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Toxicology Made Simple
February 7, 2006
Mary McDaniel, D.O., J.D., M.P.H.
McDaniel Lambert Inc.
[email protected]
Paracelsus
“The dose
alone makes
the poison.”
Toxicity vs. Hazard


Toxicity is the inherent potential for a substance
to cause harm. It is only one factor in
determining whether a hazard exists.
Hazard is the practical likelihood that the
chemical will cause harm and that depends on
exposure, susceptibility, and sensitivity.
Dose-Response Relationship

The key to understanding
the toxicity of any chemical
is its dose-response
relationship. This means,
how does the body respond
when exposed to
progressively higher doses
of chemical.
The LD50 (Lethal Dose 50)

This test examines the relationship between
dose and the most extreme response—death.

The dose causing death in half (50%) of the
animals exposed is called the LD50.

The more potent or toxic the chemical, the
lower the LD50 and the smaller the dose
needed to cause death.
The LD50
LD50 Dose-Response Results for Methyl-Ethyl-Deathyl-Meatloaf
How Much Is Too Much?

The LD50 is frequently used to rank the
toxicity of chemicals.
Toxicity Terms

LD50 (Lethal Dose, 50% kill) – the dose of
material that is ingested, injected or applied
to the skin that kills 50% of the treated
population. Often expressed as mg
chemical/kg body weight.

LC50 (Lethal Concentration, 50% kill) –
refers to the concentration of inhaled material
that kills 50% of the treated population.
Expressed as either parts per million (ppm)
or mg/m3 of inhaled material.
Dose Levels


The dose level at which the response (in this
case, death) begins is called the threshold level.
Toxicologist also investigate dose-relationships
for other symptoms of toxicity such as:





Irritation
Anemia
Liver enzyme changes
In those studies, the threshold level is the no
observed adverse effect level – NOAEL.
The no observed effect - NOEL
Dose-Response Relationship for a
Typical Chemical
One Size Doesn’t Fit All

The dose-response curve
in the graph is S-shaped
since each individual
responds a little
differently to the same
dose

This difference in
susceptibility is called
biologic variability.
What’s Your Limit?

Occupational exposure limits are set to
protect healthy workers and do not take
into consideration the unique
susceptibilities of the very young, very
old, the immuno suppressed or other
sensitive individuals.
Is Sugar That Bad?
What About TCE?
How are workers exposed?

Inhalation



Airborne chemicals entering the lung may act
directly, causing minor irritation or even pulmonary
edema.
Airborne chemicals may also be absorbed into the
bloodstream.
Skin and Eye

The eyes are not a major route of exposure. But are
especially susceptible to direct acting chemicals that
irritate or destroy tissue.
How are workers exposed cont’d

Ingestion



Primarily instances where food, coffee or cigarette
has become contaminated
Occurs indirectly after first being inhaled
incidentally
Injection



The least likely route of exposure.
Usually contact with used syringes
Risk is primarily blood-borne pathogens causing
illnesses ( Hepatitis B, AIDS)
Injuries can be local or long distant

Some chemicals may cause injury
at the point of initial contact - eyes,
skin, respiratory and digestive
tract. (corrosives)

Other chemicals cause systemic
toxicity after passing through
certain barriers, e.g. the skin, and
require absorption and distribution
to the nervous and reproductive
system and the fetus. (solvents)
Acute and Chronic Exposure/Health
Effects

Acute Exposure

A single exposure to a chemical
If resolved on its own—acute health effect
 If it persists for months or years—chronic health effect


Chronic Exposure

Usually lower dose exposure for long periods of time
associated with chronic effects.
What Is Hazardous?

Anything with an exposure limit by
ACGIH TLV - Threshold Limit Value
 OSHA PEL - Permissible Exposure Limit


Anything listed as a carcinogen by
NTP - National Toxicology Program
 IARC - International Agency for Research
on Cancer
 OSHA

Definition of Hazardous cont....
Physical hazards such as flammable,
explosive, oxidizer, pyrophoric, waterreactive
 Health hazards such as irritation,
corrosive, toxic, sensitizer, target organ,
developmental or reproductive toxicant,
carcinogen (even if not on one of the lists)

Health Hazard Definitions cont....
(Severe) Skin Irritant - primary skin
irritation score is 5 or more or human
evidence suggests irritation. May be
considered severe irritant as indicated in
ANSI Labeling Standard
 Skin Irritant - per ANSI Labeling
Standard, primary skin irritation score
between 3 and 5 or human evidence

Agency Definitions of Corrosivity Vary




EPA: PH less than or equal to 2 or greater
than or equal to 12.5
Consumer Product Safety Commission
(CPSC): The structure of the skin at site of
contact is destroyed or irreversibly changed
in 24 hours or less.
Department of Transportation (DOT): The
structure of the skin at site of contact is
destroyed or irreversibly changed in 4
hours or less.
OSHA: Visible destruction or irreversible
alteration in living tissue at the site of
contact.
Health Hazard Definitions cont....

Chronic Toxicity (target organs, cancer,
mutagenicity, developmental and
reproductive toxicants) - weight of
evidence approach, one well conducted
study of adverse effects requires warning
on the MSDS
Health Hazard Definitions cont....

Allergens (Sensitizers)

Sensitizers are chemicals that cause an allergic
response.


