Environmental Toxicology

PUBH807 – Principles of Environmental Health

SGU-DPHPM
Kerry Mitchell

1
At the end of this lecture, you should be able to…
1. Classify common environmental toxic agents

2. Discuss the common assessments used to establish toxicity benchmarks

3. Explain the dose-response relationship and its use in toxicity evaluation

4. Discuss the outcomes of toxicant interactions

5. Explain the importance of routes of exposure

6. Explain the use of the precautionary principle in the context of food toxicology

7. Discuss the toxicity of some food toxicants

8. Discuss the toxicity of some common household products and their derivatives

9. Identify key factors that determine the transport, fate and potential toxicity of
toxicants in the environment

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Making the Case:
Pollution vs Other Causes of Global Deaths

Credit: StatisticaCharts; Source Lancet, 2015

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 What is toxicology?
The study of poisons

Ebers
Papyrus

1500 BC
à
late 1800s
Victorian Ancient
poisoners poisoners

4
 How can we define Toxicology?

The study of the adverse effects of

chemical, biological or physical agents
on living organisms.

5
Klassen 2013
 The dose makes the poison
“Sola dosis facit venenum”

• The father of toxicology

• Swiss physician-alchemist Phillip Von
Hohenheim (Paracelsus) – 1493 – 1541
• Promoted a focus on a primary toxic
agent (toxicon) as opposed to the
Grecian concept of a mixture of
substances

• “All substances are poisons; there is none

which (that is not a poison). The right dose
differentiates a poison and a remedy.” -
Paracelsus

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 Classification of Toxic Agents
… agents capable of causing adverse effects on or to living organisms

Toxicant: naturally Toxin: toxic

or substances that
anthropogenically are produced by
produced biological systems
substances (organisms)

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FC7; OBJ1
 Toxic agents can also be classified according
to their…
• Physical State – gas, solid,
liquid
• Chemical stability / reactivity
– explosive, flammable, etc.
• General chemical structure –
aromatic, halogenated
hydrocarbon, etc.
• Biochemical mechanisms of
action – acetylcholinesterase
inhibitor, axonic toxicants

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FC7; OBJ1
 How do we study these toxic agents…?
Toxicity Testing
• In silico, in vitro and in vivo research used to determine safe
doses of exposure.
• Human toxicity is usually but not always the focus
• Essential to regulate and monitor toxic substances or toxic
substance mixtures

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FC7; OBJ2
 Key Concepts – Dose-Response Relationship

The most fundamental

and pervasive concept Types of
dose-
in toxicology defined response
Individual describes
as… relationships
the response of an
• the relationship individual organism
to varying doses
between the degree
of response of the
Quantal
biological system distribution of
and the amount of individual response
toxicant to doses in a
population
administered
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FC7; OBJ2
 Klassen (2013)

A chemical may have

different molecular,
biochemical and
cellular effects each
with its own dose-
response relationship
Quantal level dose
response
characterization =
integration of multiple
individual dose-
response relationships
occurring in different cell
types at different
molecular sites
The nature of the
toxic response might
be different at low
doses and higher
doses

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EOHC#2; OBJ#2
 3 assumptions from
1. The observed dose-response
response is due to relationships
the administered
substance

3. There is a
quantifiable 2. The magnitude
method and of response is
precise means of related to the
expressing dose
toxicity

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FC7; OBJ2
 Concepts associated with quantal dose-response
relationships
1. the minimally effective
dose of any chemical
that evokes a stated all-
or-none response is
called the threshold
dose

2. The level at which there

is 50% response is
known as the Effective
Dose 50 (ED50)
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FC7; OBJ3
 TOXICITY TESTING

Key Concepts – Common Exposure Units

• Gram (g) is the standard unit though doses are usually
expressed in smaller quantities milligram (mg).

