Safer Chemical Design Game

Worksheet for students and instructors playing

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: 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.


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.


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).


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.


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.

Game Play
Activity Instructions