GO 4 TOXICITY FACTORS.

PRINCIPLE OF TOXICOLOGY I STB 322

4.1 Explain the influence of route of administration on toxicity.

Route and Site of Exposure

The major routes (pathways) by which toxic agents gain access to the body are the
gastrointestinal tract (ingestion), lungs (inhalation), skin (topical, percutaneous, or
dermal), and other parenteral (other than intestinal canal) routes. Toxic agents
generally produce the greatest effect and the most rapid response when given directly
into the bloodstream (the intravenous route). An approximate descending order of
effectiveness for the other routes would be inhalation, intraperitoneal, subcutaneous,
intramuscular, intradermal, oral, and dermal. The “vehicle” (the material in which
the chemical is dissolved) and other formulation factors can markedly alter
absorption after ingestion, inhalation, or topical exposure. In addition, the route of
administration can influence the toxicity of agents. For example, an agent that is
detoxified in the liver would be expected to be less toxic when given via the portal
circulation (oral) than when given via the systemic circulation (inhalation).

Routes of Administration
Oral administration is often referred to as administration per os (PO). Compounds
can be administered mixed in the diet, dissolved in drinking water, by gastric gavage,
by controlled-release capsules, or by gelatin capsules. In the first two cases, either a
measured amount can be provided or access can be ad libitum (available 24 hours
per day), with the dose estimated from consumption measurements. For certain tests
pair-feeding of controls should be considered; that is, controls are permitted only the
amount of food consumed by treated animals. In any case it is essential to consider
possible nutritional effects caused by reduction of food intake due to distasteful or
repellent test materials. In gastric gavage, the test material is administered through a
stomach tube or gavage needle; if a solvent is necessary for preparation of dosing
solutions or suspensions, the vehicle is administered also to control animals.

Dermal administration is required for estimation of toxicity of chemicals that may

be absorbed through the skin, as well as for estimation of skin irritation and
photosensitization. Compounds are applied, either directly or in a suitable solvent,
to the skin of experimental animals after hair has been removed by clipping. Often
dry materials are mixed with water to make a thick paste that can be applied in a
manner that ensures adequate contact with the skin. Frequently the animals must be
restrained to prevent licking and hence oral uptake of the material. Solvent and
restraint controls should be considered when stress is involved. Skin irritancy tests

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may be conducted on either animals or humans, using volunteer test panels for
human test

Inhalation. The respiratory system is an important portal of entry, and for evaluation
purposes animals must be exposed to atmospheres containing potential toxicants.
The generation and control of the physical characteristics of such contaminated
atmospheres is technically complex and expensive in practice. The alternative—
direct instillation into the lung through the trachea—presents problems of
reproducibility as well as stress and for these reasons is generally unsatisfactory.
Inhalation toxicity studies are conducted in inhalation chambers. The complete
system contains an apparatus for the generation of aerosol particles, dusts, or gas
mixtures of defined composition and particle size, a chamber for the exposure of
experimental animals, and a sampling apparatus for the determination of the actual
concentration within the chamber.
Other methods of injection include intravenous (IV), intramuscular (IM),
intraperitoneal (IP), and subcutaneous (SC). Infusion of test materials over an
extended period is also possible. Again, both solvent controls and untreated controls
are necessary for proper interpretation of the results. There are at least 26 potential
routes of administration, with 10 of these being commonly used in toxicology.

Influence of Route of Administration

Reserpine was administered daily either subcutaneously or intraperitoneally
in the following vehicle: 5% polyethylene glycol, 1% benzyl alcohol and 0.25%
citric acid. Control rats received 1 ml/kg of this vehicle. Experimental groups were
selected randomly and animals were housed two/cage for convenience in estimating
food and water consumption. Food and water intake was measured by difference.
Each group received 50 g/day of purina rat chow which was placed directly inside
the cage. These animals were also presented 125 ml/day via standard water bottles.
Due to the high degree of physical deterioration and difficulty in handling chronic
reserpinized animals, certain criteria for the duration of any single experiment were
used. Drug administration to any experimental group was terminated when either an
LD-50 was attained, or when the mean body weight of the group had decreased by
more than 30%.
The sedation produced by this regimen did not appear to be cumulative as
indicated by the gross behaviour of these animals, maximal sedation developed
within 8 hours, whereas minimal sedation was apparent within 24 hours. Complete
recovery to normal behaviour was not observed, but the degree of sedation at both
the 8th and the 24th hour was similar on each day of reserving administration. An
extremely interesting behavioural syndrome developed in most animals following
15 doses of reserving. 24 hours following previous dose reserpinized animals
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became extremely hyperactive excitable and hypersensitive to handling and sound
stimuli. In some cages, an increase in fighting behaviour was also observed.
Unfortunately, this behaviour was evident until about the 30th day of administration
and was greatly diminished thereafter.

