Module 10: Safer Chemical Design Game – worksheet

for students and instructors playing www.gwiz.yale.edu

Teacher’s Notes

This activity (including game play time) is estimated to take approximately 2 hours.

Human and aquatic toxicity are complicated processes which depend on several variables.
Most of these variables are related to physical and chemical properties of the chemical.

This activity is based on the educational game “Safer Chemical Design Game” and is
intended to introduce students to safer chemical design concepts by focusing on
manipulating physicochemical parameters to minimize toxicity of a hypothetical
commercial chemical. The game simulates various real-world constraints that may affect
chemical product development as students design a novel detergent. The students (players)
are challenged to design a safer, and more sustainable chemical product using multi-criteria
decision analysis. They can select different combinations of molecular parameters that lead
to qualitative outputs related to toxicity, biodegradability, biotransformation, and overall
chemical performance. In doing so, the player must navigate potential trade-offs that result
from their choices.
The game has two levels - each level is divided into three challenges, or tasks, that are
related to the attributes of the chemical product, including potential for human toxicity,
aquatic toxicity, and performance (function). As students progress through different
challenges, they are offered “Tips” which include additional information to aid their
parameter choices. Both levels require the lower order learning objective of fact
memorization as well as the higher order learning objective of knowledge transfer. The
design of the chemical product is evaluated on function and avoidance of toxicity. A key
feature of the game is the ability of the player to redesign and improve their product based
on real-time feedback. Feedback is included after every task which allows the student to
change their selection criteria and improve design.

Lesson planning: Introduce key concepts related to human and aquatic toxicity (see below)
and use the game to reinforce the message. Use the eight questions in the worksheet as an
individual assignment or as an in-class discussion. These questions are designed to be
answered as student plays the game.
Supplemental Readings:

ToxTutor – National Institute of Health. Retrieved from: https://toxtutor.nlm.nih.gov

Accessed May 2018

Voutchkova, A. M.; Osimitz, T. G.; Anastas, P. T., Toward a Comprehensive Molecular

Design Framework for Reduced Hazard. Chemical reviews 2010, 110 (10), 5845-5882

Anastas, P. T.; Zimmerman, J. B., Safer by Design. Green Chemistry 2016, 18 (16), 4324-
4324.

Zimmerman, J. B.; Anastas, P. T., Toward designing safer chemicals. Science 2015, 347
(6219), 215-215.

Zimmerman, J. B.; Anastas, P. T., Toward substitution with no regrets. Science 2015, 347
(6227), 1198-1199.

Cowan-Ellsberry C, Belanger S, Dorn P, et al. Environmental Safety of the Use of Major

Surfactant Classes in North America. Critical Reviews in Environmental Science and
Technology. 2014;44(17):1893-1993. doi:10.1080/10739149.2013.803777.
Student Learning Objectives: By the end of this module, the student will be able to:

• Define the four key components of ADME

• Relate physicochemical properties of chemicals to the impact they have on ADME
and performance
• Predict which physicochemical properties of chemicals have an impact on ADME
and performance

Background and Information:

What will affect toxicity?
(Module 3: ADME and Toxicity by Dr. Grace Lasker of Molecular Design Research
Network. NSF Division of Chemistry and the Environmental Protection Agency under
Grant No. 1339637.)

Chemical impact on health is usually investigated via the concept of ADME. This is how
a chemical is Absorbed, Distributed, Metabolized, or Eliminated in living systems. Not all
chemicals are impactful in the same ways, sometimes metabolism, for example, may not
be an issue because of the way our liver metabolizes some compounds and converts them
into inert substances. Some chemicals have means to be excreted, while others may not.
Considering all aspects of how chemicals get into the body, how they move within the
body, and how they get out of the body can help us assess the toxicity of a chemical.

