Toxicology

Instructional Learning Objectives

After completing this chapter, students should

be able to do the following:
i. explain how toxicants enter and eliminated
from biological organisms
ii. understand effects of toxicants, including
response vs dose
iii. apply probit equations to determine
response to dose
iv. Explain exposure limits such as Threshold
Limit Value (TLV) and Permissible Limit
(PEL)

2
Outlines

1. Introduction - Toxicology Studies & Definition

2. Routes of Entry
3. Causes and Effects
4. Models of Doses
5. Response Curves
6. Threshold Limit Values

3
Introduction – Toxicological Studies

v Objective – To quantify effects of suspect

toxicant on target organism
v Parameters that must be pre-identified
Ø Toxicant
• chemical composition + physical state
Ø Target Organism
• single cell → higher animals
Ø Effect @ response to be monitored
Ø Dose Range
• method of delivery
Ø Period of Test
• acute toxicity: short-term (single exposure)
• chronic toxicity: long-term exposure

4
Introduction – Definition

A. Toxicology: study of adverse effects of

toxicants on biological organisms
B. Toxicants: chemical or physical agent
including dusts, fibers, noise and radiation
C. Toxicity: property of the agent describing its
effect on biological organisms
D. Toxic Hazard: likelihood of damage to
biological organisms based on exposure

5
Routes of Entry
There are four primary routes by which
organisms are exposed to toxic

INHALATION *

INGESTION

ABSORPTION *

INJECTION

* Industrially most significant

 Routes of Entry
INGESTION INHALATION
Swallowing a Breathing and
substance smoking causes us
causes to inhale
penetration into substances which
the blood enter the lungs.
stream via the Substance inhaled
stomach and into the lungs are
small intestine. readily absorbed
into the blood
þ INHALATION stream.
þ INGESTION
þ ABSORPTION þ INHALATION
þ INJECTION þ INGESTION
þ ABSORPTION
þ INJECTION
Routes of Entry

INJECTION ABSORPTION
Injection occurs Entering the body
when substances through the skin
are forced through causes substances to
this skin. This can enter the blood
occur as a result of stream at a slower
such means as rate than by inhalation
compressed air, or or absorption.
by having the skin However, the resulting
scratched by a entry and distribution
penetrating object. within the body is the
same.
þ INHALATION þ INHALATION
þ INGESTION þ INGESTION
þ ABSORPTION þ ABSORPTION
þ INJECTION þ INJECTION
Routes of Entry - How Toxicants are Removed

q Excretion: through the kidneys, liver, lungs or

other organs,
q Detoxification: by changing the chemical into
something less harmful by biotransformation,
q Storage: in the fatty tissue.

v The kidneys are the dominant means of excretion

process
v The liver is the dominant organ in the
detoxification process
v Storage in the fatty areas, bones, liver and kidney.
e.g. Heavy metal, Hg, Pb

9
Causes & Effect

Various Responses to Toxicants

DANGER
n Effects that are irreversible:
CANCER
CAUSING
– Carcinogen causes cancer AGENT

– Mutagen causes chromosome damage

– Teratogen : (Latin - “The Study of

Monsters”) causes birth defects

n Effects that may or may not be irreversible:

• Dermatotoxic affects skin • Nephrotoxic affects kidneys
• Hemotoxic affects blood • Neurotoxic affects nervous
• Hepatotoxic affects liver system.
• Pulmonotoxic affects lungs
Dose Vs. Response

DOSE - amount of exposure to an agent.

RESPONSE - the reaction to the dose.
EXPOSURE - contact with an agent

Example - Eating a plate of NASI LEMAK AYAM and

ROTI CANAI TELUR may be just fine but eating six
plates at one time may produce a very undesirable
response.

“The dose makes the poison”

Therapeutic Toxic
Increasing Dose Effect
Effect

11
Dose Vs. Response

Dose-response curve
graphically represents
the relationship
between the dose of a
stimulant (e.g.
chemicals, drugs) and
the response
produced

Biological organism
respond differently to
the same dose
of a toxicant due to
age, sex, weight,
general health, etc.

