Toxicology

Reporters:
Evangeline V. Capili
Sweet Gilleen P. Borromeo
Victoria P. Borja
Introduction

 Toxicant: can be a chemical, physical or

biological agent that may have an adverse
effect on biological organisms.
 Toxicology: Qualitative or quantitative study of
the adverse effects of toxicants on a biological
organism.
 Toxicity: Property of the agent describing its
effect on biological organism.
 Industrial Hygiene: Technique to reduce toxic
hazard of a substance.
Paracelsus stated the problem;

 All substances are poison; there is none which is not

poison.
 The right dose differentiate between a poison and a
remedy.
 Harmless substances, such as water, can become
fatal if delivered to the biological organism in large
enough doses.
 A fundamental principle of toxicology is; there are
no harmless substance s, only harmless ways of
using substances.
Types of toxicants

 Chemical Toxicants: include inorganic substances {e.g. lead,

mercury, asbestos, hydrofluoric acid, and chlorine gas} organic
compounds {e.g. methyl alcohol}, most medications, and poisons
from living things {e.g. snake’s venoms}.
 Biological Toxicants: include those bacteria and viruses that are
able to induce disease in living organism.
 Physical toxicants: include things not usually thought of under the
heading of “toxic” by many people: dust, fiber, direct blows,
concussion, sound and vibration, heat and cold, non-ionizing
electromagnetic radiation such as infrared and visible light and
ionizing radiation such as X-rays and alpha, beta, gamma
radiation.
Toxicants
 You have to know about:

• The way toxicants enter biological organisms.

• The way toxicants eliminated from biological organisms. TOXICOLOGY
• The effect of toxicants on a biological organisms.

• Methods to prevent or reduce the entry of toxicants into

biological organism. Industrial Hygiene
 How toxicants enter biological
organisms

• Toxicants enter biological organisms by the following

routes.
 Ingestion: through the mouth into the stomach.
 Inhalation: through the mouth or nose in the lungs.
 Injection: through cuts into the skin.
 Dermal absorption: through skin membrane.
Methods for control

 Ingestion: enforcement of rules on eating, drinking

and smoking.
 Inhalation: ventilation, respirators, hoods and other
personal protection equipment.
 Injection: proper protective clothing.
 Dermal absorption: proper protective clothing.
Figure 2-1 shows the expected blood-level concentration as a function
of time and route of entry. The blood-level concentration is a function
of a wide range of parameters, so large variations in this behavior are
expected.

Figure 2-1. Toxic blood-level concentration as a function of route of exposure. Wide

variations are expected as a result of rate and extent of absorption, distribution,
biotransformation, and excretion. The gastrointestinal (GI) tract, the skin, and the
respiratory system play significant roles in the various routes of entry.
How toxicants are eliminated from
biological organisms?

 Excretion: through the kidney, liver, lungs or others.

Kidneys are the dominant means.
 Detoxification: by changing the chemical into
something less harmful by bio-transformation. Liver
is the dominant organ.
 Storage: in the fatty tissue.
Toxic effects that are irreversible

 Carcinogen causes cancer.

 Mutagen causes chromosome damage.
 Reproductive hazard causes damage to reproductive
system.
 Teratogen causes birth defects.
Effects may or may not be reversible

 Dermatotoxic affects skin.

 Hemotoxic affects blood.
 Hepatotoxic affects liver.
 Nephrotoxic affects kidneys.
 Neurotoxic affects nervous system.
 Pulmonotoxic affects lungs.
Toxicological Studies

 The main objective: to quantify the effects of the suspect

toxicant on a target organism.
 Animals are normally used, usually with the hope that the
results can be extrapolated to humans.
 Before a study, the following items must be identified.
The toxicant
The target organism
The effect or response to be monitored
The dose range
The period test
Toxicological Studies

 The dose units depend on the method of delivery.

 For substances delivered {through ingestion or
injection}, the dose is measured in milligrams of
agent per kilogram of the body weight.
 For gaseous airborne substances the dose is measure
in ppm or milligrams of agent per cubic meter of
air.
 For airborne particulates, the dose is measure d in
milligrams of agent per cubic meter of air.
Toxicological Studies

 The period of the test depends on whether long or

short term effects are on interest
 Acute Toxicity- effect of a single exposure or a
serious of exposure close together in a short period
of time.
 Chronic Toxicity- effect of multiple exposures
occurring over along period of time.
 Chronic toxicity is difficult to perform most
toxicological are based on acute exposures
Toxicology experiments with animals
 2.5 Dose versus Response

 Biological organisms
respond differently to the
same dose of a toxicant.
 These differences are a
result of:
- Age - Diet
- Sex - General Health
- Weight - Other factors
 Dose versus Response (cont.)

