Transcript Toxicology - AP Environmental Science

Toxicology
Toxicology: the study of how natural or manmade poisons cause undesirable effects in
living organisms.
Undesirable Effects: damaging to either the
survival or normal function of the individual.
Addresses a variety of questions:
EX: in agriculture, toxicology determines the
possible health effects from exposure to
pesticides or herbicides, or the effect of
animal feed additives, such as growth factors,
on people.
-In laboratory experiments on animals to
establish dose-response relationships.
- deals with the way chemicals and waste
products affect the health of an individual.
Basic Terminology
Toxin: toxic substances produced naturally. A
toxin is any poisonous substance of microbial
(bacteria or other tiny plants or animals),
vegetable, animal or non-synthetic chemical
origin that reacts with specific cellular
components to kill cells, alter growth or
development, or kill the organism.
Toxicant: any chemical that can injure or kill humans, animals,
or plants; a poison.
- used when talking about toxic substances that are produced by or
are a by-product of human-made activities.
EX: dioxin (2,3-7,8-tetrachlorodibenzo-p-dioxin {TCDD}), produced
as a by-product of certain chlorinated chemicals
Arsenic, a toxic metal, may occur as a natural contaminant of
groundwater OR may contaminate groundwater as a by-product
of industrial activities. If the second case is true, such toxic
substances are referred to as toxicants, rather than toxins.
Toxic: poisonous or deadly effects on the body
by inhalation (breathing), ingestion (eating),
or absorption, or by direct contact with a
chemical
Toxicity describes the degree to which a
substance is poisonous or can cause injury.
Depends on a variety of factors:
1. Dose: the actual amount of a chemical that
enters the body.
The amount of exposure and the type of toxin
will determine the toxic effect.
Acute (short term) exposure occurs over a very
short period of time, usually 24 hours.
Chronic exposures occur over long periods of
time such as weeks, months, or years.
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Dose-response is a relationship between
exposure and health effect, that can be
established by measuring the response
relative to an increasing dose.
Threshold dose: a dose or exposure level
below which the harmful or adverse effects of
a substance are not seen in a population.
also referred to as the no observed adverse
effect level (NOAEL), or the no effect level
(NEL).
- for substances causing cancer (carcinogens),
no safe level of exposure exists, since any
exposure could result in cancer.
LOAEL – least observed adverse effect level –
when negative results are first seen in a test
population
2. Duration - how long – chronic or acute
3. Shape and structure of the chemical
itself: determines how it will interact with
cells and other chemicals
Effect of pH on Absorption
4. Route of exposure: dermal, oral, respiratory
Gastrointestinal Tract:
- absorption depends on structure of
chemical
Respiratory Tract:
- inhalation or aspiration of gas, liquid or solid
particles
- absorption depends on solubility of the substance
into the blood or the size of the particles
Size of Particulate Matter: Dust, soot
- particle > 10 micrometers generally don’t enter the
respiratory tract – deposited in nose and sinus cavity
– trapped in mucus and expelled
- particles < 0.01 micrometers – exhaled
- particles between 0.01 and 10 micrometers can be
lodged in respiratory tract – the smaller the particle
the deeper in the lungs they travel
Skin – relatively impermeable due to the
compact dead cells at the surface
- permeable to non-polar substances like
chemical solvents
- substances may (although in small
amounts) be absorbed through the hair
follicles, sweat glands and sebaceous glands
5. Barriers to Absorption:
Blood brain barrier: Located in the capillary
wall of the blood vessels in the brain – tightly joined
and don’t let charged materials into the brain –
allows lipid soluble (fat like substances) into the
brain
Placenta – made up of layers of tissue derived
both from the mother and child – usually prevents
the transfer of most toxicants
Exception: methyl mercury – higher in fetuses
than mothers because of a less effective
(developed) blood brain barrier
6. Binding and Storage: site of toxin/toxicant storage
- Permanent binding or Reversible binding –
depends on the type of chemical bond
- covalent bonds tend to be permanent
- ionic or weak molecular bonds tend to be
reversible
Changes in Toxicant Levels in a Body
- can be problematic in the future if the storage site
