Toxicology: Class Notes Test 1: Risk Assessment Safety Evaluation

Front 1

What is a poison?

Back 1

Any substance causing injury by chemical or physicochemical means.

Front 2

What is a bioassay?

Back 2

An experiment to measure effects of chemicals in living systems.

Front 3

What is toxicity?

Back 3

The inherent capacity of a substance to produce injury.

Front 4

What is risk?

Back 4

The probability of an injury under defined exposure conditions.

Front 5

What is safety?

Back 5

The probablity of injury under defined exposure conditions (for example a sealed toxin is safer than one in an open beaker)

Front 6

What is the basic premise of relative risk?

Back 6

All actions invoke some risk. There is no life without risk.

Front 7

What is the basic approach when considering relative risk?

Back 7

Define acceptable level of risk. Determine a 'Virtually Safe Dose'.

Front 8

What is a virtually safe dose?

Back 8

In the US this is a dose of a chemical defined so that a lifetime exposure for excess death risk is no more than one in one million.

Front 9

What is a hazard?

Back 9

The nature of adverse or harmful effects; potential for causing harm. This incorporates toxicant's intrinsic activity.

Front 10

What is risk?

Back 10

[Hazard/Safeguards]. Likelihood (probability, odds) of injury based on actions or conditions of use or exposure.

Front 11

What is relative risk?

Back 11

Theoretical risk vs. Proven risk.

Front 12

List the 4 aspects of Risk Assessment.

Back 12

1. Hazard identification

2. Dose response assessments

3. Exposure assessment

...1-3 help characterize...

4. Risk characterization

Front 13

What does Hazard Identification define?

Back 13

Defines the nature and severity of effects.

Front 14

What do dose response assessments look at?

Back 14

Dose vs Incidence. You extrapolate from high to low doses (uncertainty involved). You extrapolate from animals to humans (uncertainty involved).

Front 15

What do Exposure Assessments define?

Back 15

They define exposure from all sources.

Front 16

What does Exposure Assessment consider?

Back 16

Considers uniquely susceptible populations.

Front 17

What does Risk Characterization estimate?

Back 17

Estimates the incidence in a defined population for a given exposure.

Front 18

Define the difference between Risk Assessment and Risk Management?

Back 18

Risk Assessment involves scientific experiments and judgements.

Risk Mgmt involves politics and people. Involves societal and political decisions.

Front 19

What is the general philosophy of toxicology testing and risk assessment?

Back 19

Humans are AT LEAST as sensitive as the most sensitive species tested. (this is because testing is primarily done on animals)

Front 20

List 5 assumptions of laboratory animal testing?

Back 20

1. Effects in lab animals apply to humans (or you have to explain the differences away scientifically)

2. Large database for animals (there is a lot of info on animals)

3. High dose exposure (there is relatively few lab animals tested vs the likely number of humans that will be exposed)

4. Dosage: per unit body wt (mg/kg) is convenient.

5. Dosage: per unit bsa (mg/m^2) better equates to human dosage.

Front 21

What is a dilemma involved in extrapolating to very low doses?

Back 21

Large doses of toxicants tested in a relatively small number of lab animals.

Verses...

Very large numbers of people exposed to relatively small doses of toxicants.

(this makes the jump from animal studies to humans a big challenge)

Front 22

If a toxin has no threshold effect what will be observed on a graft?

Back 22

The line representing the chemical will go through zero on the x and y axis. This means that as long as chemical is present there is a response.

Front 23

Cancer causing agents are assumed to have no what?

Back 23

No threshold.

Front 24

When are safety evaluations generally applied?

Back 24

In drug development.

Front 25

What are the two purposes of drug development?

Back 25

1. Identify ALL possible adverse effects.

2. To estimate an ACCEPTABLE exposure level.

Front 26

What is NOEL?

Back 26

Highest No Observed Effect Level (dose). This is derived from chronic animal studies. The effect being studied does not have to be an adverse effect.

Front 27

What is NOAEL?

Back 27

Highest No Observed ADVERSE Effect Level. This is derived from chronic animal studies. (what is considered an adverse effect needs to be defined)

Front 28

What is an ADI?

Back 28

Acceptable Daily Intake. This is calculated from NOEL, NOAEL, etc.

Front 29

What is an Acute type of poisoning/testing defined as?

Back 29

Single/very short term types of poisoning/testing. From minutes to hours, observe up to 14 days.

Front 30

What is a Subchronic (subacute) type of poisoning/testing?

Back 30

Short term/frequent exposure. From few days to few months, often 90 days.
This is often used as a pilot to a chronic study.

Front 31

What is a chronic type of poisoning/testing?

Back 31

Long term. Months to years ~ "lifetime exposures" are different for different animals. Agent or injury accumulates over time.

Front 32

What is a local site of toxicant action?

Back 32

Site of initial contact. Skins, Lungs, Eyes, Mucous membranes.

Front 33

What is a systemic site of toxicant action?

Back 33

Site other than the contact site. AKA 'general'. Implies absorption and distribution.

Front 34

What is a target organ?

Back 34

The organ(s) most likely responsible for outcome.

Front 35

What needs to be identified in a safety evaluation?

Back 35

The active/toxic form (metabolite)

Front 36

What are idiosyncratic rxns?

Back 36

A problem areas of safety evaluations. It is an unexpected sensitivity to low doses, or resistance to high doses not predicted by animal models.

Front 37

Other than idiosyncratic rxns what else may be difficult to predict in safety evaluations?

Back 37

Interactions and Delayed toxicity.

Front 38

What is delayed toxicity?

Back 38

When a drug that is being taken is discontinued and negative effects show up later on.

Front 39

List 4 special studies?

Back 39

1. Carcinogenicity and Mutagenicity. (Genotoxic vs. Nongenotoxic)

2. Reproduction and Teratology (multigeneration studies)

3. Behavioral toxicity

4. Immunotoxicity.

Front 40

The concentration of toxicant at a site does not define what?

Back 40

It does not, by itself, define a target organ. The target organ may be an organ other than the one where the highest concentration of drug is found.

For example, Lead is found in bones but this is not the target organ because this is not what causes death in lead poisoning.

Front 41

The signs of poisoning do not always reflect what?

Back 41

The signs of poisoning does not always directly reflect the site of action.

For example, Carbon Monoxide poisoning does not affect CNS (it acts on blood).

Front 42

Human ? is unknown and not predictable with certainty.

Back 42

Carcinogenicity

Front 43

How do you calculate a Reference Dose?

Back 43

RfD = NOAEL/ (UF * MF) = ADI

UF = uncertainty factor

MF = Modifying factor

Front 44

What is the uncertainty/safety factor when human date is available?

Back 44

10

[10 * population variance]

Means we assume a 10-fold spread in our pop.

Front 45

What is the uncertainty/safety factor when adequate animal data is available?

Back 45

100

[10 * animals to humans]

Front 46

What is the uncertainty/safety factor used when there are 'other issues'? (other issues such as limited animal data, children exposed, feared effects, etc)

Back 46

1000

[10 * high dose to low dose]

Front 47

What is MF?

Back 47

Modifying Factors. Where politics plays a role.

Front 48

What do uncertainty factors provide?

Back 48

They provide a large margin of safety.

Front 49

What does risk management consider?

Back 49

Drug safety, Air/water quality standards, pesticide tolerances/food additive levels.

Front 50

What differentiates poison from remedy?

Back 50

The right dose differentiates poison from remedy.