ADME (standing for Absorption, Distribution, Metabolism, and Elimination) is an

important concept that describes the potential impact a chemical or drug may have on a
living system within the context of cellular biology and biochemistry. This is because
movement and metabolism of molecules is determined by physicochemical properties of
the molecule as well as the host system. The movement of molecules is called “kinetics”
or “pharmacokinetics” and chemical properties such as polarity, molecule weight,
molecular size, chirality, HOMO/LUMO, and many more all have an impact on the ADME
potential of a molecule/toxin. ADME is generally used to describe the impact or a drug or
pharmaceutical compound. However, the concept of ADME is applicable to non-
pharmaceutical compounds, including from toxic exposure. Drugs are specifically
designed using ADME principles; however, chemicals for commercial use are not designed
with any guidelines targeting ADME.

Absorption
There are four main routes of exposure:

• Inhalation through the respiratory system: a chemical in the form of a gas, vapor or
particulate that is inhaled and can be excreted or deposited in the respiratory system.
• Dermal through skin or eye contact.
• Ingestion through the gastrointestinal system: Absorption through the digestive
tract. Ingestion can occur through eating or smoking with contaminated hands or in
contaminated work areas.
• Injection: Introducing the material directly into the bloodstream. Injection may
occur through mechanical injury from "sharps".

To be absorbed, a substance must cross one of the layers of cells that keeps “us” “in” and
the rest of the world “out”: skin (including mucus membranes), lung, and the
gastrointestinal (GI) tract. Most substances are absorbed by passive diffusion through
membranes. A small number of biologically important atoms and molecules are actively
taken up by cells. Examples include sodium, potassium, and calcium ions, amino acids,
small sugars (mono- and di-saccarides). If your substance is very similar to one of these,
there is an increased chance of cellular uptake.

Absorption depends on chemical properties such as molecular weight, lipid solubility (log
P), and physical state. These parameters determine if the chemical passes through the cell
membranes into the body. Absorption of a chemical will result in the chemical circulating
inside the body and potentially causing adverse effects.
Distribution
In order to be distributed, the compound needs to be able to move from the site of
absorption to other areas of the living system. Not all compounds move easily. Most often
movement is via the bloodstream but other compounds may move cell-to-cell as well. In
general, there are four main ways by which small molecules cross biological lipid
membranes:

• Passive diffusion. Diffusion occurs through the lipid membrane from a high to low
concentration (aka concentration gradient).
• Filtration. Diffusion occurs through aqueous pores, still from high to low
concentration as a driving mechanism.
• Special transport. Transport is aided by a carrier molecule. Can move against the
concentration gradient (low to high).
• Endocytosis. Transport takes the form of pinocytosis for liquids and phagocytosis
for solids.

The mechanism of transport for a certain chemical is frequently unknown, and so we must
judge its potential toxicity using other variables (such as molecular weight, ionization (p
Ka), and octanol/water partition coefficient (log P).
Metabolism
Compounds begin to break down in the body by a family of enzymes in the liver called the
Cytochrome P450 system. These enzymes can convert chemicals to reactive oxygen
species (ROS), reactive intermediates, free radicals, and others. For example, redox
reactions and potential, with a transfer of electrons, influence the toxicity of a chemical at
the intracellular level. Scientific advances in toxicology and chemistry are starting to allow
scientists to better understand these kinds of interactions, and they have begun to map out
more specific pathways, called Adverse Outcome pathways (AOPs). It is through
understanding these pathways that a new generation of chemicals can be safely designed
by chemists and other scientists.

Excretion
Most excretion occurs through the kidneys as urine or as feces. Excretion is dependent on
the process of kidney filtration at the glomerulus, and is largely based on molecular size
and charge. Some molecules can be excreted through the skin as sweat and some may be
excreted through the lungs via gas exchange. If excretion is not a complete process, the
molecule or metabolic by-product can bioaccumulate and impact living systems adversely.
If a compound is lipid-soluble, it will bioaccumulate more quickly in adipose tissue.
Bioaccumulation of lipid-soluble compounds such as DDT has been shown to be correlated
with adverse health effects such as diabetes, heart disease, obesity, etc.