One of the cardinal principles of both toxicology and pharmacology is that the means
by which an agent meets in contact with, or enters, the body (i.e., the route of
exposure or administration) does much to determine the nature and magnitude of an
effect.
However, routes and their implications are not fully appreciated by most
toxicologists. In the day-to-day operations of performing studies on animals, such
an understanding of routes, their manipulation, means, and pitfalls of achieving
them, and the art and science of vehicles and formulations, is essential to the sound
and efficient conduct of any in vivo study.

MECHANISMS
There are three primary sets of reasons why differences in route of administration
are critical in determining the effect of an agent upon a biologic system:

(a) Local effects,

(b) Absorption and distribution, and
(c) Metabolism.

(a) Local effects: those peculiar to the first area or region of the body to which a test
material gains entry and/or contacts. As an example, for the dermal route, these
include irritation, corrosion, and sensitization. Likewise, for the parented routes,
effects may include irritation, pyrogenicity, sterility, and blood compatibility. In
general, the same categories of possible adverse effects (irritation, immediate
immune response, local tissue/cellular compatibility, and physiochemical
interactions) are the mechanisms of, or basis for, concern.

(b) Absorption and distribution: for a material to be toxic, the first requirement is
that it be absorbed into the organism [for which purpose being in the cavity of the
gastrointestinal (GI) tract does not qualify].
These are characteristics that influence absorption by the different routes and these
need to be understood by any person trying to evaluate and/or predict the toxicities
of different moieties.

4.2 Identify the animals used in toxicity tests.

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Rabbit, Dog, Rat, Guinea pig > Mouse, Pig, Primate, frog, Zebrafish and hamsters

4.3 Administer toxins into a guinea pig through different routes and determine the
influence of route on toxicity.

Assessment of Hypersensitivity Responses One of the most important and

challenging problems in the field of immunotoxicology is determining the potential
for chemicals to induce immunomodulation and, in the current context, to promote
hypersensitivity reactions. Thus, it becomes essential to have validated predictive
animal models and to understand the underlying mechanisms of action. The
following is a review of the currently used methods of predicting types of the most
frequently occurring hypersensitivity reactions to chemicals.

Assessment of Respiratory Hypersensitivity in Experimental Animals Methods for

detecting pulmonary hypersensitivity have been reviewed by Sarlo and Karol (1994)
and can be divided into two types:

(1) Those for detecting immunologic sensitization and

(2) Those for detecting pulmonary sensitization.

Immunologic sensitization occurs when antigen-specific immunoglobulin is

produced in response to exposure to an antigen or, in the case of type IV, when a
population of sensitized T lymphocytes is produced. Pulmonary sensitization is
determined by a change in respiratory function subsequent to the challenge of a
sensitized animal or patient. In certain cases, immunologic sensitization may be
confirmed by the detection of antigen-specific antibody; however, subsequent
challenge does not produce clinical signs of respiratory distress. It is also possible to
detect pulmonary sensitization in animal models where there is no detectable
antigen-specific antibody production. In these cases, cell-mediated or other
mechanisms may be involved or there may be a difficulty in antibody detection.

Guinea pig models have been most frequently used for detection of pulmonary
reactions to chemicals. In the guinea pig, as in the human, the lung is the major shock
organ for anaphylactic response. Like humans, the guinea pig also demonstrates
immediate- and late-onset allergic reactions as well as bronchial hyperreactivity. The
major difference in the mechanism of pulmonary responses between humans and
guinea pigs is that the antibody involved in type I reactions in the former is IgE and
in the latter is predominantly IgG1. Murine models are becoming more frequently
utilized in the evaluation of respiratory hypersensitivity. As in the human, IgE is a

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major anaphylactogenic antibody in the mouse, and more murine immunologic
reagents are available, allowing for more detailed mechanistic studies.