is broken down and releases the toxicant at a
future date
- site depends on nature of the chemical
Adipose tissue – binding of lipid soluble
chemicals (DDT and DDE)
Bone – mineral toxicants such as lead – replace
the mineral matrix in the bone
7. Excretion and Elimination:
- principle routes: urine, biliary (liver), respiratory
- urine: water soluble substances are usually excreted
through the kidneys – one of the roles of the kidney and liver is to
convert non-water soluble substances into excretable forms
- biliary – toxicants in the blood and those bound to blood
proteins are removed by the liver and become part of the bile
which is then excreted into the small intestine and eventually
leave with feces – some may be metabolized by the intestinal
flora and then be reabsorbed
- lungs – gases dissolved in the blood can diffuse out
through the lungs
- other routes: gastrointestinal, mother’s milk, sweat and saliva
8. Biotransformation and Bioactivation: Toxicants
can undergo chemical change in the organism to
produce products called metabolites
- this process is called biotransformation
– usually organisms biotransform toxicants into less
harmful products in order to excrete them
- if the metabolite is more toxic than the original
chemical then the chemical is said to have
undergone bioactivation – some chemicals in the
body that are actually harmless become toxic
through bioactivation
Benzo[a]pyrene
Polycyclic Aromatic
Hydrocarbon (PAH)
Polycyclic - 5 Rings
Aromatic – contains a
benzene ring
Hydrocarbon –
composed of C & H
BaP is a Genotoxicant
•
Capacity to interact with and damage DNA
Sources of BaP
Inefficient burning of any carbon source
Burning of fossil fuels
Energy Production
Engines
Coal and Petroleum Processing
Bacterial and Plant Synthesis
Weathering of Rock
Volcanoes and Wildfires
Charbroiled Foods
Cigarette Smoke
Prevalence of BaP in environment
make the probability of contact
very high.
IMPORTANCE?
Possible Mutagenic Effects of BaP
Cellular Metabolism of BaP
BaP stimulates the production of Cytochrome
p450
•
Cyt p450 is a detoxification enzyme
The Paradox
•
Cyt p450 bioactivates BaP causing
it to be an active genotoxicant
Stimulation of Cytochrome p450
BaP enters organism
- respiration
- dermal absorption
- ingestion
BaP migrates across cellular
membrane
BaP
Cytoplasm
Stimulation of Cytochrome p450
BaP enters organism
- respiration
- dermal absorption
- ingestion
BaP migrates across cellular
membrane
Cytoplasm
BaP
Stimulation of Cytochrome p450
BaP binds to a protein
complex called
Aryl Hydrocarbon
Hydroxylase (Ah)
BaP
Ah
hsp90
Stimulation of Cytochrome p450
BaP binds to a protein
complex called
Aryl Hydrocarbon
Hydroxylase (Ah)
BaP
Ah
hsp90
Stimulation of Cytochrome p450
Causes the release of a heat
shock protein (hsp90)
BaP
hsp90
Ah
Stimulation of Cytochrome p450
Hsp90 is replaced by another
protein called
Aryl hydrocarbon receptor
nuclear transferase (Arnt)
BaP
hsp90
Ah
Arnt
Stimulation of Cytochrome p450
Allows for the BaP complex
to be translocated into the
nucleus
BaP
Ah
Arnt
Nucleus
Stimulation of Cytochrome p450
Allows for the BaP complex
to be translocated into the
nucleus
BaP
Nucleus
Ah
Arnt
Stimulation of Cytochrome p450
In the nucleus
• BaP complex stimulates the production of Cyt
p450
Stimulation of Cytochrome p450
In the nucleus
• BaP complex stimulates the production of Cyt
p450
•
Cyt p450 acts on BaP in cell
Bioactivation of BaP by Cyt p450
Cyt p450 adds
oxygen to BaP to
form BaP-7,8-epoxide
Bioactivation of BaP by Cyt p450
Another enzyme breaks
the epoxide bond by
adding water forming
BaP-7,8-diol
Bioactivation of BaP by Cyt p450
Cyt p450 adds another oxygen forming BaP7,8-diol-9,10-epoxide
Bioactivation of BaP by Cyt p450
BaP-7,8-diol-9,10-epoxide is the major
carcinogenic form of BaP
Binds covalently to DNA, RNA and proteins
Binds preferentially to guanine
Bioactivation of BaP by Cyt p450
Effects of BaP-DNA Adducts
Normally guanine binds to cytosine
BaP-DNA adduct with guanine disrupts
hydrogen bonding with cytosine
Normal Bonding in DNA
Effects of BaP-DNA Adducts
Results of G – C Disruption:
• Single Strand Breakage
• Replication problems
• G:C  T:A mutations
•
Possible precursors to Cancer
Importance of Studying BaP
•
Major pollutant easily incorporated into
tissues that has the potential to lead to
mutations and cancer
•
Biomarker for human health risk assessment
9. Individual human factors:
- individual susceptibility the differences in
types of responses to hazardous substances
between people. Each person is unique, and
because of that, there may be great
differences in the response to exposure.