Objective of the game

Imagine you are a chemist at a large chemical company. Your department is requesting
that you develop environmentally friendly chemicals. As a part of this initiative, you were
asked to design a detergent that not only has an optimal cleaning performance, but also is
safer for humans and environment. If your product is successful, it will be widely produced
and distributed in major chain stores.

Goal
Your task is to design a benign detergent that has optimal cleaning capabilities. As a
chemist, you can thoughtfully design a chemical to have certain characteristics (e.g., be an
efficient cleaning agent or have a reduced toxicity). You can achieve this by manipulating
its physical and chemical properties. Your goal is to adjust these properties such that the
detergent does not cause harmful (adverse) effects to humans and fish without sacrificing
the product’s cleaning ability.

Game Play
This game has two levels:

In Level 1, you will address detergent toxicity by limiting its absorption through the
membranes. You will design a detergent that will not be absorbed into the body through
skin, lungs, or intestines, and will not harm fish in bodies of water, like lakes or ponds.

In Level 2 the detergent is absorbed into the body. This is problematic, but as a chemist,
you are able to minimize its toxicity and effects on the body. Note: Distribution,
Metabolism, and Excretion are processes that occur when a chemical enters the body.
Taken together with Absorption, the processes are referred to as “ADME” (Absorption-
Distribution-Metabolism-Excretion).

Information on detergents
Detergents are substances that are used to remove grease and grime. Their performance is
due to their unique structure. One end of their molecule, called head, is attracted to water
(hydrophilic), while the other end, called tail, is attracted to dirt and grease (lipophilic).

Figure 1: Detergent’s structure.

Detergent heads and tails can vary, and they are made of different chemical functional
groups. For example, tails consist of a hydrocarbon chain, which can be branched, linear,
or aromatic. Heads, on the other hand, may include sulfonate, phosphate, sulfate or
carboxylate functional group which define surfactant’s character (antimicrobial &
antifungal hand soap, versus cleaner or fragrance carrier).

The most common use is grease removal. Once the grease is detected, it is surrounded by
hydrophobic (lipophilic) tails forming a structure called micelle. Micelle are typically
spherical in shape and allow greasy compounds, which are normally insoluble, to dissolve.

Figure 2: Structure of micelle.

Real World Application

• The computer game simulates the real-world constraints that may affect chemical
product development as the student designs a novel product. It is important to
think about the product holistically, and find a ‘sweet spot’ for reduced toxicity
and increased performance.

• The game is made based on real world data.

Pre-Game Question
Speculate how molecular weight, lipid solubility, physical state (solid vs liquid) and vapor
pressure of the detergent will impact absorption into the body.

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Activity Instructions
(Please note that the game is played online and it requires internet connection)

1. Go to www.gwiz.yale.edu and wait until it loads. Depending on the internet

connection, the process can take up to 2 minutes.
2. Accept Copyright and all Terms of Use.
3. Begin the game by reading the instruction in Overview, Goal and Gameplay tabs.
4. We recommend playing in the Beginner mode.
5. Familiarize yourself with the game mechanics by clicking on the small arrow
button, rather than clicking OK.
Note: In level 1, you will have Human Toxicity Challenge, Aquatic Toxicity Challenge
and Performance Challenge. You need to complete all three to progress to Level 2. All
three challenges are interdependent, which means that selection that you will make in one
challenge, will carry over to another one. Remember, the goal is to design one detergent
which is not toxic to human and aquatic life while being an efficient detergent.

The Human Toxicity challenge has three subtasks: Skin, Respiratory, and GI absorption.
After adjusting physicochemical parameters for each subtask, you will receive feedback,
which will allow you to go back and change your parameter selection.
If you have additional questions about the game mechanics, press the Help button.