Methods utilized for respiratory exposure to chemicals are inhalation or either

intranasal or intratracheal administration. There are advantages and disadvantages
to each. Inhalation more closely represents environmental exposure by allowing for
chemical contact with the upper as well as the lower respiratory tract. However, the
equipment required is expensive and difficult to maintain. Exposure via the
intranasal route is easily accomplished and allows for distribution of antigen to the
upper and lower respiratory tract; however, studies have shown that a large
proportion of the material can be recovered from the stomach (Robinson et al.,
1996). In contrast, intratracheal instillation results in exposure to the lower
respiratory tract only, and this procedure requires the use of anesthesia.

4.4 Describe the effects of chemical interactions on toxicity.

Skin Effects of chemical on guinea pigs

Contact dermatitis is the commonest Beryllium related toxic effect. Exposure to
soluble Beryllium compounds may result in papulovesicular lesions on the skin,
which is a delayed type hypersensitivity reaction. The hypersensitivity is
cellmediated, and passive transfer with lymphoid cells has been accomplished in
guinea pigs. If contact is made with an insoluble beryllium compound, a chronic
granulomatous lesion develops, which may be necrotizing or ulcerative. If insoluble
berylliumcontaining material becomes embedded under the skin, the lesion will not
heal and may progress in severity. Use of a beryllium patch test to identify beryllium-
sensitive individuals may in itself be sensitizing, so any use of this procedure as a
diagnostic test is discouraged.

4.5 Describe the biological toxicity e.g. barriers, biotransformation, sensitivity of

organs, etc.
INTRODUCTON.
The detection of biological toxins is important in the areas of food safety,
industry, and in environmental monitoring. Events in the recent past have indicated
the involvement of biological toxins as terrorist threats. They have been used in the
military arena for quite a while. One of the earliest documented uses is perhaps the
donation of blankets infected with small pox by a British general to American
Indians to purposely infect them with this dreaded disease (History Channel on TV,
2005). Over the years, different countries in the West and elsewhere have developed

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‘weapon zed toxins’ that can annihilate large numbers of a population at a relatively
low cost compared to other weapons of mass destruction (WMD).
Biological Toxicity Definition
Toxicity is a measurement of the dosage needed of a particular substance to
damage a living organism. A substance becomes toxic at the dose which begins to
damage an organism. Contrary to popular belief, all substances have a certain
toxicity. Even water and oxygen are dangerous to organisms at certain
concentrations. Furthermore, different species experience toxins in different ways.
The toxicity of a certain substance, like sulfur for instance, will vary with the species.
To humans, large doses of sulfur are fatal. However, to the organisms living in the
heat of volcanic vents at the bottom of the ocean, sulfur is a necessary and welcome
nutrient.
Toxicity is determined by an organisms reactions to various dosages of a
chemical. The lethal dose is determined by a test in which organisms are dosed with
the chemical in question. The dosage which kills half of the population is considered
the lethal dose. This is referred to as an LD50 test, and used to be a standard measure
of toxicity. However, the ethics and reliability of this test have been called into
question in recent decades. Once it was understood that different toxins can effect
similar organisms in vastly different ways, it was no longer reliable to use laboratory
animals to predict human toxicity levels. New tests and measures are being
developed to study and determine toxicity in ethical and reliable ways. The field of
studying the toxicity of different chemicals is called Toxicology.
The most important thing to remember about toxicity is that everything is
a toxin, and only the dosage matters. Toxins work in many different ways, and
toxicology has many means of measuring and documenting the damage that different
toxins due. While some toxins seem extremely potent because they deliver a lot of
damage at once, other toxins which seep into the body slowly can do as much or
more damage.
TOXICITY AND EXPOSURE
Acute Toxicity
Certain chemicals or substances can be toxic even in a minor, or one-time
exposure. This is known as an acute exposure, and all substances have an acute
toxicity. Some substances can be very toxic acutely, even in a single exposure.
Consider snake venom. To be efficient for the snake, a very small amount of venom
must incapacitate their prey. It would cost them too much water and energy to
produce large amounts of venom, and it would also be hard to inject in a single
dosing.