Consider a toxicological test run on a large number of individuals. Each individual is

exposed to the same dose and the response is recorded. A plot of the type shown in
Figure 2-2 is prepared with the data. The fraction or percentage of individuals
experiencing a specific response is plotted.

Figure 2-2. A Gaussian or normal distribution representing the biological response

to exposure to a toxicant.
 Dose versus Response (cont.)

To compute the probability, mean and variance…

Equation 2.1

The standard deviation and mean characterize the shape and the location of the normal
distribution curve, respectively. They are computed from the original data f(xi) using the
equations
Equation 2.2 Equation 2.3

The mean determines the location of the curve with respect to the x axis, and
the standard deviation determines the shape.
 Dose versus Response (cont.)

Figure 2-3, shows the effect of the standard deviation on the

shape.

Figure 2-3. Effect of the

standard deviation on a
normal distribution with a
mean of 0. The distribution
becomes more pronounced
around the mean as the
standard deviation
decreases.

As the standard deviation decreases, the distribution curve becomes more

pronounced around the mean value.
 Dose versus Response (cont.)

Figure 2-4. Percentage of individuals affected based on a response

between 1 and 2 standard deviations of the mean.

The area under the curve of Figure 2-2 represents the percentage of individuals affected for a
specified response interval. In particular, the response interval within 1 standard deviation of the
mean represents 68% of the individuals, as shown in Figure 2-4a. A response interval of 2
standard deviations represents 95.5% of the total individuals (Figure 2-4b). The area under the
entire curve represents 100% of the individuals.
 Example no. 1
Seventy-five people are tested for skin irritation because of a specific dose of a
substance. The responses are recorded on a scale from 0 to 10, with 0 indicating no
response and 10 indicating a high response. The number of individuals exhibiting a
specific response is given in the following table:
Number of
Response
individuals affected

a. Plot a histogram of the number

0 0 of individuals affected versus
1 5 the response.
2 10
b. Determine the mean And the
3 13
standard deviation.
4 13
5 11 c. Plot the normal distribution on
6 9 the histogram of the original
7 6 data.
8 3
9 3
10 2
Total = 75
 Solution

a. The histogram is shown in Figure 2-5. The number of individuals

affected is plotted versus the response. An alternative method is to plot
the percentage of individuals versus the response.

Figure 2-5. Percentage

of individuals affected
based on response.
 b. The mean is computed using Equation 2-2

The variance is computed using Equation 2-3:

c. The normal distribution is computed using Equation 2-1. Substituting

the mean and standard deviations, we find
The distribution is converted to a function representing the number of
individuals affected by multiplying by the total number of individuals, in this
case 75. The corresponding values are shown in Table 2-3 and Figure 2-5.
x 75 f(x)
0 0.0232 1.74 Table 2-3. Theoretical
1 0.0519 3.89 Frequency and Number
2 0.0948 7.11 of People Affected for
3 0.1417 10.6 Each Response for
4 0.173 13.0 Example 2-1
4.51 0.178 13.3 The toxicological
5 0.174 13.0 experiment is repeated for a
6 0.143 10.7
number of different doses,
and normal curves similar to
7 0.096 7.18 Figure 2-3 are drawn. The
8 0.0527 3.95 standard deviation and mean
9 0.0237 1.78 response are determined
10 0.00874 0.655 from the data for each dose.
A complete dose-response curve is produced by plotting the
cumulative mean response at each dose. Error bars are drawn
at ±σ around the mean. A typical result is shown in Figure 2-6.
Figure 2-6. Dose-response curve. The
bars around the data points represent
the standard deviation in response to a
specific dose.

Figure 2-7. Response versus log dose

curve. This form presents a much
straighter function than the one shown
in Figure 2-6.