• Environmental exposure units are expressed as the

concentration of the toxicant in a unit of media

• mg per liter – mg/L (liquids)

• equal to parts per million – ppm
• mg per kilogram – mg/Kg (solids)
• equal to parts per million – ppm
• mg per cubic meter – mg/m3 (air)

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FC7; OBJ3
 Key Concepts – LD50 & LC50
(Median Lethal Dose)
LD50 - the concentration
of a substance, given all
at once which causes
the death of 50% of the
test population in a
specific period of time
FC7; OBJ3
(Median Lethal
Concentration) LC50 -
the concentration of a
substance in air, which
causes the death of 50%
of the test population in
a specific period of time
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 Key Concepts – NOEL & NOAEL

No observed adverse effect level

No observed effect level (NOEL) -
(NOAEL) - Greatest concentration
Greatest concentration or amount
or amount of a substance, found
of a substance, found by
by experiment or observation,
experiment or observation, that
which causes no detectable
causes no detectable alterations
ADVERSE alteration of
of morphology, functional
morphology, functional capacity,
capacity, growth, development, or
growth, development, or life span
life span of the target organisms
of the target organism

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FC7; OBJ3
 Key Concepts – LOEL & LOAEL
Lowest observed effect
level (LOEL) - Lowest
concentration or amount of
a substance, found by
experiment or observation,
that causes alterations of
morphology, functional
capacity, growth,
development, or life span of
the target organisms
FC7; OBJ3
Lowest observed adverse
effect level (LOAEL) - Lowest
concentration or amount of
a substance, found by
experiment or observation,
which causes ADVERSE
alteration of morphology,
functional capacity, growth,
development, or life span of
the target organism.
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 Our Points of Departure (POD) all together
…also known as “threshold doses”

OD
P

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FC7; OBJ3 Image Credit: USFDA
 Individual Susceptibility
VERY IMPORTANT CONSIDERATION

• Differences in types of responses to toxicants between

people.
• Exposure in one person may have no effect, while a
second person may become seriously ill, a third may
even develop a chronic disease.
• Sensitive sub-populations
• Immunosuppressed
• Pregnant
• Pre/Post natal
• Young
• Old

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FC7; OBJ3
 Modifying Factors
• Genes
• Genetic differences affect the degree of response to exposure to toxicants
• E.g. 50% of the Caucasian population has a gene deletion for the enzyme glutathione S-
transferase M1 and cigarette smokers who express two null alleles may be at slightly
increased risk of developing lung cancer compared with smokers who have one or both
copies of the normal gene
• E.g. Genetic variations that result in impaired glucose metabolism in some black populations
• Age
• Metabolic processes that aid in xenobiotic clearance are often altered at
juvenile and advancing ages.
• E.g. newborns have relatively low gastric emptying, gastrointestinal motility and expression
of metabolic enzymes.
• Sex
• Physical and biochemical variations results in varying degrees of responses to
toxicants in males and females.
• Growth and sex hormones influence the expression and function of toxicant
metabolizing enzymes which in turn alter disposition and toxicity.
• Circadian Rhythm
• Regulates molecular and physiological processes
• E.g. Inconsistent night-shift work and cancer
• E.g. Increased drug toxicity in animal models during dark cycles.
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 Note: Toxicokinetic (TK) and toxicodynamic (TD) considerations
inherent in interspecies and interindividual extrapolations for safety
factor estimations are applied to threshold doses to calculate
guideline values
• TK: the processes of absorption, distribution, elimination, and
metabolism of a toxicant
• TD: the actions and interactions of the toxicant within the organism and
describes processes at organ, tissue, cellular, and molecular levels

UF MF

UNCERTAINTY FACTOR MODIFYING FACTOR

SAFTEY FACTOR 21
Klassen 2013
FC7; OBJ3
 Key Concepts – Reference Doses & Guideline Values
APPLICATION OF TOXICITY TESTING

• Reference Dose (RfD) - an estimate, of daily to a chemical that is

assumed to be without adverse health impact in humans | used by
USEPA
• Acceptable daily intake (ADI) - the amount of a specific substance that
can be ingested on a daily basis over a lifetime without an appreciable
health risk | used by FAO/WHO

DO YOU REMEMBER
THE DOSES THAT ARE
Basic Calculation COSIDERED “POD”?

