless cell death occurs very rapidly, it is usually accompanied by some inﬂammatory

response. Epithelial and connective tissues can regenerate, or repair damage, relatively

well. Smooth and skeletal muscle can also regenerate, although not as well. Cardiac

muscle and nervous tissue cannot regenerate at all.

Tumors or neoplasms result from changes in the genetic and nuclear mechanisms for

cell growth and reproduction. Their cells usually resemble the cells from which they

derived but lac k the normal structure or function of the original tissue s. Tumors may

be either benign or malignant, as described in Section 17.4.5.

17.4.7 Effects on Particular Organs or Organ Systems

The discussion in this section concerns effects in organs or organ systems of vertebrate

animals. Within that group the emphasis is, of course, on humans.

As mentioned above, particular toxins will tend to target particular organs or organ

systems. The liver and the kidney are common targets of toxic activity because of their

role in detoxiﬁcation and their large blood ﬂow. The skin and eyes, lungs, and digestive

tract are vulnerable to the more reactive toxicants, as they are the sites of ﬁrst entry to the

organism. The nervous system has both unique protection and vulne rability.

Liver The liver receives almost all the venous blood ﬂow prior to its return to the heart

and lungs. All of the blood from the stomach and intestines go directly to the liver. Thus,

substances absorbed in the GI tract may be biotransformed before reaching other organs.

Although the liver detoxiﬁes most compounds, some are converted to more toxic forms.

As the generator of most of the bioactivated compounds (see Section 18.5), the liver is also

the site of ﬁrst and most concentrated contact. The liver is the main site of toxic damage

for a number of chlorinated organics, such as carbon tetrachloride, trichloroethylene,

PCBs, and lindane.

Hepatic (pertaining to the liver) damage can occur in a number of ways. Fatty

liver is an accumulation of lipid globules inside the liver cells and is cause d by several

TABLE 17.3 Summary of Some Histological Effects

Anemia Loss of oxygen transport capacity of the blood

Atrophy Wasting of tissues

Dysplasia Abnormal change in size or shape of cells or tissues

Edema Excessive water collecting in body cavities

Erythema Redness of the skin caused by inﬂammation

Fibrosis Production of new ﬁbrous connective tissue (scar tissue) as a result of

inﬂammation or to replace necrotic cells

Hemorrhage Presence of blood outside the vessels due to injury

Inﬂammation Process in which cells exude substances as part of a repair process; exudate may

include blood serum, ﬁbrin, pus, erythrocytes, mucous, or lymphocytes

Lesion Any abnormal change to a cell, tissue, or organ

Necrosis Cell death within a living organism

Neoplasm Tumor, normal cells that have been transformed into a form with uncontrolled

growth that may or may not be malignant

Vasodilation Enlargement of blood vessels

Source: Rand and Petrocelli (1985).

TOXIC EFFECTS

721

mechanisms that impair the release of triglycerides to the blood. Carbon tetrachloride and

ethanol are among the substances that can cause this. Necrosis is caused by carbon tetra-

chloride, which forms fre e radicals in the liver, as well as by other halogenated hydroc ar-

bons. Cirrhosis is the formation of scar tissue in the liver. It is also caused by carbon

tetrachloride, although ethanol is most commonly associated with this condition.

Although there is evidence to the contrary, the effect of ethanol may be related to nutri-

tional deﬁciency associated with alcoholism. Cholestasis is an inﬂammation of the ducts

carrying bile or a decrease in bile ﬂow by other mechanisms. There are many types of

liver cancer, and many chemicals are known to cause cancer in laboratory animals. The

role of chemicals in human liver cancer is less clear, except for the notable case of vinyl

chloride, which is known as a potent cause of angiosarcoma.

Carbon tetrachloride may act in several ways. Besides forming radicals, it can also be

converted to phosgene. It also has an indirect effect. It causes a large release of the

hormone epinephrine by sympathetic nerves. As with other hormones, epinephrine is

quickly broken down after performing its function. This takes place in the liver, and

the high levels caused by carbon tetrachloride can result in liver dam age.

Liver damage can be detected clinically by several functional tests, such as the rate

at which it clears certain injected dyes or bilirubin, a chemical produced normally by

the breakdown of heme from red blood cells. More sensitive than the liver function

tests are tests for certain enzymes. Often when the excretory capability of the liver is

impaired, the effects are visible as jaundice, the yellowing of the skin and the whites

of the eyes caused by the accumulation of bilirubin.