12
 Dose Vs. Response

What Can Be Learned From A Dose-Response

Curve? (Assessment of toxicity)

The Median Lethal Dose The Median Lethal Concentration

LD50
The amount (dose) of a chemical
which produces death in 50%
of a population of test animals
to which it is administered by
any of a variety of methods
mg/kg
Normally expressed as
milligrams of substance per
kilogram of animal body
weight
LC50
The concentration of a chemical in
an environment (generally air or
water) which produces death in
50% of an exposed population
of test animals in a specified
time frame
mg/L
Normally expressed as milligrams
of substance per liter of air or
water (or as ppm)
Dose Vs. Response
From Chemical Process Safety, Third Edition,
By Daniel A. Crowl and Joseph F. Louvar (ISBN: 0131382268)

Figure 2-13 Two toxicants with differing relative toxicities at different doses. Toxicant A is more
toxic at high doses, whereas toxicant B is more toxic at low doses.

14
Dose vs. Response → Probit Analysis

• The dose level of the various hazard event

(e.g. toxic release) against fatality (or
severe injuries or damage) can be
conveniently determined using Probit
Analysis.

• It is a Graphical and Look-up Table

approach to determine probability of
fatality (or damage or injuries)

15
 Dose vs. Response → Probit Analysis

The graph plots the

relationship between
percentages
(fraction), P and
Probit variable, Y as
given by the equation :

1 Y -5 æ u 2
ö
P= 1 2 ò-¥
exp ç - ÷ du
( 2p ) è 2ø

16
Dose vs. Response → Probit Analysis
The relationship between percentages (fraction), P and
Probit variable, Y as given by the equation on previous
slide :
18
Dose vs. Response → Probit Analysis

The Probit variable

can be computed from :

Y = k1 +k2 ln V

Where
V is the causative
variables

19
Dose vs. Response → Probit Analysis

Below is the correlation that can be used to convert

Probits to percentage (%) – without table and graph.

20
Dose vs. Response → Quick Exercise 1

21
Dose vs. Response → Quick Exercise 1

22
Dose vs. Response → Probit Analysis

As the plot of Response vs. Log Dose is obtained

(slide 12), the relevant Probit variables could be
obtained by transforming the plot to straight-line
Probit vs. Log Dose curve.

Establish the straight-line

equation

Y = mslope·log(dose) + intercept

23
Dose vs. Response → Probit Analysis
From Chemical Process Safety, Third Edition,
By Daniel A. Crowl and Joseph F. Louvar (ISBN: 0131382268)

Figure 2-10 The probit transformation converts the sigmoidal response versus log dose curve
into a straight line when plotted on a linear probit scale. (Source: D. J. Finney,
Probit Analysis, 3rd ed. (Cambridge: Cambridge University Press, 1971), p. 24.
Reprinted by permission.)

24
 Dose vs. Response → Quick Exercise 2

A data was reported involving the toxicity of rotenone to the insect

species Macrosiphoniella sanborni. The rotenone was applied in a
medium of 0.5% saponin, containing 5% alcohol. The insect were
examined and classified one day after spraying.

25
Dose vs. Response → Quick Exercise 2

26
Dose vs. Response → Quick Exercise 2

27
Threshold Limit Values & Types

§ The lowest value on the response vs. dose curve is called as

the threshold dose

§ Below this value, the body can detoxify and eliminate the
agent without any effects

v TLVTWA Time weighted average for a normal 8 hour

workday or 40 hour workweek

v TLVSTEL Short-term exposure limit. The maximum

concentration can be exposed to for up to 15 minutes.
Four excursions per day with at least 60 minutes between

v TLVC Ceiling limit. This concentration should not be

exceeded
28
TLV – Example Values

Acetone 500 ppm

Ammonia 25 ppm
CO 25 ppm ppm = parts per
million by volume
Chlorine 0.5 ppm
Gasoline 300 ppm
Hexane 50 ppm
Phosgene 0.1 ppm
For flammables, TLV is ¼ of lower flammable limit.

29
Chapter 1: Introduction
Threshold Limit Values

Converting from mg/m3 to ppm

22.4 æ T ö æ 1 ö
C ppm = ç ÷ç ÷ ( mg / m 3
)
M è 273 ø è P ø

§ M is molecular weight
§ T is temperature in Kelvin
§ P is pressure in atm

30
PEL - Permissible Exposure Level
Published by OSHA, and have legal authority.
Defined the same as TLV.
Most PELs are same as TLVs.
Not updated as regularly as TLVs.
Most companies use lowest of the two values.

For some chemicals, i.e. benzene, vinyl chloride, a specific OSHA

regulation has been published. Each regulation is unique, but most
require EXPLICIT data that workers are not exposed.
See OSHA.gov web site for regulations.

31
Chapter 1: Introduction
 Tutorial 1

Chapter 2: Toxicology (Crowl & Louvar)

2-5, 2-8, 2-10, 2-21 & 2-22

32