!"#
ADI / RfD = $%&'() &%*("+
UF – Uncertainty Factor Safety Factor
MF – Modifying Factor
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FC7; OBJ3
 Key Concepts – Acute & Chronic Toxicity
Adverse effects occurring within a (insert period of time) after exposure to a given concentration of a
test substance are considered à

Acute: within 24h Sub-acute - 1 Sub-chronic - for 1 Chronic - more

of a starting point month or less to 3 months than 3 months
• LD50 • Clinical chemistry • Establish • length of time
• Initial • Histopathology threshold doses; dependent on
identification of e.g NOAEL, LOAEL species
target organ • Target organ(s) • Identify long term
• Establishes confirmation effects.
reversibility • Calculate
Guidance values;
e.g. RfD, ADI, TDI

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FC7; OBJ3
 RISK ASSESSMENT FRAMEWORK

Klassen 2013

Lo
ok This framework shows, under the red highlight, the 4 key steps
at
th
e
of risk assessment plus an interactive, 2-way process where
sta research needs from the risk assessment process drive new
rs…
TOXICOLOGICAL research, and new TOXICOLOGICAL research
findings modify risk assessment outcomes.
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FC7; OBJ3
 Key Concepts – Local & Systemic Toxicity

Local Toxicity – effects Systemic Toxicity –

are those that occur at effects elicited at site(s)
the site of first contact after absorption and
between the biological distribution of the
system and the toxicant toxicant.
(e.g. Cl2 gas) (e.g. Pb)

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FC7; OBJ3
 Attributes of the Target Organ

Most chemicals that produce systemic toxicity do

not cause a similar degree of toxicity in all organs,
but usually demonstrate major toxicity to one or
two organs. These are referred to as the target
organs of toxicity for that chemical.

This depends on the:

• toxicant’s ability to react with the target and adversely
affect its function
• toxicant’s ability to alter the target in a way that is
mechanistically related to toxicity

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FC7; OBJ3
 Key Concepts – Interaction of Toxicants
CLASSIC INTERACTION MODELS

Addition ...combined effect of two chemicals is equal to the

sum of the effects of agent alone

Synergy ...combined effect of two chemicals is greater than the

sum of the effects of the agent alone

Potentiation ... one substance does not produce any toxicity on a

particular tissue or system but when added to another
chemical makes that chemical much more toxic

Antagonism ...two chemicals administered together interfere with

each other’s actions

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FC7; OBJ4
 Illustration of response following various chemical interactions
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Klassen (2013)
 Key Concepts – Characteristics of Exposure that
Exposure Route (Definitely)
• Route by which a toxic agent
comes into contact with an
organism (ingestion, inhalation,
dermal, etc.)
FC7; OBJ5
Affect Toxicity
Duration & Frequency (Also
Important)
• Time during which an organism
was exposed to substance (acute,
subacute, sub-chronic & chronic)
• Relationship between elimination
rate and frequency of exposure;
usually smaller cumulative doses
result in more damage than a
single large dose
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 Characteristics of Exposure that Affect Toxicity -
Exposure Routes

Routes by which toxic agents gain access to the body

Most Effective
Dermal Intramuscular Intraperitoneal Intravenous

Ingestion Subcutaneous Inhalation

Least Effective

Approximate order of effectiveness

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FC7; OBJ5
 Duration and Frequency

• Toxicity depends
greatly on the
duration and
frequency of
exposure

• Effects tend of
occur when the
chemical
accumulates in
the biological
Klassen 2013 system

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FC7; OBJ5
 What about Environmental Toxicants?
- Contemporary Examples

Consumer products Food

•Formaldehyde in
personal care products
•Lead especially in
children's toys, wall
paint & house dust
•Carbamates in
household insecticides
•Hg level in wild caught
fish
•Bisphenol A in liquids
stored in cans
•Phthalates in bottled
water

Can you think of any? 32

Let’s talk about Food Toxicants

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Who determines what goes in the food or not?

