Center For Green Chemistry
and Green Engineering at Yale
Chemical Exposure and Dosage
Lecture #22
Date:
Course #
Center For Green Chemistry
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Approaching Risks: Exposure versus Smart Design
The traditional approach to hazards focuses on reducing
risk by minimizing exposure.
• For example, wearing personal protective equipment
or space ventilation if the chemical is volatile.
Green chemistry focuses on reducing risk by reducing hazard.
• If there is no hazard, exposure becomes irrelevant.
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LEED-Leadership in Energy and Environmental Design
Green Buildings
• Certification for design, Country Name Gross Square Meters* Number of Projects
construction and operation of China 34.62 931
green buildings. Canada 34.39 2,586
India 15.90 644
• Guidelines for site management, Brazil 7.43 380
storm water & water use, building Republic of Korea 5.95 97
Taiwan 5.66 99
materials, energy conservation, Germany 5.03 215
and air quality. Turkey 4.78 191
Sweden 3.88 210
• Certification is granted on 4 levels United Arab Emirates 3.64 180
– certified, silver, gold, and United States** 336.84 27,699
platinum based on accumulated Countries in terms of cumulative LEED-certified GSM space as of
points. December 2016. LEED-certified spaces use fewer energy and water
resources; save money for families, businesses, and taxpayers; reduce
carbon emissions; and prioritize environmental and human health.
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Dose
Dose is the amount of a substance administered at given times.
For example:
• 650 mg Tylenol as a single dose
• 500 mg Penicillin every 8 hours for 10 days
• 10 mg DDT per day for 90 days
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Dose Makes the Poison
An apparently nontoxic chemical
can be toxic at high doses.
Highly toxic chemicals can be life saving
when given in appropriate doses.
Sugarcane
Center For Green Chemistry
and Green Engineering at Yale Source: Wikimedia Commons
Lethal Doses
Approximate Lethal Doses of Common Chemicals
(Calculated for a 160 lb. human from data on rats)
Chemical Lethal Dose
Sugar (sucrose) 3 quarts
Alcohol (ethyl alcohol) 3 quarts
Salt (sodium chloride) 1 quart
Herbicide (2, 4-D) one half cup
Arsenic (arsenic acid) 1-2 teaspoons
Nicotine one half teaspoon
Food poison (botulism) microscopic
Source: Marczewski, A.E., and Kamrin, M. Toxicology for the citizen, Retrieved August 17, 2000:
www.iet.msu.edu/toxconcepts/toxconcepts.htm.
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How is toxicity testing done?
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Outline
• Risk Assessment
• Hazard
• Exposure
• Dose
• Dose Response Curve
• LOAEL, NOAEL, and Reference Dose
• Tools for Hazard Characterization
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Dose-Response
The dose-response relationship is a
fundamental and essential concept in
toxicology. It correlates exposures and the
spectrum of induced effects.
The dose-response relationship is based on
observed data from experimental animal,
human clinical, or cell studies.
Dose-response assessment is a step
in the risk assessment process
(Image Source: ORAU, ©)
Center For Green Chemistry
and Green Engineering at Yale Toxicologyschools.com
Toxtutor.nml.nih.gov
Dose-Response
Knowledge of the dose-response
relationship:
• establishes causality that the chemical
has in fact induced the observed effects.
• establishes the lowest dose where an
induced effect occurs - the threshold
effect.
• determines the rate at which injury
builds up - the slope for the dose The Linearized Multistage Model is used to
response. extrapolate cancer risk from a dose-response
curve using the cancer slope factor.
(Image Source: NLM)
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Variance in Population Susceptibility
As demonstrated above, a graph of the individual responses
can be depicted as a bell-shaped standard distribution curve.
Center For Green Chemistry
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Dose-response
When we graph the dose of a substance and the
percentage of a population that responds to that dose,
the result is called the dose-response curve.
When plotting the response at various doses, the dose-
response curve normally takes the form of a sigmoid
curve that is shaped like the letter “S”.
For most effects, small doses are not toxic. The point at
which toxicity first appears is known as the threshold
dose level.
Shape and slope of the dose-response curve for
predicting the toxicity of a substance at specific
dose levels.
