THE EFFECT MECHANISM

OFTOXINS

organisms generally by chemical or physical-chemical

Toxins affect living These mechanisms can be examined in
Ways and cause harmful results.
the following three groups:

1. Selective chemical effects

2. Nonspecific chemical effects
3. Special toxic effects

SELECTIVE EFFECTS

Chemical substances show their severe toxic effects under their lethal dose
at definite concentrations in a region of the body specific for them. Normal
cell components or cell membranes where the chemical substances show
their effects inthe living organism are named target points. These points
may be very important for the cell's functions and the inhibition of these
functions by the effect of the chemicals (toxins) damages the cel.

NONSPECIFIC TOXICEFFECTS
Some chemical substances donot show their toxic effects at specifc organs
selectively, however they have a widespread effect. For example, Ston
dcicds and bases destroy all living cells, an effect probably caused by he
denaturation and precipitation of the pioteins in the cell membr
Organic solvents are harmful to lipid nembranes and cause the dissOCr
ation of nucleoprotein complexes. Many nert materials show these kin
of nonspecific effects, although they have different structures and donot
involve functional groups.

23
 Food
24 Introduction to Toxicology and

SPECIAL TOXIC EFFECTS

Special toxic effects are classified into three groups: mutagenesis, carcino
genesis and teratogeneSiS.

Mutagenesis
The substances that form genetic differences in the genetic symbols of an
organism are named genetic toxins. Many of the genetic diseases of
humans have been shown to arise as a result of changes in the DNA
structure, chromosomal structure or chromosome number. Gene-locus
mutations or point mutations are changes in the DNA sequence within
agene. The process of forming gene-locus mutations is called mutagen
esis or mutagenicity. The substances that cause mutagenesis are called
mutagens and the species, which is exposed to mutagens, is called a
mutant. Chemical substances that are considered mutagens are subdi
vided into three groups according to their effects on the DNA molecule.
These are:

1. Destructive: Hydrogenperoxide, nitrates and nitrites can be

given as examples of this group. Hydrogen peroxide causes gene
locus nutations in microorganisms. Nitrates and nitrites are
mutagenic toward bacteria, but no mutagenic activity has been
detected in humans.
2. Addition: Chemicals that show this type of mutagenic effect are
alkyl group-containing substances such as epoxides, dialkyl sulfats
and lactones.
3. Substitution: Nucleic acids can be given as examples of the group
of chemical substances that cause a change in the DNA molecule
by substitution.
It has beenstated that mutagens can be produced during the
cOoking of foods. This was demonstrated in the broiling of dried
fish andof beef, when amino acids and protein were pyrolized.
Several mutagens have been identified as heterocyclic amines and
Some are carcinogenic.

Table 4.1 shows the mutagens and carcihogens formned in the gut and
in food. As seen in the table, frying, grilling or broiling of protein-ricn
foods, especally meat derived from animal muscle tissue, in particular,
causes the formation of extremely potent salmonella mutagens.

CARCINOGENESIS
Carcinogenesis Or carcinogeniciy is defined as the abnormal growth ot
SOmatiC CCS. Ine substances that cuuse carcinogenesis are called carCm
 The Effect Mechanism of Toxins 25

Table 4.1 Mutagens and Carcinogens Formed in the Gut and in Food
Nitroso compounds Substances formed from reaction of amines with a
(nitrosamines and nitrosating agent (nitrite or nitrate), e.g, N-nitroso
nitrosamides) dimethylamine, -pyyrolidine, -piperidine
Mutagens formed () Polycyclic hydrocarbons formed by pyrolysis of
during cooking organic matter during grilling and smoking
operations (benzo(a)pyrene)
(ii) Pyrolysis products of proteins and amino acids
formed during broiling of dried fish and meat
(hamburger)
(ii) Sugar caramelization products (ammoniacaramel)
(iv) Substances formed during Maillard reactions
(5-hydroxymethylfurfural)
(V) Fatty acid hydroperoxides and cholesterol epoxide
from unsaturated fats
Ethylcarbamate Found in wines treated with diethylpyrocarbonate and
in naturally fermented foods and beverages

Adapted from Carr, 1985 and Larsen and Poulsen, 1987.