• In the USA, any additive (direct or

indirect) must be approved by
the FDA Toxicokinetics Acute toxicity
• Based on a review of premarket
scientific data on safety and toxicity
• Establishes a Generally Acceptable
as Safe (GRAS) list Sub-chronic Chronic
• Determines Acceptable Daily Intake toxicity toxicity
(ADI) dependent on the calculation
of NO[A]EL

Grenada – the Ministry of Health authorized by the Food and Drug Act.
EU – the European Food Safety Authority authorized by the General Food Law
Regulation 34
 Classification of Food Additives
1. Direct Additives
• Substances intentionally added to food to augment desired
characteristics
• E.g. emulsifiers, nutrients, preservatives, coloring agents
2. Indirect Additives (Contaminants)
• Substances present in food contact articles that have the
potential to migrate into food products being packaged,
stored and processed
• E.g. adhesives, polymers, bleaching agents, etc.

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 A Regulatory Conundrum
• FDA maintains a list of approved indirect additives that result in no
appreciable effect on human health.

1. Migration is not expected to result in dietary above threshold concentrations or

concentrations above 1% of the ADI

2. Substance has not been shown to be a human or animal carcinogen

3. Under intended use conditions, the additive must not produce a technical effect in
the food into which it migrates

4. The additives use must not have shown any significant adverse impact on the
environment

Search Key: “recycling code and health”

Link: http://www.h2no.org/plastic_recycling_codes.asp 36
 A case of Yellow 6 (Sunset Yellow FCF)
the most commonly used red dye in the United States

• A petroleum-derived red azo dye used in

food, cosmetics, and drugs BTW, what’s this
• RfD = 0 - 2.5 mg/kg bw dose and how is
generally
• Studies have shown a possible link calculated?
between this compound and ADHD-like
behavior in children (results vary,
inconclusive)
• FDA's stance is that this coloring may act
as a trigger to those who are genetically
predisposed, but evidence is weak
(Arnold et al. 2012).
• Foods containing this additive must be
labelled “may have an adverse effect on
activity and attention in children” in the
EU
• Some EU countries have banned this
additive, others recommend removal.

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 higher rising

strengthens the dough

flour improver

enhances elasticity
Credit: http://goindiya.blogspot.com

EU
Argentina IARC 2B – Possibly Carcinogenic
Brazil to Humans – Monograph 73
China • There is inadequate evidence
Sri Lanka Banned in humans for the
South carcinogenicity of potassium
Korea
Nigeria
bromate.
India • There is sufficient evidence in
Canada experimental animals for the
Manufactures carcinogenicity of
USA • potassium bromate.
should voluntarily
Japan
stop using it
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The Precautionary Principle

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…in the context of public health and environmental protection

Precautionary Principle
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1240435/pdf/ehp0109-000871.pdf

When an activity raises threats of harm to human health or the

environment, precautionary measures should be taken even if
some cause and effect relationships are not fully established
scientifically
The Principle applied to Legislation…
1. taking preventive action in the
face of uncertainty
2. shifting the burden of proof to
the proponents of an activity;
3. exploring a wide range of
alternatives to possibly harmful
actions
4. increasing public participation in
decision making
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Applying the Precautionary Principle | How does it work?
Usually found within the context of risk analysis

Preliminary Conditions Guidelines followed

1. identification of potentially
adverse effects
2. available scientific data
3. scientific uncertainty
1. the fullest possible
scientific evaluation
2. a risk evaluation and an
evaluation of the potential
consequences of inaction
3. the participation of all
interested parties in the
study of precautionary
measures, once the results
of the scientific evaluation
and/or the risk evaluation
are available.

