Transcript BB Toxicology and Risk Assess RR

Toxicity Evaluation of Chemical
Contaminants,
Regulations, Criteria and Standards
and of Aspects of
Risk Assessment and Risk
Communication
Lecture Outline
 Regulations: TSCA, FIFRA, EPA office of
Pesticide Program
 Definitions: Xenobiotics, Risk assessment,
Toxicity, Exposure, Dose, Response
 Pharmacology vs Environmental Toxicology :
Routes of exposure, uptake-distribution metabolismstorage-excretion, dose-response curves, interaction:
additive-synergistic and antagonistic effects.
 Bioassays : acute-subchronic , chronic
effects and safety factors
Environmental Toxicology
“All substances are poisons;
there is none which is not a poison.
The right dose differentiates a poison
from a remedy.”
An Individual View
“The sensitivity of the individual
differentiates a poison from a remedy.
The fundamental principle of toxicology
is the individual dose response curve.”
S. G. Gilbert (1997)
EPA
 Office of Chemical Safety and Pollution Prevention
(OCSPP)
 OSCPP’s mission is to protect you, your family, and
the environment from potential risks from toxic
chemicals.
 Through innovative partnerships and
collaboration, pollution is prevented before it
begins.
 This reduces waste, saves energy and natural
resources, and leaves our homes, schools and
workplaces cleaner and safer.
Environmental Toxicology was driven
by the following acts
 Toxic Substances Act
 Resource Conservation and Recovery Act
 Comprehensive Environmental Response
Act
 Federal Pesticides Act
 Clean Water Act
 Clean Air Act
The Toxic Substances Control Act
(TSCA) 1976

TSCA) provides EPA with authority to require reporting,
record-keeping and testing relating to chemical
substances and/or mixtures.
Specific Objectives
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To allow EPA to regulate new commercial chemicals
before they enter the market
To regulate existing chemicals when they pose
unreasonable risk to health and/or to the environment
To regulate their distribution and use
Federal Insecticide, Fungicide, and
Rodenticide Act 1996
(FIFRA)
 The Federal Insecticide,
Fungicide, and Rodenticide Act
(FIFRA) provides for federal
regulation of pesticide
distribution, sale, and use.
FIFRA
 All pesticides distributed or sold in the
United States must be registered
(licensed) by EPA.
 Before EPA may register a pesticide under
FIFRA, the applicant must show that using
the pesticide according to specifications
"will not generally cause unreasonable
adverse effects on the environment.''
FIFRA
 FIFRA defines the term ''unreasonable
adverse effects on the environment'' to
mean:
 '(1) any unreasonable risk to man or the
environment, taking into account the
economic, social, and environmental costs
and benefits of the use of any pesticide,
 OR
 (2) a human dietary risk from residues
that result from a use of a pesticide in or on
any food inconsistent with the Federal
standards
Office of Pesticide Programs
 Office of Pesticide Programs (OPP)
 OPP regulates the use of all pesticides
in the United States and establishes
maximum levels for pesticide residues
in food, thereby safeguarding the
nation's food supply.
Office of Pesticide Programs
 EPA has extended access to
information on risk assessment and
risk management actions to help
increase transparency of decision
making and facilitate consultation
with the public.
Office of Pesticide Programs
 In addition to regulatory functions,
information is provided on issues
ranging from worker protection to
misuse of pesticides.
Toxic Chemicals
Definitions
 Contamination. The introduction into soil, air or
water of a chemical, radioactive material or live
organism that will adversely affect the quality of that
medium.
 Standards vs Criteria. Numerical standards that are
established for the concentrations of chemical
substances in soil, groundwater, surface water, and
sediments that relate to the suitability of a site for
specific land uses and land use categories. Criteria
are also often referred to as guidelines.
Definitions
 Pathway. The route along which a
chemical substance or hazardous material
moves in the environment.

 Receptor. The person or organisms,
including plants, subjected to chemical
exposure.
Definitions
 Xenobiotics: human produced chemicals and
 introduced to the environment;
 Fate of Xenobiotics:
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
Bioaccumulation
Biotransformation
biological
Biodegradation
: build up in the food chain
: structure alteration: natural,
: broken down by biological activity
Definitions
 Risk Assessment.
 The scientific examination of the nature
and magnitude of risk to define the effects
on both human and other receptors of the
exposure to contaminant(s).
Definitions
 Risk Management.

The selection and implementation of a strategy of
control of risk, followed by monitoring and evaluation
of the effectiveness of that strategy.