ogens. IHistorically, several types of chemicals were discovered to have

carcinogenic potential in experimena systemns after having first been
suspectedof causing cancer in man{Soot and(coal tar were first suspected
to be carcinogenic in the late 18th centurù, when Sir Percival Scott
observed that many of his patients who had cancer of the scrotum were
chimney sweeps. Exposure to soot began at a young age in Great Britain,
where soft coal has been used for many centuries, and it was customary
to train young boys to be chinney sweeps. Subsequent research has
indicated that individuals are more sensitive to carcinogens when exposure
first occurs early in life.
Carcinogens can be separated into eight classes and these classes
can be divided into two general categories: genotoxic and epigenetic
(Table 4.2).
Genotoxic carcinogens, because of their effects on genetic material.
occa
pose a clear quantitative hazard to humans. These carcinogens are
manner
sionally effective after asingle exposure and act in a cumulative
carcinogens
On the other hand, the carcinogenic effects ofepigenetic lead
exposure that to
usually occurwith high, sustained levels of
longed physiological abnormalities, hormonal imbalances or tissue iniury
have been identified to be ca
- Many animal and plant products suitable time
laboratory animals when administered for a
genic to
Me conpounds of not..1
an appropriate dose. Table 4.3 summarize
26 Introduction to Toxicology and Food

origin in the human diet that are carcinogenic to experimental animals.

Carcinogenic substances are also formed during the preparation of foods.
For example, soil nitrate is armajor source of plant nitrogen. It is converted
to nitrite by plants and bacteria. A nirite canIeact with a nítrogen
containing compound (amine) to form an N-nitroso compound that is a
carcinogen. Secondary andtertiary amines infood and water are precursors
"for the nitrosatable amines. N-nitroso compounds, widespread in the
environment, have been found in cured meats, a number of cheeses and
certain dried dairy products (nonfat dry milk), some saltwater hsh and
some beers due to the barley malt. Recently, decreased industrial use of
nitrates andnitrites as food additives and increased use of ascorbates have
led to reduced N-nitrate levels in cured meats.
Some compounds that are added to foods intentionally or that con
taminate foods during the food chain are shown in Table 4.4. The risks
of all of these factors summarized in Tables 4.2-4.4 in the causes of
human cancers are largely unknown. These substances have shown
carcinogenic effects when tested on experimental animals for an appro
priate duration and dosage. However, the sufficient period of exposure
and dose necessary for carcinogenic effects on humans is a subject that
still needs investigation.

TERATOGENESIS
Teratogenesis, or teratogenicity, is defined as giving birth to abnormally
developed or underdeveloped babies. The fact that the environmental
factors would cause congenital defects (malformations) was first stated by
Murphy in 1929 by observing that some pregnant mothers who were
exposed to x-rays bore mentally retarded children. In 1941, Gregg drew
attention to the association of death, blindness and deatness among the
offspring of women exposed to rubella (German measles) during preg
nancy. Some(20 years late the occurrence of 10,000 malformed infants
born of mothers who had taken the drug thalidomide during their preg
nancy was reported. The term congenital defect refers to all morphological,
biocheyical and functionaB abnormalities produced before or after birth.
The [ubstances that cause congenital defects are called teratogens.
Table 4.5 summarizes some selected substances that have been found
toshow teratogenic activity animal experiments. The deficiency of some
nutrients, as well as theiConsunmption in excess amounts, may cause
teratogeniceffects. Vitamin Aand nicotinic acid can be given as examples
of these types of nutritive compounds. Teratogenic effects of contaminants
in foods like nitrosamines, lead and aflatoxins, or some natural products
like caffeine were also detected in animal experiments.
Table 4.2 Classes of CarcinogenicChemicals
Type Mode of Actuon
Genotoxic Carcinogen
Primary carcinogens Form covalent bonds with
macromolecules, interact with
DNA
Secondary carcinogens Gain electrophilic properties by
enzymatic reactions (converted
to type 1 bymetabolic activation)
inorganic carcinogens Lead to changes in DNA
Epigenetic Carcinogens)
Solid-state carcinogens Exact mechanism unknown
Hormones Alter endocrine system balance
immunosuppressors Affect the immune system
Cocarcinogens Enhance the effect of primary and
secondary carcinogens when
given at the same time
Promoters Enhance the effect ofprimary and
secondary carcinogens when
given subsequently
Exanple
bis (chloromethyl) ether, ethy lene
imine, dimethyl sulfate
2-paphthylamine, benzoia)py
aflatoxin B,, dimethytnitrosam1ne
VInyl chloride
nickel, chromium, ead. Zinc, Fron
asbestos V
Sestradiol, diethylstilbestrol
azathioprine
pyrene, catechol, sulturdioxide,
ethanol/
phenol, bile acids, sacçhar1n
 28 Introduction to Toxicology and Food