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 A key element of the EU’s chemical and environmental management policies…

Basic premise…
• When there is credible evidence of threat to human or environmental
health, preventive and protective action should be taken despite scientific
uncertainty

REACH (Registration, Compare with:

Evaluation, Authorisation and TSCA - Toxic Substances
Restriction of Chemicals) - EC Control Act 1979 - aims to
1907/2006 - aims to improve regulate new commercial
the protection of human chemicals before they enter
health and the environment the market, to regulate
through the better and chemicals already existing in
earlier identification of the 1976 that pose an
intrinsic properties of "unreasonable risk to
chemical substances. health or to the
environment" and to
regulate these chemicals'
distribution and use.
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 Image credit: publichealthwatch

Let’s talk about Household Toxicants

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Mitro et al. 2016 Toxic Household Dust
Blog Article: https://www.nrdc.org/experts/veena-singla/toxic-dust-dangerous-chemical-brew-every-home

Hazardous chemicals migrate out of

everyday products and building materials
and collect in dust
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Mitro et al. 2016 Toxic Household Dust

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Mitro et al. 2016 Toxic Household Dust

Translation: This means

that if an EPA site manager
tested the dust in a typical
living room, he would be
concerned...

46
Mitro et al. 2016
Toxic Household Dust

Translation: This means

that if an EPA site manager
tested the dust in a typical
living room, he would be
concerned...

47
 Toxic Household Dust

Link: https://pubs.acs.org/doi/abs/10.1021/acs.est.6b02023

48
 What can you do while science and policy gets it
together?
1. Remove dust from your hands.
• Wash your hands and your children’s hands
frequently, and always before eating.
• Give preference to plain soap and water,
avoiding fragranced and antibacterial soaps.
2. Keep household dust to a minimum.
• Dust with a damp cloth, regularly go over floors
with a wet mop, and use a vacuum with a high- Credit: CPF
efficiency particulate air (HEPA) filter.
3. Be on the lookout.
• Look for ways to reduce any unnecessary
exposure to toxicants

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 Toxic Household Air
Agent Effects

Particulate matter (from Cardiovascular and respiratory disorders, other

household dust and negative health outcomes mentioned in previous
cooking related slides
combustion products)
Bleach (sodium Irritation of eyes and respiratory tract
hypochlorite)

Polishing agents Dermal irritation, linked to carcinogenicity

(naphtha)

Air Fresheners (may Endocrine disruption, neurological disorders,

contain methoxychlor, carcinogenicity
phthalates, benzene,
toluene)
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FDA Regulation of Cosmetics - "articles intended to be rubbed,
poured, sprinkled, or sprayed on, introduced into, or otherwise
applied to the human body...for cleansing, beautifying, promoting
attractiveness, or altering the appearance”

In general, except for color additives and those ingredients that

are prohibited or restricted by regulation, a manufacturer may
use any ingredient in the formulation of a cosmetic, provided
that:
• the ingredient and the finished cosmetic are safe under labeled
or customary conditions of use,
• the product is properly labeled, and
• the use of the ingredient does not otherwise cause the cosmetic
to be adulterated or misbranded under the laws that FDA
enforces.
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 1. Under U.S. regulations (FDA and
CSPC respectively), fragrance
and flavor ingredients can be
listed simply as “Fragrance” or
“Flavor.”

2. Fragrance and flavor formulas

Perfume and household fragrances
manufacturers are currently not
required to reveal ingredients present
in their products. (Toxpedia, 2017)
are complex mixtures of many
different natural and synthetic
chemical ingredients, and they
are the kinds of cosmetic
components that are most
likely to be “trade secrets.”

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Toxicants in our Open Environment…
53
 Important Differentiation

Contamination
Presence or introduction of an undesired
xenobiotic or foreign agent in a medium

Pollution
Presence or introduction of an undesired
xenobiotic or foreign agent in a medium that has
adverse effects
54
 What is Environmental Toxicology?