Kidney A toxin that affects the kidney is called a nephrotoxin.The kidney is very sensi-

tive to toxins, both because of its high rate of perfusion (blood ﬂow) and because it is an

important site of biotransformation. This may be som ewhat of a surprise because the

kidney is usually thought of exclusively as an excretory organ. In fact, it has several

other important metabolic and physiologic functions. The major functions are (1) removal

of waste products from the blood; (2) regulation of red blood cell levels in response

to oxygen levels; (3) regulation of blood pressure, volume, electrolytes, and pH; and

(4) metabolism of calcium and vitamin D. Thus, kidney damage can be manifested in

diverse ways. However, toxic effects on the excretion function are the most commonly

observed.

Elimination in the kidney occurs by three processes: (1) glomerular ﬁltration, (2) tubular

resorption, and (3) tubular secretion. Most nephrotoxins seem ﬁrst to attack the proximal

tubule of the nephron.The glomerulus is also susceptible, and the entire nephron may be

affected if exposure is high enough. For example, mercury reduces active reso rption of

sodium in the proximal tubule. This reduces the passive resorption of water, increasing

urine production initially. Subsequently, glomer ular damage shuts down urine production

completely, allowing waste products to accumulate dangerously in the blood. If recovery

occurs, another period of high urine production occurs. The entire cycle may take several

months. Lead affects the upper part of the proximal tubule, where glucose and amino acid

resorption occurs. Thus, this damage can be observed by detecting these compounds in the

urine. Although an important effect of carbon tetrachloride is severe hepatic necrosis, if it

causes mortality it is usually a result of kidney failure.

Kidney damage can also be detected by changes in blood chemistry. Blood urea

nitrogen (BUN), a product of protein breakdown, and creatinine, a metabolite of creatine,

are excreted by glomerular ﬁltration. Damage to the glomerus reduces the ﬁltration rate,

722 THE SCIENCE OF POISONS

causing these substances to accumulate in the blood, where they can be detected. The

normal kidney allows only low-molar-mass proteins to pass into the urine; therefore,

elevated high-molar-mass protein content in the urine indicates damage.

The kidney uses a lot of oxygen, making it sensitive to ischemia (lack of oxygen due to

reduced blood ﬂow). The kidney is the organ most sensitive to cadmium and is also

harmed by inorganic divalent mercury, lead, and other metals, as well as chlorinated

hydrocarbons. Glycol metabolizes to oxalic acid, which forms salt deposits in the tubules

as calcium oxalate. Rhubarb leaves have sufﬁciently high oxalic acid levels to cause this

problem when eaten. Some chemicals, including arsine gas, benzene, lead, methyl chlo-

ride, napththalene, trinitrotoluene, and analine dyes, cause hemolysis of red blood cells.

This releases pigments such as hemoglobin, which in turn are associated with acute renal

(kidney) failure.

Skin and Eye The stratum corneum (see Section 9.1) is the main barrier to chemical

toxins. Chemicals that penetrate it tend to be absorbed systemically. The skin does not

just passively transport contaminants. It is capable of metabolizing them. One of the

earliest known chemical causes of cancer in humans is that of the skin caused by the topi-

cal appl ication of oils containing polynuclear aromatic hydrocarbons (PAHs). The skin

biotransforms PAHs into compounds more carcinogenic than the original. Many petro-

leum-based or coal-tar materials are photoactive; that is, sunlight increases their toxicity.

Biotransformation of toxins may take place in the epidermis or the dermis.

The skin suffers toxic effects itself, including cancer, primary irritation, allergic

reactions, hair loss, pigment disturbances, ulceration, and chloracne. Dermatitis is an

inﬂammation of the dermis. Irritant contact dermatitis and allergic dermatitis can both

be caused by exposure to chemicals and produce similar symptoms, including hives,

rashes, blistering, eczema, or skin thickening. The difference between them is that a

true allergy takes time to develop, typically at least two weeks; whereas irritation does

not require a previous exposure. For example, no one reacts to poison ivy when ﬁrst

exposed. Only after a second or subsequent exposure does the itchy rash develop.