Risk management may include direct remedial
actions or other strategies that reduce the
probability, intensity, frequency or duration of the
exposure to contamination.
Definitions
 Environmental Toxicology: adverse health
effects resulting from exposure to toxic
chemicals via inhalation, absorption and
/or ingestion
Acute
96hr
Sub-acute
1 month
Sub-chronic 1 year
Chronic
life span
usually 1 exposure
repeated doses
repeated doses
repeated doses
Definitions
 Adverse Effect.
 An undesirable or harmful effect to an organism,
indicated by some result such as mortality,
altered food consumption, altered body and
organ weights, altered enzyme concentrations
or visible pathological changes.
Toxicity
Toxicity is the ability of a chemical
to damage an organ system, to
disrupt a biochemical process, or
to disturb an enzyme system.
Exposure
Over time,
 The chemical might Accumulate
 OR re-destribute
 Metabolized
 Excreted
Routes of Exposure
Definitions
 Exposure :
the contact with an agent : oral,
dermal or by inhalation
 Hazard: the possibility that an agent
can cause harm
 Risk: the possibility of adverse health
effect including disease , injury or
death following exposure to an agent
Definitions
 Dose: amount of exposure to an
agent
 Response : reaction to the dose
 For example: drinking one glass
of milk might be fine, but drinking
a gallon of milk may result in
unpleasant response.
Dose- Response
 Hazard+ Exposure= Risk
 Depends on
1Individual sensitivity,
2dose
3the agent.
Dose : Body Weight
For exposure to a chemical agent, dose is usually
expressed in relation to body weight.
This is because for a fixed amount of toxic agent, the
dose, and likewise the effect, depends directly on
weight.
We know, for example, that one shot of alcohol would
have a very big effect on a child weighting 10 lbs and a
much smaller effect on an adult weighing 200 lbs.
Dose : Body Weight
To take this into account, dose is measured in units of
milligrams of toxicant per kilogram of body weight,
abbreviated mg/kg.
If someone consumed 100 mg of caffeine,
approximately the amount in a cup of coffee or two
cans of caffeinated soda, and if they weighed 70 kg
(about 155 lbs), the dose would be 100 mg/70 kg of
body weight or 1.4 mg/kg.
On the other hand, if a child weighing only 10 kg (about
22 lbs) consumed the same 100 mg of caffeine, the
dose would 10 mg/kg, seven times as large because
the body weight is one seventh.
Dose
Thus amount of exposure and the size of
individual determine the dose and are
critical factors in toxicology.
This principle can be an extremely
important factor in home lead or
pesticide exposures, where the dose a
child receives is far greater than the
adult due to the small size and extra
sensitivity of the child.
Effects of amount on
response
 Demonstration of the importance of
amount of the Dose
 Fill three same size glasses with
approximately ¾ water. (This
represents the approximate water content
of an individual).
Effects of amount on
response
 Then add 1 drop of red food color in
the first glass,
 3 drops in the second glass and
 7 drops in the last glass.
Effects of Amount on Response
Effects of amount on
response
 Stir with a pencil :
 Notice the color intensity based
on number of drops.
 This represents Color
diffusion/distribution in the body
Effects of Size on Response
Effects of Size on Response
 Fill one large glass and the small glass with
approximately ¾ water.
 The small glass represents a small child in
contrast to the adult size glass.
Effects of Size on Response
 Add one drop of food color in the
each glass.
 The small glass will be much
darker.
Effects of Size on Response
Difference between
Pharmacology
and
Environmental Toxicology
Definitions

Pharmacology:
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the scientific study of the origin, nature, chemistry,
effects, and use of drugs
Toxicology:
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the science that investigates the adverse effects of
chemicals on health

Web: www.asmalldoseof.org
.
Routes of Administration/Exposure
 Pharmacology:
 Routes of administration: oral,
Intramascular, Intravevous,
subcutaneous, topical
 Toxicology:
 Routes of exposure: oral, inhalation,
dermal
Key Factors Related to Routes
of Administration/Exposure
 In administration of medication, different
routes are used based upon the efficacy
of absorption of drugs from each route.
 In environmental health, different toxins
are absorbed through different routes of
exposure, which results in variations in
toxicity.
Administration/Exposure
 Pharmacology:
 Administration regimen: A drug can be
administered one time, short-term, or longterm.
 Toxicology:
 Exposure is the actual contact that a person has
with a chemical. It can be one-time, shortterm, or long-term.
Dose
 Pharmacology:
 Dose refers to the amount of a drug
absorbed from an administration.
 Toxicology:
 Dose refers to the amount of a chemical
absorbed into the body from an
exposure.
Key Factors Related to Dose
 In pharmacology, we have good
control over who receives what
dosage of what substance.
 In environmental health, it is usually
difficult to control or determine
who receives what dose of which
toxin(s).
Key Factors Related to
Administration/Exposure
 Drugs are taken voluntarily.
 Hazardous chemical exposures are
often involuntary.
 With both drugs and hazardous
chemicals, children’s behavior
entails special exposure risks.
Distribution, Metabolism and
Excretion
 Pharmacology and Toxicology:
 Distribution, metabolism and excretion
describe what happens to the drug or toxin
in the body.
 Distribution: organs that are reached
 Metabolism: chemical transformation
metabolites
 Excretion: elimination
.
Dose-Response Curve
 Pharmacology:
 Dose-response curve
graphically represents
the relationship
between the dose
of a drug and the response elicited
death
.
Dose-Response Curve
 Toxicology:
 Dose-response curve
describes the
relationship of the
body’s response to
different amounts of
an agent
Toxicology
Key Factors Related to Dose
Response
 The dose-response curve may
differ for different populations.
 Individuals vary with regard to
response to drugs or toxins.
Responses - Pharmacology
 Pharmacology:
 Low dose
no observable response
(subtherapeutic)

dose -- therapeutic
response (and side effects)
 > therapeutic dose --- toxicity
Responses - Toxicology
 Toxicology:

Only toxic effects are of
concern.
 Low doses
NOEL
(no observable effect
level)
 Exceeding the NOEL ------ toxicity
death
Interactions
 Pharmacology:
 Drug interactions define the effect one
drug has on another.
 Toxicology:
 Toxicological interactions define the
effect one chemical has on another.
Interactions
 3 types of effects:
 Additive: the sum = the whole
 Synergistic or potentiated: one
enhances the other’s effect
 Antagonistic: one reduces the effect
of the other
Potency
 Pharmacology:
 Potency refers to the relative amount of
drug required to produce the desired
response.
 Toxicology:
 The potency of a toxic chemical refers to
the relative amount it takes to elicit a
toxic effect compared with other
chemicals.
Biological Monitoring
 Pharmacology:
 Biological monitoring is done for some
drugs.
 Toxicology:
 Biological monitoring is done for some
toxic exposures.
The Regulatory Process
 The regulatory process for approval to sell
a medication includes several stages of
testing on animals and humans.
 The regulatory process for food, drug,
cosmetic, or pesticide in nature require
original testing for human health risks.
Bioassays
The measurement of biological
system responses resulting from an
exposure to a chemical substance
such as a drug or a pesticide.
Testing can be done by exposing
body cells, worms, fish, and other
animals .
Research
Assessment
Management
EPA Scientific Research/
Data Collection
Risk Assessment
• Animal Toxicology
• Clinical Studies
• Epidemiology
• Cell/Tissue
Experiments
• Computational
Methods
• Monitoring/
Surveillance
Dose-Response
Characterization
Risk Management
Control
Options
Research
Needs
Risk
Hazard
CharacteriCharacterization
zation
Collaboration
• Other Federal Agencies
• States/Local Agencies
• Academia
• Industry
• Public Interest/Environmental Groups
External Input
into Research/
Assessment
Exposure
Characterization
Non-risk
Analyses
D
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n
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Evaluation of Chemical Toxicity
 The main objective is to be able to project
animal results to humans.
 The TEST chemical is labeled (radioactive)
and fed to laboratory animals.
 It is assumed that metabolism of the
compound in animals follow the same
patterns in humans. (It is not always the
case, byproducts might not be the same).
Evaluation of Chemical Toxicity
 A) Acute Toxicities (96hrs)
 The US federal regulations require that an
acute test of the chemical in question be
determined in at least two animal species,
with one species being a non-rodent.
 Test results are reported as LD 50/LC50
which stands for Lethal Dose/Lethal
Concentration which kills 50% of Test
animals.
B)
Subacute toxicity:(3 months)
 Chemical is fed to animals for three
months at different doses.
 A Dose response curve is developed.
 The highest dose which produces no
adverse effects is used to estimate for a
safe dose for human consumption.
Evaluation of Chemical Toxicity
 C : Sub-chronic
 Exposure for one year
D) Chronic Toxicity Testing
(Animal life span)
 It follows the acute and subacute testing.
 Rodents are normally used because their life is
about four years life span.
 Testing lasts for three generations .
 The dose where animals produce normally and
their off springs show no mutagenic or teratogenic
effects is used to estimate the safe dose for
humans.
Toxicity Testing
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This dose will be divided by a
safety factor of
10,
100,
1000, or
10,000
depending on the toxicity of the
compound.
Bioassay Curve
Dose-Response Curves
10
5
0
1 2 3 4 5 6 7 8
Dose
Response
Response
15
12
10
8
6
4
2
0
1
4
7
10
Dose
13
16
Chronic Toxicity/Safety Factors
 a) Divide by 10
when chronic or subchronic human
exposure data identifying a NOAEL
(NO Observed Adverse Effect
Levels) are available,
 and are supported by chronic or
subchronic Toxicity in other species.
Safety Factors(cont.)
 b) Divide by 100
 When good chronic Toxicity data
identifying NOAEL are available for
one or more animal species ( and
human data are not available) OR
 when good chronic or subchronic
Toxicity data identifying a
LOAEL(lowest) in humans are
available
Safety Factors(cont.)
 c) Divide by 1000
 When limited or incomplete chronic or
subchronic Toxicity data are available
, OR
 when good chronic data that identify
a LOAEL but not NOAEL for one or
more animal species are available.
Safety Factors(cont.)
 d) Divide by 10,000
 When a subchronic study identifying a
LOAEL BUT NOT a NOAEL