Toxicology and Adverse Drug Reactions

Question 1

Define toxicology:

Answer 1

The study of adverse effects that are detrimental to either the survival or normal functioning of the individual.

Question 2

What is the major cause for drug failure in preclinical trials?

Answer 2

Toxicology.

Question 3

What is the major cause for drug failure in phase 1 clinical trials?

Answer 3

Clinical safety.

Question 4

What is the major cause for drug failure in registration phase?

Answer 4

Clinical safety.

Question 5

What are some factors other than dose which could influence toxicology?

Answer 5

Time (constant of multiple exposure), route of exposure (IV, oral etc) and target (pharmacology).

Question 6

Define Haber’s rule:

Answer 6

Cxt=k where C is concentration and t is time. This suggests that exposure to a low concentration of a poisonous gas for a long time often had the same effect (death) as exposure to a high concentration for a short time.

Question 7

How my toxicology be predicted?

Answer 7

Toxicology may be an intrinsic property of the molecule that results from interaction with a particular biological system, therefore is may be possible to predict the likely disposition and metabolism from physico-chemical parameters. In silico (computer) testing is relatively cheap and very fast.

Question 8

What is front loaded or discovery toxicology?

Answer 8

In recent years, toxicology has integrated supporting scientific disciplines into the drug discovery process in both large and small phamaceutical companies with the aim of influencing drug design at early stages well in advance of GLP pre-clinical toxicology testing.

Question 9

What are the requirements of toxicology testing?

Answer 9

Often drugs, food, chemicals, cosmetics and pesticides have to be tested for toxicology. The purpose of regulatory toxicology is to ensure that the benefits of chemical substances intended for use by humans outweigh the risk from their use.

Question 10

What is the primary aim of most toxicology studies?

Answer 10

To determine the potential for harmful effects in the intact living organism, and in many cases, by extrapolation to humans.

Question 11

Describe how test development for toxicology is an evolving science:

Answer 11

A lot of work is concentrated for developing new tests that explain the toxicity of compounds not seen in pre-clinical studies, and predict the toxicity of novel analogues.

Question 12

Describe the basic principles of toxicology:

Answer 12

Toxicology tests usually involve exposing animals or plants to the test substance under controlled conditions. For existing chemicals, toxicological information may be obtained from humans and animals such as those given drugs during clinical trials, exposed at the work place or in the general environment.

Question 13

There are 6 factors which toxicology studies should address. List these:

Answer 13

1. The injury produced (structure, functional or biochemical).
2. The dose-response relationship.
3. The mechanism(s) of toxicity.
4. The factors affecting the toxic response (route or exposure, species/sex of test animal, formulation).
5. Development of approached for recognition/detection of specific toxic responses.
6. Reversibility of response (spontaneous through heading, antidotal through treatment).

Question 14

By what factors may the toxic end points need to be evaluated in vitro and in vivo?

Answer 14

Cytotoxicity
Systemic toxicity
Sub-chronic toxicity
Genotoxicity (cancer)
Irritation/intracutaneous reactivity
Sensitisation

Question 15

Toxicology testing involves 5 levels of selection. List these:

Answer 15

1. Test species
2. End point (response)
3. Dose
4. Route
5. Duration of test

Question 16

List some features which may influence ADME:

Answer 16

Species, strain, gender, age, nutritional status.

Question 17

What are some biological considerations for test species?

Answer 17

Test species may not have the relavant target.
Test species may e subject to diurnal variation (timing of dosing may be important).
Environment, including temperature, humidity and photoperiod.

Question 18

Describe 4 toxicology end points:

Answer 18

1. Pharmacological (behavioual, pharmacodynamic, pharmacokinetic).
2. Direct toxicity (e.g. skin irritancy).
3. Genotoxicity (bacterial mutagenicity tests, 2-year carcinogenicity in 2 mammalian species).
4. Immunotoxicity (immune suppression, allergic reactions).

Question 19

How may safe and toxic doses be represented on a dose-response curve?

Answer 19

Those values to the left of the curve are considered to be ‘safe’ doses, and those to the right of the curve are considered to be toxic doses.

Question 20

How does endpoint detection cause a problem, and how is this overcome by population studies?

Answer 20

Due to the non-reversibility of many toxic end points it is not possible to look at the response of a tissue to increasing doses, so instead the dose required to produce a desired end point is studied in a population, with death as the endpoint.

Question 21

Describe no effect levels:

Answer 21

It is possible to have no-effect at the extreme left of the curve, so that a threshold dosage exists. It is therefore possible to determine a “no observable adverse effect level (NOAEL)” which can be used as a basis of assigning safe levels for exposure.

Question 22

In populations, safe versus toxic doses may be examined in three ways:

Answer 22

1. Dose required for pharmacological activity.
2. Dose required for sub-lethal toxicity.
3. Lethal dose.

Question 23

What factors may influence the curve shape of the frequency log-dosage curve?

Answer 23

Endogenous (genetic polymorphisms) and exogenous (drug interactions) factors. There may include cellular defense mechanisms (e.g. GSH) reverses of biochemical function. Saturation of the biochemical processes that produces the toxicant (metabolism) may result in a plateau for toxicity.

Question 24

Describe acute toxicity tests:

Answer 24

These are designed to determine the effects that occur within a short period after dosing. Usually only a single dose of compound is given, perhaps by different routes. Historically, they have been used to determine dose-response relationships and endpoints such as LD50.

Question 25

Define the therapeutic index:

Answer 25

The ratio of the doses required to produce a toxic and a desired response. TI=LD50/EC50.

The larger the number, the safer the compound. Greater than 10 is considered relatively safe.

Question 26

What replaced the LD50 system for testing toxicity in 2000?

Answer 26

The BTS recommendation, where doses of 5mg/kg, 50mg/kg and 500mg/kg were tested and toxicity and survival were observed.

Question 27

Describe sub-acute toxicity tests:

Answer 27

These involve exposing the animals to the compound for 28-90 days. Exposure is frequent and daily. These tests provide information on the target organs and the major toxic effects. Toxic effects that have a slow onset can be detected. Measurements of compound in tissues can be made and correlated with any toxic effects observed.