For convenience, the response is plotted versus the logarithm of the

dose, as shown in Figure 2-7. This form provides a much straighter line
in the middle of the response curve than the simple response versus
dose form of Figure 2-6.
Lethal Dose Curves


Dose Limit Values

 ED – Effective dose for f

percent of population.
Reversible response
 TD – Toxic dose for f
percent of population.
Undesirable response
that is irreversible
 LD– Lethal dose for f
percent of population.
2.6 Models for Dose and Response
Curve


Relationship Between Percentages
and Probits

Figure 2-9. The relationship

between percentages and
probits. Source: D. J. Finney,
Probit Analysis, 3rd ed.
(Cambridge: Cambridge
University Press, 1971), p.
23. Reprinted by permission.
Relationship Between Percentages
and Probits
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.
Probit Correlations for a Variety of Exposures

 Using probits, most response versus dose

curve can be represented by:
 Eq. 2-5 Y = k1 + k2*ln(V)
Y – Probit
V – Causative variable
 Example no. 2
A blast produces a peak overpressure of 47,000 N/m2 . What
fraction of structures will be damaged by exposure to this
overpressure? What fraction of people exposed will die as a
result of lung hemorrhage? What fraction will have eardrums
ruptured? What conclusions about the effects of this blast can
be drawn?

Solution: (Solve using eq. 2-5 and substitute the corresponding

values from table 2.5)

Y = k1 + k2*ln(V)
 Percentage
Y
Affected
Y= - 23.8+ 2.92 x
Structural Damage : ln(47,000) 7.61 99.6

: Y= - 77.11+ 6.91 x
Died from lung
ln(47,000) -2.76 0 (Y is negative)
hemorrhage

Y= - 15.6 + 1.93 x
Eardrums uptures 56 56
ln(47,000)

Conclusion

The blast is not serious enough to expect fatalities, but serious

enough to cause extensive damage to surrounding structures
and to rupture eardrums of more than half of the people
exposed.
Chemical Vapors

 When dealing with exposures of a chemical

vapor (toxic cloud) then the probit constants
are correlated by:
– Y = a + b ln Cnt
– a, b and n are experimentally determined constants
– C is concentration in ppm
– t is the exposure time in minutes
Chemical Vapors

 When the exposed subjects receive different doses

as a function of time
t2

C t   C dt   C ti
n n
i
n

t1 i
2.7 Relative Toxicity
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.
2.8 Threshold Limit Values
 The American Conference of Governmental Industrial
Hygienists (ACGHIH) has established threshold doses,
called TLV, for a large number of chemical agents.
 TLV= airborne concentrations that correspond to
conditions under which no adverse effects are normally
expected during a worker’s lifetime.
 The exposure occurs only during normal working hours
– 8 hrs/day, 5 days/week (not continuous exposure).
 TLV was formerly called MAC (maximum allowable
concentration). Process Safety - CPE
Threshold Limit Values
Converting from mg/m3 to ppm

 M is molecular weight
 T is temperature in Kelvin
 P is pressure in atm
2.9 National Fire Protection Association
(NFPA) Diamond

 Another method that is used to characterize the hazardous

properties of chemicals is the National Fire Protection Association
(NFPA) diamond.
 The NFPA is a professional society that was established in 1896
to reduce worldwide fatalities and injuries due to fires and other
hazards.
 Their primary function is to promote consensus codes and
standards, including the National Electrical Code (NEC).
 The NFPA diamond frequently appears on chemical containers
and storage vessels.
 The main purpose of the diamond is to provide a quick means for
emergency response personnel to recognize the chemical
hazards that they may face during a fire or other emergency.
The NFPA diamond consists of 4 separate areas shown in Figure 2-14. The
respective areas correspond to health, fire, stability, and special hazards.

• NFPA diamonds are frequently found on chemical containers in laboratories.

Example no. 3
Required:
a. The potential death of group 1 and group 2
b. The overall potential death.
 First Group – 500 Individuals
Time Conc.

50 200 40,000 2,000,000

30 100 10,000 300,000

10 50 2,500 25,000

For the first group the potential chlorine death is

283 individuals.
 2nd Group – 500 Individuals
Time Conc.

150 200 40,000 6,000,000

50 100 10,000 500,000

20 50 2,500 50,000

For the 2nd group the potential chlorine death is

436 individuals.
b. The overall potential death.

First Group - 283

2nd Group - 436

Overall death = 283 + 436 = 719

Death Percent = 79.1%