Center For Green Chemistry
and Green Engineering at Yale Toxicologyschools.com
Toxtutor.nml.nih.gov
LD50, NOAEL, LOAEL, and RfD
LD 50- A common dose estimate for acute
toxicity is the LD50 (Lethal Dose 50%).
This is a statistically derived dose at which 50%
of the individuals will be expected to die.
LD 50
NOAEL - No Observed Adverse Effect Level
Highest data point at which there was no
adverse effect.
NOAEL UF = Uncertainty factor
RfD =
UF (10-1000) LOAEL - Low Observed Adverse Effect Level
Lowest data point at which there was an
RfD – estimate of a daily oral exposure to the human adverse effect.
population, that’s likely to be without risk of an effect.
Center For Green Chemistry
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Determining the Relative Safety of Pharmaceuticals
Toxicologists, pharmacologists, and others use effective and toxic dose levels to determine the relative safety of pharmaceuticals. As
shown in this figure, two dose-response curves are presented for the same drug, one for effectiveness and the other for toxicity. In this
case, a dose that is 50% to 75% effective does not cause toxicity. However, a 90% effective dose may result in a small amount of toxicity.
Center For Green Chemistry
and Green Engineering at Yale Toxicologyschools.com
Toxtutor.nml.nih.gov
Margin of Safety
The shaded area represents the doses at
which the substance produces an
effective dose response while the toxic
dose response remains below the TD50.
Although more patients may benefit
from higher doses, that is offset by the
probability that toxicity will occur.
Ideally, effective dose DOES NOT
overlap with the toxic dose.
Otherwise this becomes an
ethical issue.
Center For Green Chemistry
and Green Engineering at Yale Toxicologyschools.com
Toxtutor.nml.nih.gov
In-Class Discussion - Which Solvent Would You Use?
Solvent 99-2
100
90 Solvent 99-7
80
70
% Mortality
60
50
40
30
20
10
0
0 50 100 150 200 250 300 350
Inhaled Dose (ppm)
Plotted here are two theoretical curves for the toxicity of solvents used in the cleaning of silicon
compounds. Both solvent 99-2 and 99-7 performed equally well against a variety of manufactured silicon
compounds. The task at hand for you is to determine which solvent would you pick to be “safer” for use.
As you can see from the accompanying data, both compounds have an equivalent Lethal dose 50 value
(LD50). These are based on average values during a 6 hour exposure period.
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In-Class Discussion - Which Solvent Would You Use?
Solvent 99-2
100
90 Solvent 99-7
80
70
% Mortality
60
50
40
30
20
10
0
0 50 100 150 200 250 300 350
Inhaled Dose (ppm)
Solvent 99-7 causes lethality at much lower levels than 99-2 (20ppm versus 100ppm respectively), and
the response is much more predictable (i.e. less population heterogeneity). Solvent 99-2 because
higher levels can be inhaled before any harmful effects should begin.
Center For Green Chemistry
and Green Engineering at Yale Courtesy of Dr. Karolina Mellor
Hazard Assessment
• Review and analysis of toxicology data and assessing if the substance causes toxic effects.
• Sources include animal and human studies and computational data.
• These studies have difficulty with showing causation (if a risk factor lead to disease).
Mihelcic, J. R.; Zimmerman, J. B., Environmental engineering: Fundamentals,
Center For Green Chemistry
and Green Engineering at Yale sustainability, design. Wiley Global Education: 2014.
Exposure Assessment
• Determines the extent and frequency of human exposure to target chemicals.
• Guidelines for residential, industrial and commercial sites.
• For engineers, the knowledge of risk and exposure provides information whether the site needs to be remediated.
Center For Green Chemistry Mihelcic, J. R.; Zimmerman, J. B., Environmental engineering: Fundamentals,
and Green Engineering at Yale
sustainability, design. Wiley Global Education: 2014.
Tools For Hazard Characterization
• ChemHAT - easy way to access summarized information on chemical
hazards in the workplace.
• ChemSpider
toxicity assessments based on experimental or predicted LD 50.
• Protox
• Safer Choice - for consumers, businesses, and purchasers to find products
that perform and are safer for human health and the environment.
Center For Green Chemistry
and Green Engineering at Yale