Table 4.3 Compounds of NaturalOrigin in the Human Diet

that are Carcinogenic to Experimental Animals
Complete Carcinogens
Aydrazines - Found in edible mushrooms (Japan)
Safrole Sassafras plant, black pepper (spice flavor)
Pyyrolizidine alkaloids Herbs, herbal teas, occasionally in honey
rGossypol Unrefined cottonseed oil
Estrogens Wheat germ, unpolished rice
Bracken fern (Japan)
Methylazoxymethanol from cycasin (cycad plants)
larrageenan - Red seaweeds
Tânnins Tea, wine, plants
Ethylcarbamate Wine, beer, yogurt
Tumor Promoters
(notcacng
torud
)
Phorbol esters Herb teas
Lynghyatoxin A Contaminant from edible algae
Carcinogens from foods Containing Mold
Aflatoxins (aspergillus)
Sterigmatocystin (aspergillus, penicillium)
Patulin Apple mold (aspergillus, penicillium)
Luteoskyrin (penicillium islandicu1)
From Carr, 1985, with permission.

Table 44 Compounds Added Industrially to the Human Food Chain that

can be Carcinogenic to Experimental Animals
Food Additives
Examples
Colorings amaranth (Yellow
Flavorings safrole, oil of calamus
Preservatives bER) diethylpyrecarbonate, 8-hydroxyquinoline
Sweeteners
(DEPe)
cyclamates, saccharin, dulcin
Contaminants Examples
Hormones diethylstilbestrol
Pesticides DDT, dieldrin, ethylene dibromide, chlordane
,PoButants from soil arsenic, heavy metals, asbestos (cement water pipes),
and water vinyl chloride (PVCwater pipes), polychlorinated
biphenyls (industrial coolants and flame-retardants),
TCDD (toxic impurity of herbicide 2,4,5
trichlorophenol)
From Carr, 1985, with permission.
 TheEffect Mechanism of Toxins 29

Table 4.5 Selected Teratogens in Animal Models

,pietary deficiency: Vitamins A, Dand E, ascorbicacid, riboflavin,
nicotinamide, folic acid, panthothenic acid, trace metals (Zn, Mn,thiamine,
Cd, Co),
protein
Vitamin excess: Vitamin A, nicotinic acid
Karbohydrates: Galactose, 2-deoxyglucose, bacterial lipopolysaccharides
Antibiotics: Penicillin, tetracyclines, streptomycin, sulfanilamide
Chelating agents: EDTA
Trace metals: Methylmercury, inorganic mercury salts, lead,
strontium, selenium thallium,
Azo dyes: Trypan blue, Evans blue, Niagara skyblue 6B
Agents producing hypoxia: Carbon mongxide, carbon dioxide (eellutiel
Chemicals: Nicotine, quinine, saponin, boric acid, salicylate, 2,3,4,8
tetracholorodibenzORdigxin,
.Bolvents: nitrosamines, caffeine
Dimethyl sulfoxide, chloroform, 1,1-di-chloroethane, carbon Dmso
tetrachloride, benzene, xylene, cyclohexanone, propylene glycol, alkane,
sulfonates, acetamides, formamides
Mycotoxins: Rubratoxin B, aflatoxin B,, ochratoxin A
Physical agents: Radiation
. ifections: 10 viruses known, including rubella

Adapted from Harbison, 1980.

Teratogenic events have not been experimentally observed in human

beings, however, soie hormOnes such as estrogens and
acCspted as teratogenic to man. Also, the chemicals that showcoItisones are
effects in animals were found to be harmful according to theteratogenic
some clinical observations. results of

Jack