6. Read the Task description for the Skin Absorption Subtask.

7. Go to Molecular Weight parameter and move the slider to 250. Do you see how the
output window becomes red? Click on the light bulb to learn why.
8. Adjust the slider until the output window becomes green.
9. Repeat the process for log P and Physical State. Make sure to read light bulb tips
for both parameters.
10. Once you are satisfied with your property selection, press Next button to continue
and receive feedback.
a. If one of parameters is outside of the preferred range, you can click Back
and reselect your values.
 11. Complete Respiratory and GI Absorption Subtasks and progress to Aquatic
Toxicity Challenge.

QUESTION 1

How do high and low values of the selected physicochemical parameters (molecular weight,
lipid solubility, physical state) affect absorption? Was your pre-game prediction
correct/incorrect?

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12. Continue to adjust parameters relevant to the performance of the detergent.

Note: Performance is a measure of a chemical’s effectiveness. It tells us how well the

detergent will do its job (a great cleaning ability). For detergents and soaps, performance
is quantifiable through the hydrophilic-lipophilic balance (HLB).

In this phase of product development, you will optimize the HLB. You should know that
the HLB value will vary with the log P value selected during earlier design phases. Thus,
changing the HLB value will also impact the absorption of the molecule. Make sure that
while adjusting HLB, you don’t go out of preferred range for log P!

The consideration of multiple outcomes such as absorption and product performance is an

example of the real-world constraints that may affect chemical product development.
QUESTION 2

Using the game outcome, what is the HLB “sweet spot” which enables the detergent to be
an effective cleaner and be nontoxic?

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QUESTION 3

Why do you think Log P and HLB are depended on each other? Tip: recall detergent’s
structure.

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QUESTION 4

Many detergents available on the market are designed for a specific function: be a good
cleaning agent. As you can see from the game, it is relatively easy to control one parameter.
When a company decides to design a product with a dual function like safety AND high
performance, the task becomes more challenging. Why do you think that is?

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In the game, were you able to design a detergent that will not absorb and have a high
performance?

Was it easy or difficult?

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Can you think of other examples of products from your daily lives, which perform a dual
function?

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13. Progress to Level 2 and begin by reading Overview, Goal and Gameplay tabs.

Note: Level 2 has three Challenges: Human Toxicity Challenge, Aquatic Toxicity
Challenge and Performance Challenge. You will need to complete all three to successfully
finish the game. Similar to Level 1, parameter selection is carried over to another challenge,
since you are still developing one product with one set of parameters.

In this level, you need to design a chemical that will have a limited distribution, increased
degradation and limited bioaccumulation. You will also notice that properties and chemical
functional groups which control these processes are different than in Level 1.
 14. Read the Task Description for Distribution and adjust four given parameters. Click
Next to receive feedback.

QUESTION 5

Which molecules (high or low surface area) will enhance distribution through the
membrane and why?

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15. Continue the Human Toxicity Challenge by completing Metabolism and

Accumulation & Excretion Subtasks.

QUESTION 6

Which functional groups impair excretion and contribute to accumulation in the organism?

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16. In Aquatic Toxicity Challenge, you are asked to select up to 3 functional groups
which enhance biodegradation. You can access that feature by clicking on the arrow
 button in the Functional Groups window. Make sure to scroll down to access all the
functional groups you can choose from.

QUESTION 7

Why does branching play a critical role in biodegradation of the chemical?

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17. Once you complete Aquatic Toxicity Challenge and receive feedback, please
proceed to Performance Challenge. This time the HLB value which you see is the
result of your functional group selection in the earlier challenge. If your HLB value
is out of the preferred range, you need to change functional groups by clicking Edit
Functional Groups. Please remember that your re-selection will also impact
Aquatic Toxicity Challenge result.

QUESTION 8

Do the same functional groups that enhance biodegradation (Aquatic Toxicity Challenge)
contribute to the increased performance?

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As future chemists, why do you think this is important to consider different functional
groups and the role they play in the design process?

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What if instead of two parameters (safety and performance) you also need to consider cost
as a third parameter?

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This material is based upon work supported by the NSF Division of Chemistry and the
Environmental Protection Agency under Grant No. 1339637.