Common causes of ulceration include acids and burns. In addition, contact with cement

and chromi um-containing materials are well known to cause skin ulcers. The latter

includes leathers that have been tanned with chromi um compounds. Chloracne is an

disease characterized by acute formation of an acnelike skin rash. It is caused by halo-

genated hydrocarbons, especially polychlorinated polyaromatic hydroc arbons. Chloracne

is a classic symptom of dioxin poisoning.

Ultraviolet light from the sun is a form of ionizing radiation that can cause skin

cancer, or melanom a . The basal cells and melanocytes are vulnerable to UV. It is feared

that the destruction of stratospheric ozone by substances such as chloroﬂuorocarbons

will result in increased UV radiation at the ground level, leading to increased melanoma.

Such an increase has already been observed in Australia, which has also experienced

declines in stratospheric ozone.

The eye is vulnerable to irritant s such as smog, solvents, detergents, and corrosive sub-

stances. Other pollutants act systemically and can damage the optic nerve. For example,

methanol and carbon disulﬁde damage the central vision in this way, and pent avalent

arsenic and carbon monoxide affect peripheral vision.

Lungs The lungs are vulnerable to a wide variety of chemical irritant s, such as ozone,

chlorine, ammonia, and components of photochemical smog. Damage can be either acute

TOXIC EFFECTS 723

or chronic, depending on the level of exposure. Acute effects include bronchial constric-

tion and pulmonary edema (accumulation of ﬂuid in the airways). Arsenical compounds

can cause irritation, but chronic exposure can result in lung cancer.

Some inhaled solvents, such as perchloroethyene and xylene, are transported to the

liver and biotransformed. The resulting metabolites then return to the lungs, where they

can cause cell damage and edema.

Many types of particles also harm the lungs, including smoke from cigarettes or other

combustion sources, or dusts from industrial operations producing particles of asbestos,

silicates, coal or even cotton, ﬂax, or hemp. In the disease called silicosis, particles of

certain crystalline forms of silica are engulfed by macrophages in the lungs, which

then attempt to sequester the particles in lysosomes. However, the particles rupture the

lysosome membranes. This releases the lysosome enzymes into the cytoplasm and

destroys the cell, as well as causing damage to the lung tissue. In addition, the particles

are released to continue the cycle of damage. Ultimately, ﬁbrosis results, making breath-

ing more difﬁcult. In late stages the heart is affected, leading to congestive heart failure.

Asbestos particles also cause ﬁbrosis in the lungs, which can lead to lung cancer. Many

other particles cause ﬁbrosis, including coal dust, kaolin, talc, and a number of metal or

metal oxide particles. Another result of chronic damage is emphysema, in which the

walls separating one alveolus from another are destroyed.

The mucociliary escalator is responsible for removing many of the particles trapped in

the bronchial tubes, including infectious microorganisms. However, some toxic sub-

stances, notably tobacco smo ke, paralyze it for 20 to 40 minutes. Mucus stagnates, but

the irritation actually increases mucus secretion. These effects can partially or totally

block smaller bronchi and exposes the habitual smoker to the possible indirect effects

of lower respiratory tract infections and chronic bronchitis (inﬂammation of the bronc hi).

The inhaled irritants described above can have a similar effect.

Occupational exposure to a variety of substances is known to be capable of causing

asthma. This is an allergic reaction in which exposure causes histamine to be released.

Histamine stimulates the bronchi to contract, greatly increasing breathing resistance.

This is known to affect bakers exposed to ﬂour and workers exposed to wood dust,

as well as butchers exposed to fumes caused by heat-sealing PVC ﬁlms for wrapping

meat. Some people become sensitized to to luene diisocyanate, which is used in poly-

urethane products. Subsequent exposures to very small amounts can cause a severe

asthma attack.

Other exposures cause a different allergic reaction, deeper in the lungs at the bronch-

iolar level leading into the alveoli. The symptoms, which include coughing, sputum

production, fever, and fatigue, resemble pneumonia. A fraction of the people affected

slowly develop shortness of breath without fever. Both of these often result in misdiag-

nosis. This condition has been found in farmers exposed to thermophilic actinomycete

spores (farmer’s lung), workers exposed to bird droppings, laboratory technicians who

become sensitive to the urine of experimental rats, and strangely, archeolog ists who

remove wrappings from Egyptian mummies.