Exposure in one person may have no effect,
while a second person may become seriously
ill, and a third may develop cancer.
- sensitive sub-population those persons who
are more at risk from illness due to exposure
to hazardous substances than the average,
healthy person. These persons usually
include the very young, the chronically ill, and
the very old. It may also include pregnant
women and women of childbearing age.
Depending on the type of contaminant, other
factors (e.g., age, weight, lifestyle, sex) could
be used to describe the population.
Toxic Symptom: any feeling or sign indicating
the presence of a poison in the system.
Toxic Effects: the health effects that occur due
to exposure to a toxic substance; also known
as a poisonous effect on the body.
Selective Toxicity: a chemical will produce
injury to one kind of living matter without
harming another form of life, even though the
two may exist close together.
Types of Toxic substances:
1. Heavy Metals: Pb, Hg, Cd
2. Solvents and Vapors
Nearly everyone is exposed to solvents.
Occupational exposures can range from the use of
"white-out" by administrative personnel, to the use of
chemicals by technicians in a nail salon. When a
solvent evaporates, the vapors may also pose a
threat to the exposed population.
3. Radiation and Radioactive Materials
4. Dioxin/Furans
Dioxin, (or TCDD) was originally discovered
as a contaminant in the herbicide Agent
Orange. Dioxin is also a by-product of
chlorine processing in paper producing
industries.
Dioxin Poisoning
5. Pesticides
The EPA defines pesticide as any
substance or mixture of substances intended
to prevent, destroy, repel, or mitigate any
pest. EX: insecticide, fungicide, rodenticide,
piscocide, herbicide
6. Plant Toxins
Different portions of a plant may contain different
concentrations of chemicals. Some chemicals made
by plants can be lethal. For example, taxon, used in
chemotherapy to kill cancer cells, is produced by a
species of the yew plant.
7. Animal Toxins
These toxins can result from venomous or poisonous
animal releases. Venomous animals are usually
defined as those that are capable of producing a
poison in a highly developed gland or group of cells,
and can deliver that toxin through biting or stinging.
Poisonous animals are generally regarded as those
whose tissues, either in part or in their whole, are
toxic.
All chemicals (or any chemical) may be poisonous at a
given dose and through a particular route. For
example, breathing too much pure oxygen, drinking
excessive amounts of water, or eating too much salt
can cause poisoning or death
Many toxins and toxicants are
ENDOCRINE DISRUPTORS
- disrupt the functioning of the endocrine
system
- a complex network of glands and hormones
that regulates many of the body's functions,
including growth, development and
maturation, as well as the way various organs
operate.
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Endocrine glands -- including the pituitary,
thyroid, adrenal, thymus, pancreas, ovaries,
and testes -- release carefully-measured
amounts of hormones into the bloodstream
that act as natural chemical messengers,
traveling to different parts of the body in order
to control and adjust many life functions
An endocrine disruptor is a synthetic chemical that
when absorbed into the body either mimics or blocks
hormones and disrupts the body's normal functions.
This disruption can happen through altering normal
hormone levels, halting or stimulating the production
of hormones, or changing the way hormones travel
through the body, thus affecting the functions that
these hormones control.