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 However, venom and poisons are not the only acute toxins. Acute toxins
include things like carbon dioxide and nitrous oxide. Carbon dioxide is produced by
your cells as they create ATP, and nitrous oxide is the gas dentists use to put their
patients under before a surgery. Both of these gases are potentially deadly at a certain
pressure and concentration in the body.
Chronic Toxicity
Chronic toxicity is the opposite of acute toxicity. It is a measure of how toxic a
substance is over a longer period of time. This could be anything from weeks to
years, but it is just as significant to understand the chronic toxicity of a substance.
Many substances we use in consumer products are new to science. It is easy to test
their acute toxicity, because it is easy to administer a single dose and observe and
organism for a week or less. When observing chemicals for signs of being a chronic
toxin, the observer must watch the system for the entire life of an organism.

For this reason, the chronic toxicity of many products used in households is not well
understood. The Food and Drug Administration (FDA), as well as other regulatory
agencies, actively work to keep toxic chemicals out of the hands of consumers.
However, with the number of new chemicals and products appearing every year, it
is virtually impossible for these organizations to police everything. Combined with
the subtle and sometimes hidden illness associated with chronic toxins, this makes
finding and measuring chronic toxicity difficult. Scientists use the sciences of
statistics and epidemiology to track and understand chronic toxicants from products,
the environment, and other sources.

BIOTRANSFORMATION
Biotransformation is the process by which substances that enter the body are
changed from hydrophobic to hydrophilic molecules to facilitate elimination from
the body. This process usually generates products with few or no toxicological
effects. Bio-transformations sometimes yield toxic metabolites, through a process
known as bio-activation. The chemical reactions responsible for changing a
lipophilic toxicant into a chemical form are known as Phase I and Phase II bio-
transformations. The two groups are defined based on the reactions that are
catalyzed. Phase I reactions transform hydrophobic chemicals to more polar
products via oxidation, hydrolysis, or similar reactions.

BARRIERS
Biological barriers are living organisms that help protect the body. Millions of
harmless bacteria live on the human skin. Many more live in the GI tract. The
harmless bacteria use up food and space so harmful bacteria cannot grow.

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SENSITIVITY OF ORGANS

In one interpretation, both biology and systems theory define sensitivity in terms of
influence of a certain stimulus on a reaction. In systems theory, sensitivity is a
measure for how strong the reaction to a certain stimulus is; the stronger the reaction
to the same stimulus, the more sensitive (to that stimulus) the system is. In biology,
sensitivity is a measure for how strong a stimulus has to be, before a system reacts
to it; the smaller a stimulus is sufficient to elicit a reaction, the more sensitive a
system is.

In another interpretation, biology distinguishes between the normal physiological

reaction that is needed for the organism to be able to function, and a bigger than
normal and potentially dangerous reaction (hypersensitivity), that is detrimental for
normal function.

.
4.6 Explain the effects of dose and duration of exposure on toxicity.

For many years it was believed that the harmful effects of all toxic chemicals
increased with an increasing dose or exposure, and that there was a low threshold
dose below which there was no harmful effect. It was also assumed that both adults
and children responded similarly to toxic exposures. Scientific evidence now shows
that some chemicals, especially endocrine disrupting compounds, can exert negative
effects at extremely low levels of exposure, sometimes with more serious or different
effects than at higher doses. The timing, duration and pattern of exposure are just as
important as the dose. While it’s good to limit exposure to toxic chemicals and
radiation at every stage of life, it is even more important during critical periods,
including gestation, childhood and pregnancy.

4.7 Describe the effects of the following host factors on toxicity: i) Species, strain
and individual differences. ii) Sex, Hormonal status and pregnancy. iii) Age iv)
Nutritional Status v) Diseases.

Reproductive toxicity:
Reproductive toxicity refers to the potential risk from a given chemical, physical or
biologic agent to adversely affect both male and female fertility as well as offspring
development. Reproductive toxicants may adversely affect sexual function, fertility
as well as causing developmental toxicity in the offspring.

