Professional Documents
Culture Documents
Pharmaceutical Industry:
Toxicology
Dave Cragin, Ph.D., DABT
柯大卫
Professor of the International Program in
Pharmaceutical Engineering Management
北京大学
和
Adjunct Professor of Health Policy and Public
Health
University of the Sciences, Philadelphia
1
Uses of Risk Assessment in the
Pharmaceutical Industry:
Toxicology
2
Is anything completely safe?
Completely Non-toxic?
3
Is anything completely safe?
Non-toxic?
Woman drinks so much water she dies
POSTED: 10:33 p.m. EST, January 13, 2007
A woman who competed in a radio station's
contest to see how much water she could
drink without going to the bathroom died of
water intoxication.
Victim was trying to win video game console
for her children.
4
The dose differentiates a poison from a
remedy
Paracelsus, 1493-1541
7
Terminology – Threshold
Threshold – Dose above which health
effects are likely to occur and below
which no effects will occur.
Exposure below the threshold = zero
risk
8
Acceptable Daily exposure: A dose
that is unlikely to cause an adverse
effect if an individual is exposed, by
any route, at or below this dose
every day for life
• Risk-Based Manufacture of Pharmaceutical
Products (RiskMaPP), ISPE, 2010
9
Toxicology
Risk Assessment
10
Key questions for ADEs
What is the adverse effect that
occurs at the lowest dose?
For most drugs, the “adverse effect” is
the pharmacologic effect
Who is most sensitive to the effect?
Pregnant women?
Children?
Others?
11
Key questions for ADEs
If we protect against the effect that
occurs at the lowest dose, we
protect against other adverse effects
as well
True for patients and employees
12
Key questions for ADEs
Are the health effects of the
chemical well established?
Do we have human or lab animal
data?
• Animal data require more extrapolation
13
Toxicology for Risk Assessment:
Part 2. Setting the contaminant limit
for a chemical in food
David Cragin, Ph.D., DABT
柯大卫
Professor of the International Program in Pharmaceutical
Engineering Management
Peking University, Beijing
北京大学
&
Adjunct Professor of Health Policy and Public Health
University of the Sciences, Philadelphia
14
Why food?
北京大学 requested it
China-specific real example
Excellent example shows that ADEs are
applicable to any material
– Food or drug
– Any chemical
15
Regulatory Risk Assessment Example
16
Regulatory Risk Assessment Example:
Toxicity – Questions to Consider
17
Regulatory Risk Assessment Example:
Exposure – Questions to Consider
or
The maximum daily intake of that food?
18
Regulatory Risk Assessment Example:
Exposure – Questions to Consider
19
Melamine
Pharmacokinetics, Metabolism and Excretion
Rapidly absorbed
Excreted unmetabolized
Plasma half-life = 2.7 hours (WHO, 2008)
– What are the risk implications of rapid excretion?
20
Melamine
Toxicity
21
Melamine
Toxicity
22
Melamine
Toxicity
23
Time Frame for Toxicity:
Acute effects
Acute toxicity– sudden in onset,
from exposure to a relatively large
amount of material over a short
period. Usually reversible unless
lethal.
Examples: Eye and skin irritation,
allergic response
25
Melamine
Toxicity
26
Time Frame for Toxicity:
Subchronic effects
Subchronic toxicity– Delayed in
onset, from repeated exposure to a
relatively small amounts of material
over a prolonged period. May be
slowly reversible.
Examples of subchronic effects:
reproductive effects, anemia, immune
suppression, hormonal effects
27
Melamine
Chronic Toxicity
No data
28
Time Frame for Toxicity:
Chronic effects
Chronic toxicity– Delayed in onset,
from repeated exposure to a
relatively small amounts of material
over a lifetime. Usually irreversible
effects.
Examples of chronic toxicity: Cancer,
heart disease, kidney disease, nerve
damage
• Example: Tobacco smoke
29
Melamine
Toxicity
30
Melamine
Toxicity
31
Melamine
Toxicity
32
Melamine
What is an acceptable level of exposure?
33
Melamine
What is an acceptable level of exposure?
34
How do you calculate an acceptable
level of chemical in food?
35
How do you calculate an acceptable
level of chemical in food?
36
How do you calculate an acceptable
level of chemical in food?
37
Melamine presents a low hazard:
Why was there a problem?
38
Background to the Melamine Tragedy
Any action taken to reduce one risk, creates or increases other risks
– These collateral risks are often obvious only in retrospect
Unscrupulous individuals figured out how to fool the quality standard by adding
melamine to milk.
– According to the China Daily News, infant formula contained up to 6,196 ppm
melamine (China Daily, Oct 3, 2008)
Health based standard was 2.5 ppm
39
Summary/Conclusions
40
Summary/Conclusions
41