• Multidisciplinary branch of
toxicology that focuses on
• The sources of toxicants or
potential toxicants in the
environment
• Their fate and transport under
various environmental
conditions and through food
chains
• Their adverse effects on Source: Dong 2007
population dynamics of affected
species

55
 Fate of toxicants in the environment…

Once in the …to different …constantly

environment, a environmental subject to
toxicant may move media (air, water, chemical, physical
from the point of soil, living and/or biological
source organisms) transformations

56
 Fate of environmental toxicants…
Bioaccumulation
• the intake and retention of a
substance in an organism by
all possible means, including
contact, respiration and
ingestion.
• the intake and retention of a
substance in an organism
entirely by respiration from
water in aquatic ecosystems
or from air in terrestrial ones
is known as
bioconcentration.
Alexander 1999
…movement in the environment
Biomagnification
• when the substance is
passed up the food chain
to higher trophic levels,
such that in predators it
exceeds the concentration
to be expected where
equilibrium prevails
between an organism and
its environment
57
 Fate of environmental toxicants…
…movement in biological systems; e.g. mammals

Absorption: may occur through the alimentary tract, skin, lungs, via the
eye, mammary gland, or uterus, as well as from sites of injection.

Distribution: or translocation of a toxicant is via the bloodstream to

reactive sites (target organs), including storage depots
The total fate
of a xenobiotic
can be called
METABOLISM
Biotransformation: conversion of a substance into a substance with a
different chemical structure (more or less toxic)

Excretion: of toxicant from the body

58
 Classification of Environmental Toxicants
Persistent –
susceptible to
degradation in the
environment over
relatively extended
Degradable – periods of time
susceptible to Nondegradable –
degradation in the not susceptible to
environment in degradation in the
relatively short environment
periods of time

Classification
according to
Persistence

59
 PUTTING IT ALL TOGETHER

What determines the fate and transport of these toxicants in the

environment?
• The fate and transport of environmental toxicants
depends greatly on the physical and chemical
properties of the toxicant & the environmental BIOAVAILABILITY
media. represents the
amount of a
• These properties along with biological toxicant that is
accessible to an
characteristics of the affected organism, play an organism for
uptake and
important role in the toxicant’s uptake, metabolism

distribution, biotransformation, adverse effect.

• They also play an important role in
bioaccumulation and biomagnification
phenomena.
60
Examples….

Who knows what will happen to this

toxicant in the environment… 61
E.g. properties of the toxicant…
Solubility …but in a what?
A chemical property that really matters

Lipophilicity:
Hydrophilicity This results in
ability of a
ability of a bioaccumulation
chemical
chemical
compound to
compound to
dissolve in fats,
dissolve in
oils, lipids, and
water and polar
non-polar
solvents Th
solvents cha e nota
rac
teri ble
DDT stic of

Other such properties:

• Oxidation state, physical state, melting point, boiling
point, reduction potential etc. 62
E.g. properties of the environment…
pH
Looking at that scale…

• A numeric scale used to specify the acidity or basicity of an aqueous

solution

Notable factor in Flint,

Michigan

Many pesticides
Most metals are soluble in
(organophosphates,
acidic environments but
organochlorines, carbamates,
precipitate in alkaline
etc.) are hydrolyzed in neutral
environments
to alkaline environments

Other such properties:

• Temperature, reduction potential, physical state, presence of
other substances, etc. 63
E.g. biological characteristics of the organism… Age
Is it better to be old or young?

Disproportionately heavy
exposures coupled with
biologic sensitivity
characteristics of early
growth and development
result in children being
more at risk than adults
for lead poisoning
Image Credit: Vermont Department of Health

Other characteristics:
• Gender, health status, nutritional status, body weight, adiposity, etc,. 64
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