Tests on the lungs can be used to detect damage to exposed persons or to form a base-

line for workers who are at risk of exposure. The chest x-ray is one such test. A fai rly

simple, noninvasive test is the spirogram, in which the subject breathes through a device

that measures volume and ﬂow (see Figure 9.11). Measurements include the forced vital

capacity (FVC), which is the maximum volume the person can exhale, and the ﬂow

rate over certain periods of the exhalation. Respiratory frequency, commonly called

724 THE SCIENCE OF POISONS

breathing rate, is sensitive to certain irritants and correlated to their concentration. Ozone

and NO

increase the frequency, whereas SO

and formaldehyde decrease it.

Immune System The immune system consists of various organs, including the bone

marrow, spleen, thymus, and lymph nodes, plus specializ ed cells and plasma proteins pro-

duced by those organs which circulate in the blood and lymphatic system. The cells are

the lymphocytes, or white blood cells, and include T cells and B cells. The proteins

include the immunoglobulins, interleukins, and the complement system. Together they

act to rid the body of chemical and biological contaminants. There are three types of

immune system derangements. Immunosuppressants reduce immune response and

render the body more vulnerable to foreign substances. Immunostimulants cause hyper-

sensitivity reactions or allergies. Autoimmune dise ase is the condition where the immune

system attacks its own substances as if they were foreign.

Many pollutants are immunosuppresive. For example, PCBs are thought to reduce

production of immunoglobulins. Others include:

 Heavy metals: lead, cadmium, chromium, methyl mercury, sodium arsenite and

arsenate, arsenic trioxide.

 Pesticides: DDT, dieldrin, carbaryl, carbofuran, methylparathion, maneb, chlordane,

hexachlorobenzene.

 Halogenated hydrocarbons: PCB, polybrominated biphenyls, TCDD, TCE, chloro-

form, pentachlorophenol.

 Others: benzo[a]pyrene, DES, benzene.

Immunostimulants usually cause their reaction within 15 minutes of exposure. A ﬁrst

exposure does not cause a reaction since the immune system must generate immunoglo-

bulin antibodies. Second and later exposures cause the release of histamine, heparin,

serotonin, prostaglandins, and other compounds. These result in symptoms such as asthma

and rhinitis. Examples of immunostimulant toxins include nickel, beryllium, and the

pesticide pyrethrum. A delayed hypersensitivity reaction may also appear between 12

and 48 hours after exposure to substances such as nickel, chromium, and formaldehyde.

Symptoms include contact dermatitis. Autoimmune diseases are reportedly caused by

agents such as dieldrin, gold, and mercury.

Nervous System The nervous system is exceedingly sensitive, partly because its role

is so critical in higher animals. It also is relatively vulnerable to isc hemia because it

has a high metabolic rate and a low capacity for anaerobic metabolism. Thus, it is the

ﬁrst site of action for carbon monoxide. The central nervous system also has special pro-

tection in the blood–brain barrier (see Section 18.4). Peripheral nerves have a similar,

although less effective barrier.

Here we will mention three main types of neurotoxic effects:

 Physical damage to neurons, including the myelin covering

 Disruption of signal transmission by individual neurons, such as by changing the per-

meability of the neuron membrane to ions, which includes stimulants and depressants

 Interference with signal transmission at the synapses between neurons or between

neurons and muscles

TOXIC EFFECTS 725

Physical damage may target either the long axons by which neurons transmit signals

over distance, or the cells of peripheral nerves or the brain (Table 17.4). Lead, especially

organic lead such as tetraethyllead, mercury, organic arsenicals, chronic alcoholism, and

hexachlorophene intoxication, are all associated with edema (extracellular ﬂuid) in the

brain.

A toxin that affects neural transmission is Saxitoxin (from dinoﬂagelates), which

prevents sodium from entering the neuron as the signal passes. Pyrethrins (natural and

synthetic insecticides) and DDT increase sodium permeability, causing repeated ﬁring

of the neuron, resulting in convulsant activity. Some compounds, such as lead, triethyltin,

cyanate, hexachlorophene, chronic carbon monoxide, and isoniazid, decrease the mye lin

insulation on axons. If the brain is affected, symptoms include mental dullnes s, restless-

ness, muscle tremor, convulsions, memory loss, and epilepsy.