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Effects
Many drugs can affect the human reproductive system. Their effects can be
desired (hormonal contraception), a minor unwanted side effect (many
antidepressants) or a major public health problem (thalidomide).
However, most studies of reproductive toxicity have focused on occupational or
environmental exposure to chemicals and their effects on reproduction. Both
consumption of alcohol and tobacco smoking are known to be "toxic for
reproduction" in the sense used here. One well-known group of substances which
are toxic for reproduction are teratogens ¨C substances which cause birth defects.
(S)-thalidomide is possibly the most notorious of these.

Examples
Bisphenol A
Bisphenol A is an example of an endocrine disruptor which negatively affects
reproductive development. Bisphenol A is a known as an estrogen mimicker
(xenoestrogen) and a likely androgen mimicker. It is used in the production of
various plastic products. Bisphenol A exposure in fetal female rats leads to
mammary gland morphogenesis, increased formation of ovarian tumors, and
increased risk of developing mammary gland neoplasia in adult life. Bisphenol A
also affects male fertility by resulting in lower sperm quality and sex function.

Lead
Lead, a heavy metal that can exist in both organic and inorganic forms, is associated
with adverse effects on male libido, erectile disfunction, premature ejaculation and
poor sperm quality. Lead is believed to predominantly affect male reproduction by
the disruption of hormones, which reduces the quantity of sperm production in the
seminiferous tubules. .

Dibromochloropropane:
Dibromochloropropane is well-known reproductive toxicant that is known to cause
dose dependent testicular toxicity Workers in chemical factories exposed to
Dibromochloropropane have been shown to develop oligospermia and azoospermia.

Ionizing Radiation
Ionizing radiation in the form alpha, beta and gamma emissions are well known to
adversely affect male fertility. Exposure in the range of 0.1 to1.2 Gy is associated
with spermatogonial injury; whereas between 4-6 Gy reductions of sperm counts
have been reported.

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Diethylstilbestrol
A synthetic estrogen known to be another reproductive toxin, was used from 1938
to 1971 to prevent spontaneous abortions. Diethylstilbestrol causes cancer and
mutations by producing highly reactive metabolites, also causing DNA adducts to
form. Exposure to diethylstilbestrol in the womb can cause atypical reproductive
tract formation. Specifically, females exposed to diethylstilbestrol in utero during
the first trimester have are more likely to develop clear cell vaginal carcinoma, and
males have an increased risk of hypospadias.

Toxicity in species strain and individual difference:

Toxicity is the degree to which a chemical substance or a particular mixture of
substances can damage an organism. Toxicity can refer to the effect on a whole
organism, such as an animal, bacterium, or plant, as well as the effect on a
substructure of the organism, such as a cell (cytotoxicity) or an organ such as the
liver (hepatotoxicity). By extension, the word may be metaphorically used to
describe toxic effects on larger and more complex groups, such as the family unit or
society at large. Sometimes the word is more or less synonymous with poisoning in
everyday usage.
A central concept of toxicology is that the effects of a toxicant are dose-dependent;
even water can lead to water intoxication when taken in too high a dose, whereas for
even a very toxic substance such as snake venom there is a dose below which there
is no detectable toxic effect. Toxicity is species-specific, making cross-species
analysis problematic.

Types
There are generally five types of toxic entities;
1. Chemical
2. Biological
3. Physical
4. Radiation and
5. Behavioural toxicity

Disease-causing microorganisms and parasites are toxic in a broad sense but are
generally called pathogens rather than toxicants.

Factors influencing toxicity:

Toxicity of a substance can be affected by many different factors, such as the
pathway of administration (whether the toxicant is applied to the skin, ingested,
inhaled, injected), the time of exposure (a brief encounter or long term), the number
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of exposures (a single dose or multiple doses over time), the physical form of the
toxicant (solid, liquid, gas), the genetic makeup of an individual, an individual's
overall health, and many others. Several of the terms used to describe these factors
have been included here.