EX: Estrogen disruptors – send false signals to the
body and disrupt the normal functions of estrogen
Exposure to endocrine disruptors:
1. direct contact with pesticides and other chemicals
2. ingestion of contaminated water, food, or air.
3. found in insecticides, herbicides, fumigants and
fungicides that are used in agriculture as well as in
the home
4. Industrial workers can be exposed to chemicals
such as detergents, resins, and plasticizers
5. enter the air or water as a byproduct of many
chemical and manufacturing processes
6. when plastics and other materials are burned.
7. can leach out of plastics, including the type of
plastic used to make hospital intravenous bags
8. Many endocrine disruptors are persistent in the
environment and accumulate in fat, so the greatest
exposures come from eating fatty foods and fish
from contaminated water.
Results of Endocrine Disruption:
Feminization/masculinization
Changes in fertility
Hormonally related cancer
Birth Defects
Premature puberty
MEASURING TOXICITY:
1. Lethal dose-50% (LD50): the dose lethal to 50% of the
test population
- usually reported in milligrams of chemical toxicant
per kilogram of body weight (mg/kg)
- toxicity and LD50 are inversely related – the greater
the toxicity, the lower the LD50 – PAGE 155
2. Lethal concentration-50% (LC50): the lethal
concentration of the toxic substance in air or water for
50 % of the test population
3. Effective dose-50% (ED50): the dose of toxic
substance that is 50% successful (effective) in
producing a specific response
Measurements are reported as doseresponsive curves which shows the effect of
different doses on a population
scientists typically start with high doses and work
down to the threshold levels (maximum dose
with no visible effect)
LD50
(mg of toxicant per kg of test organism)
SPECIAL CONSIDERATIONS
Children
Greater susceptibility:
1. still developing
- changes in early development affect all
subsequent changes
2. not as effective at dealing with toxic
substances
3. weigh less
4. behaviors: crawling, chewing
Carcinogens:
cancer causing agents
“suspected carcinogens” – those determined by feeding
extremely large doses (unreasonable exposure) to rats
Why? Too long/expensive to work with small amounts and
large numbers of test animals
PROBLEM: once a chemical is “suspect”, scientist work
backward and extrapolate the harmful dose
- the body works with low dosages of toxicants
differently than large doses (chronic vs. acute) and
some studies indicate that very low doses may
stimulate the body to fight the effects of the
chemicals
Chemical Mixtures:
- exposure is not always simple but a complex
mixture of chemicals
chemical mixtures interact several ways
Additive: the chemicals work together and the result is
cumulative
Synergistic: the chemicals work together in an
enhanced method – greater than simply adding the
effects together
Antagonistic: the chemicals hinder one another and
the combined effect is less than the added,
anticipated effect
Disposal Issues:
“DILUTION IS THE SOLUTION TO
POLLUTION”
wash it down with plenty of water…..
Problem? Longer term effects, interactions,
accumulations
Countered by the Boomerang Paradigm – what
you throw away will come back to you (or the
following generations)
Leads to RISK ASSESSMENT:
statistical method to quantify the risks of a particular action
Adverse Human Health Risk Assessment
1.
Hazard Identification - identify the possible risk
substance
2.
Dose-Response Assessment – how much is
required to cause problems?
3.
Exposure Assessment – how long, how much,
where?
4.
Risk Characterization – running the math – what is
the likely hood of an individual or population to
have an adverse effect?
Risk is then controlled by RISK
MANAGEMENT – laws and regulations for
the development and use of the hazardous
substances
PRECAUTIONARY PRINCIPLE: anything new should be analyzed
with a high level of scrutiny until proven safe
may slow down progress, but may save lives
Ecological Risk Assessment: same basic process as human
health risk assessment except on a much wider scale – includes
many more variables and unpredictability
Cost Benefit Analysis: sometimes addressing a problem is very
expensive and the benefit to addressing it must outweigh the
cost – usually if human health is concerned the cost is
outweighed by the benefit, but if the benefit is considered to low
for the cost the problem may not be addressed in an adequate
way