The category of interference with transmission includes stimulants and depressants.

Stimulants increase the excitability of neurons. They include the rat poison strychnine

as well as the popular xanthines. The latter include caffeine, found in coffee and tea,

and theophylline and theobromine (both found in chocolate) (Table 17.5). Xanthines

prevent the breakdown of cyclic adenosine monophosphate (cAMP), which is connected

with the regulation of the active transport of sodium and potassium across the neuronal

TABLE 17.4 Toxins That Damage the Nervous System Physically

Demyelinating Toxins Peripheral Motor Toxins Brain Toxins

Acetyl tetramethyl tetralin Acrylamide Acetylpyridine

Bicycloheanone oxalydihydrazone Arsenic DDT

Chronic carbon monoxide Azide Mercury

Chronic cyanide Bromophenylacetyluria Manganese

Cyanate Carbon disulﬁde

Diphtheria toxin Chlorodinitrobenzene

Ethidium dibromide Cyanoacetate

Ethylnitrosourea Diisopropyl ﬂuorophosphate

Hexachlorophene Dinitrobenzene

Isoniazid Dinitrotoluene

Lead Disulﬁram

Lysolecithin Doxorubicin

Pyrithiamine Ethambutol

Salicylanilides Ethylene glycol

Tellurium Formate

Thallium Hexane and 2,5-hexanedione

Triethyltin Iminodipropronitrile

Iodoform

Methanol

Methyl-N-butyl ketone and

2,5-hexanediol

Methyl mercury

Perhexilene

Phosphorus

Tetraethyllead

Triorthocresyl phosphate

Vincristine

Source: Williams and Burson (1985).

726 THE SCIENCE OF POISONS

membrane. Caffeine mimics adrenaline in its action, stimulating the heart, increasing

stomach acidity and urine output, and increasing the metabolic rate by 10%.

Depressants act by decreasing the excitability of neurons. Ethanol is known to

depress neural excitability by decreasing sodium and potassium conductance. However,

the most important from an environmental point of view are the agents that cause narco-

sis, or central nervous system depression. This is one of the most common toxic effects

and is caused b y solvent partitioning of lipophilic solvents to plasma membranes. The

mechanism is not well understood but may be related to a decrease in ion ﬂuxes through

the membrane. The symptoms include disorientation, giddiness, and euphoria; at higher

levels the symptoms progress to paralysis, unconsciousness, and death.

This prope rty of solvents accounts for their use as anaesthetics. Ethyl ether was one of

the earliest applied this way. Chloroform came into common use because its vapors are

not explosive. However, its use for this purpose has been discontinued because of other

toxic effects, including its carcinogenicity. The potency of these solvents as an ana-

esthetic, along with their toxic effects, is well correlated with their p olarity as measured

by the octanol–water partition coefﬁcient, K

. Octanol is a surrogate for biological

lipids, so K

also measures the tendency of a substance to partition into the plasma

membrane.

Synaptic transmission can be affected by a toxin binding with receptors (e.g., the toxin

produced by Clostridium tetani in tetanus ), by blocking neurotransmitter release (botuli-

num toxin produced by Clostridium botulinum) or by inhibiting cholinesterases (organo-

phosphate or carbamate pesticides; Section 17.1).

Reproductive System The reproduct ive system suffers effects independen t of those that

directly affect offspring. The testes are protected by a barrier similar to, although less

TABLE 17.5 Caffeine Amounts in Popular Beverages

Milligrams

Coffee

5-oz cup, drip method 146

5-oz cup, percolator method 110

5-oz cup, instant 53

Tea

5-oz cup, brewed 1 minute 9–33

5-oz cup, brewed 3–5 minutes 20–50

Cocoa and chocolate

1 oz milk chocolate 6

1 oz baking chocolate 35

Soft drinks

12 oz Mountain Dew 52

12 oz Pepsi Cola 37

12 oz Coca-Cola 34

Nonprescription drugs (standard dosage)

NoDoz 200

Excedrin 132

Anacin 64

Source: Simpson and Ogorzaly (1995); original Consumer Report,

1981, Vol. 46, pp. 598–599.

TOXIC EFFECTS

727