Effect of age in toxicity:

There are often large differences among humans in the intensity of response to toxic
chemicals, and variations in susceptibility of an individual over a lifetime. These can
be attributed to a variety of factors capable of influencing absorption rate,
distribution in the body, biotransformation and/or excretion rate of a particular
chemical.

Influence of Age
Compared to adults, very young children are often more susceptible to chemical
toxicity because of their relatively greater inhalation volumes and gastrointestinal
absorption rate due to greater permeability of the intestinal epithelium, and because
of immature detoxification enzyme systems and a relatively smaller excretion rate
of toxic chemicals. The central nervous system appears to be particularly susceptible
at the early stage of development with regard to neurotoxicity of various chemicals,
for example, lead and methylmercury. On the other hand, the elderly may be
susceptible because of chemical exposure history and increased body stores of some
xenobiotics, or pre-existing compromised function of target organs and/or relevant
enzymes resulting in lowered detoxification and excretion rate.

Nutritional status:
Exposure to environmental pollutants is a global health problem and is associated
with the development of many chronic diseases, including cardiovascular disease,
diabetes and metabolic syndrome. There is a growing body of evidence that nutrition
can both positively and negatively modulate the toxic effects of pollutant exposure.

Diets high in proinflammatory fats, such as linoleic acid, can worsen pollutant
toxicity, whereas diets rich in bioactive and anti-inflammatory food components,
including omega-3 fatty acids and polyphenols, can weaken toxicant-associated
inflammation.
Overnutrition (i.e. obesity) and undernutrition (i.e. famine) have been observed to
alter prenatal epigenetic tags that may increase the risk of offspring developing
disease later in life.

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Disease as host factors on toxicity:
Host factor is a medical term referring to the traits of an individual person or animal
that affect susceptibility to disease, especially in comparison to other individuals.
The term arose in the context of infectious disease research, in contrast to "organism
factors", such as the virulence and infectivity of a microbe. Host factors that may
vary in a population and affect disease susceptibility can be innate or acquired.
Some examples:

General Health
©Psychological characteristics and attitude
©Nutritional state
©Social ties
©Previous exposure to the organism or related antigens
©Haplotype or other specific genetic differences of immune function
©Substance abuse
©Race

4.8 Describe the physical and social factors that modify toxicity in organisms.

Factors Influencing Toxicity

In some instances, individuals can have unpredictable reactions, or idiosyncratic
responses, to a drug or other substance. An idiosyncratic response is uncommon, and
it is sometimes impossible to understand whether it is the result of a genetic
predisposition or has some other cause such as the status of the immune system. It
could result in an abnormally small or short, or abnormally large or long response to
the drug or other substance. Or, the response could be qualitatively different than
what has been observed in most other individuals.
The toxicity of a substance usually depends on the following factors:
©Innate chemical activity
©Dosage, especially dose-time relationship
©Exposure route
Species
Toxic responses can vary substantially depending on the species. Most differences
between species are attributable to differences in metabolism. Others may be due to
anatomical or physiological differences. For example, rats cannot vomit and expel

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toxicants before they are absorbed or cause severe irritation, whereas humans and
dogs are capable of vomiting.

Selective toxicity refers to species differences in toxicity between two species

simultaneously exposed. This is the basis for the effectiveness of pesticides and
drugs.
©Life stage, such as infant, young adult, or elderly adult
Gender:
Gender can play a big role in influencing toxicity. Physiologic differences between
men and women, including differences in pharmacokinetics and pharmacodynamics,
can affect drug activity.
©Ability to be absorbed
©Metabolism
©Distribution within the body
Excretion
The site and rate of excretion is another major factor affecting the toxicity of a
xenobiotic. The kidney is the primary excretory organ, followed by the
gastrointestinal tract, and the lungs (for gases). Xenobiotics may also be excreted in
sweat, tears, and milk.
A large volume of blood serum is filtered through the kidney. Lipid-soluble toxicants
are reabsorbed and concentrated in kidney cells. Impaired kidney function causes
slower elimination of toxicants and increases their toxic potential.
Health of the individual, including organ function and pregnancy, which involves
physiological changes that could influence toxicity
©Nutritional status
©Presence of other chemicals
©Circadian rhythms (the time of day a drug or other substance is administered)
Exposure Route
The way an individual comes in contact with a toxic substance, or exposure route, is
important in determining toxicity. Some chemicals may be highly toxic by one route