Nickel,
Photosensitizers require exposure to sunlight—
typically while on the skin—to cause allergic
response.
Health Hazard Definitions cont....

Asphyxiants interfere with the blood’s
ability to oxygenate tissues.
Simple axphyxiants are biologically inert gases
that compete with oxygen at high
concentrations and result in insufficient
amounts of required oxygen. e.g. nitrogen
 Chemical axphyxiants, through chemical
action, interfere with the body’s ability to use
oxygen.


e.g. hydrogen cyanide
How Irritating

Eye Irritant - transient changes of the
cornea (opacity), iris (hyperemia) or
conjunctiva (swelling)

Severe Eye Irritant - significant eye injury
such as loss of corneal epithelium, corneal
opacity, iritis, conjunctivitis. Reversible
within 21 days
Neurotoxins

Central Nervous System
(CNS) toxins
Anesthetics and narcotics
 Convulsants


Peripheral Nervous System
(PNS) toxins

lead
Blood

Bone Marrow. Agents that suppress its
function include:
Benzene
 Arsenic
 Bromine
 Methyl chloride
 Ionizing radiation

Liver Toxicity

The liver is a common target organ
of chemical-induced injury.
The liver processes most foreign
chemicals
 The primary organ for the
biotransformation of chemicals


Examples of acute liver injury
include:
Lipid Accumulation
 Cholestasis
 Necrosis
 Hepatitis

Kidney Toxicity
 Directly



Metals (Mercury, lead, cadmium)
Halogenated hydrocarbons (carbon tetrachloride and
chloroform)
Certain therapeutic agents (phenacetin, aspirin, and
certain antibiotics)
 Indirect


Toxic agents include:
Toxicity:
Depositing crystals in the tubular element of the
nephron
Hemolytic agents
Pulmonary Toxins
Irritants
 Fibrosis
 Allergic Reactions
 Emphysema
 Lung Cancer

Reproductive and Developmental
Toxicity

Reproductive System


Chemicals impair the ability of males or females
to contribute to conception
Developmental Toxins

Interfere with the normal development of a
fetus.
Chemicals in the news: Chromium

Chromium compounds are
widely used in industry

Valence state dramatically
affects toxicity and chemical
properties
Chromium: deadly carcinogen or
necessary element?
Both
 Chromium III is necessary to maintain
blood glucose levels
 Chromium VI is classified as a known
human carcinogen

Stay tuned: more on
chromium next week
Chemicals in the News : Dioxins, PCBs &
Dibenzofurans

Related groups of chemicals referred to as persistent
organic pollutants (POPs)

Even found in remote areas of the world near no industrial
sources

Pose a long-term threat
to environment

Because these types of
chemicals are frequently
found together, it is hard
to accurately analyze
human effects
Dioxins, PCBs & Dibenzofurans
Consist of aromatic rings
with different degrees of
chlorination
 Have similar modes of
toxicity
 Accumulate in fatty tissues

DIOXIN
PCB
DIBENZOFURAN
Dioxins
75 chemically related
compounds
 2,3,7,8-TCDD is most toxic
 Occur naturally as byproducts
from incineration
 Other manmade sources
including chlorine bleaching at
pulp paper mills

The Scary History of Dioxin




Herbicide Agent
Orange Vietnam war
1961-71
Chemical plant
explosion in Italy
1976
1978 Love Canal, NY
1983 Times Beach,
Missouri
Seveso, Italy 1976
How is the Public Exposed to Dioxin?
Emitted as byproduct into
the air
 Breathing of fumes/ash
from municipal garbage
incineration
 Eating contaminated fish
(esp. downstream from
paper mills)

FLY ASH
How Can Workers Be Exposed

Paper pulp mills

Operating incinerators

Some pesticide
operations
Dioxin Health Effects
Chloracne
 Headaches, dizziness,
digestive disorders
 Generalized aches and
pains
 Some possibility it
causes soft tissue
sarcoma

Dioxin Health Effects
Change in blood/urine may indicate liver
damage
 Glucose metabolism
 Changes in hormonal levels
 Increases the risk of several types of
cancer


World Health Organization classifies TCDD a
human carcinogen
Dioxins are Extremely Toxic to Some
Animals
Cancer
Liver
& kidney problems
Fetal death
Birth deformities
Some animals are especially
susceptible to dioxin
Hard to draw conclusions about human
sensitivity - we may not be as sensitive
Polychlorinated biphenyls (PCBs)
Widely used from 1930 1976
 Component of hydraulic
fluids, lubricants, capacitor
fluid, flame resistant
materials
 High thermal stability
 Low water solubility

PCBs

Strong resistance to chemical
degradation

Accumulates in aquatic environments

Found in nearly all mammals, marine
species, fish and birds at some level

Magnifies in high levels through food
chain transfer (Ex: Oregon whale levels)

Reproductive system is most sensitive
Viktor Yushchenko
June 2004
Dec. 2004
Jan. 2005
PCB Health Effects
 Children
born to
mothers with a high
dietary intake of
PCBs could have
behavioral and
immune system
problems
PCB Health Effects
In workers at PCB manufacturing plants
the most common effects were severe
acne and rashes
 PCBs cause cancer in laboratory animals
exposed for long periods of time
 USEPA named PCBs a probable human
cancer causing chemical

Paracelsus
“The dose alone
makes the
poison.”
Toxicology