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but not by others. Two major reasons are differences in absorption and distribution
within the body. For example:
Absorption
The ability to be absorbed is essential to systemic toxicity. Some chemicals are
readily absorbed and others are poorly absorbed. For example, nearly all alcohols
are readily absorbed when ingested, whereas there is virtually no absorption for most
polymers. The rates and extent of absorption may vary greatly depending on the
form of a chemical and the route of exposure to it.
Metabolism
Metabolism, also known as biotransformation, is the conversion of a chemical from
one form to another by a biological organism. Metabolism is a major factor in
determining toxicity. The products of metabolism are known as metabolites. There
are two types of metabolism
Life Stage
An individual's age or life stage may be important in determining his or her response
to toxicants. Some chemicals are more toxic to infants or the elderly than to young
adults.
Detoxification
Bioactivation
In detoxification, a xenobiotic is converted to a less toxic form. This is a natural
defense mechanism of the organism. Generally, detoxification converts lipid-soluble
compounds to polar compounds.
In bioactivation, a xenobiotic may be converted to more reactive or toxic forms.
Cytochrome P-450 (CYP450) is an example of an enzyme pathway used to
metabolize drugs. In the elderly, CYP450 metabolism of drugs such as phenytoin
and carbamazepine may be decreased. Therefore, the effect of those drugs may be
less pronounced. CYP450 metabolism also can be inhibited by many drugs. Risk of
toxicity may be increased if a CYP450 enzyme-inhibiting drug is given with one that
depends on that pathway for metabolism.
There is awareness that the gut microbiota can impact the toxicity of drugs and other
chemicals. For example, gut microbes can metabolize some environmental
chemicals and bacteria-dependent metabolism of some chemicals can modulate their
toxicity. Also, environmental chemicals can alter the composition and/or the
metabolic activity of the gastrointestinal bacteria, thus contributing in a meaningful

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way to shape an individual's microbiome. The study of the consequences of these
changes is an emerging area of toxicology.
Distribution within the Body
The distribution of toxicants and toxic metabolites throughout the body ultimately
determines the sites where toxicity occurs. A major determinant of whether a
toxicant will damage cells is its lipid solubility. If a toxicant is lipid-soluble, it
readily penetrates cell membranes. Many toxicants are stored in the body. Fat tissue,
liver, kidney, and bone are the most common storage sites. Blood serves as the main
avenue for distribution. Lymph also distributes some materials.
Health Status
The health of an individual or organism can play a major role in determining the
levels and types of potential toxicity. For example, an individual may have pre-
existing kidney or liver disease. Certain conditions, such as pregnancy, also are
associated with physiological changes in kidney function that could influence
toxicity.
Nutritional Status
Diet (nutritional status) can be a major factor in determining who does or does not
develop toxicity. For example:
Consumption of fish that have absorbed mercury from contaminated water can result
in mercury toxicity; an antagonist for mercury toxicity is the nutrient selenium.
Some vegetables can accumulate cadmium from contaminated soil; an antagonist for
cadmium toxicity is the nutrient zinc.
Grapefruit contains a substance that inhibits the P450 drug detoxification pathway,
making some drugs more toxic.
Circadian Rhythms
Circadian rhythms can play a role in toxicity. For example, rats administered an
immunosuppressive drug had severe toxicity in their intestines 7 hours after light
onset compared to controls and to other times in the day. The rats had changes in
their digestive enzyme activity and other physiological indicators at this dosing time.
Other Factors
Presence of Other Chemicals
The presence of other chemicals, at the same time, earlier, or later may:

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Decrease toxicity (antagonism)
Add to toxicity (additivity)
Increase toxicity (synergism or potentiation)
For examples:
Antidotes used to counteract the effects of poisons function through antagonism
(atropine counteracts poisoning by organophosphate insecticides).
Alcohol may enhance the effect of many antihistamines and sedatives.
A synergistic interaction between the antioxidant butylated hydroxytoluene (BHT)
and a certain concentration of oxygen results in lung damage in the form of
interstitial pulmonary fibrosis.

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