This text is adapted from a chapter of A Small Dose of Toxicology by Steven G. Gilbert.
For additional citations on risk assessment topics, see A Global Bibliographic Perspective on Toxicology: Risk Assessment!
Evaluation of the potential adverse effects of some activity or exposure (risk assessment) is something we all do informally on a day-to-day basis. What we decide to do is in part the result of an ongoing risk management decision. It can be as simple as crossing the street against a red light or as complex as spending extra money for organically grown foods to reduce our exposure to pesticides. Many of the risks associated with chemical exposure are indirect or subtle effects on health; in other words, conditions, situations, or exposures to an agent that affect the quality of life.
Risk analysis and risk management play an important role in public policy. The debates range from the development of environmental impact statements for the location of buildings to those on household lead abatement and what chemicals can be allowed in the food supply. Quality of life issues such as asthma and mental impairment are now recognized as important components of risk assessment. For example, childhood exposure to lead can result in reduced IQ, which can affect individuals throughout their lifetimes. Childhood asthma can have a severe impact on an individual's ability to play and socialize.
The 1970s saw a flourishing of activity to develop and refine risk assessment methodologies. The initial focus was to develop risk assessment procedures to establish exposure limits for cancer-causing substances, the primary concerns being the food supply and the workplace. These efforts were gradually expanded to include non-cancer endpoints such as nervous system development, reproductive effects, and effects on the immune system. Researchers at national and international agencies are developing better approaches to dealing with uncertainty in health effects data and applying judgment in interpreting the results. The area of judgment is a critical aspect of risk assessment. The process of interpreting and communicating risk assessment results requires full understanding and disclosure of the assumptions, data gaps, and possible financial interests that may play a role.
Hazard x Exposure x Individual Sensitivity = Risk
Risk assessment is the process of estimating association between an exposure to a chemical or physical agent and the incidence of some adverse outcome. The relationship between hazard, exposure, and individual sensitivity is never exact. For example, understanding the hazard depends on the end point such as cancer or immune or nervous system effects. Exposure depends on the route and duration. Individual sensitivity can be influenced by genetics, age, gender, or other variables. Initially the focus was human health, but now it has broadened to include wider environmental and ecological concerns. Risk management is a more overtly political process directed at determining an action based on relevant public and environmental health goals, cost, societal issues, and other related or even unrelated issues. An important part of risk management is balancing the risks, costs, and benefits—never an easy task.
Risk assessment is a complex area that requires the application of all the principles of toxicology. It is often divided into four somewhat overlapping areas: 1) hazard identification, 2) dose/response assessment, 3) exposure assessment, and 4) risk characterization.
The first step in risk assessment is to gather health-related information associated with an exposure. Ideally, hazard identification starts before there is significant use of the agent. The structure of the compound is compared to that of compounds with known toxicity profiles, and cell-based studies are often performed to screen for toxicity. Finally, animal bioassays and human studies are performed to characterize and develop a toxicity profile. Multiple health-related endpoints are evaluated to determine if the compound is associated with adverse effects. Advantages of animal studies include experimental control and accurate knowledge of the dose.
Using knowledge gained from animal studies or observations from human populations, a more formal human epidemiology study may be performed. Human studies have the obvious advantage of being conducted on the subject of most interest, but they are time consuming and expensive, and often have many variables that are difficult to control.
Common Toxicity Endpoints for Hazard Identification
To characterize the dose/response relationship for the agent, data from the initial hazard assessment, combined with exposure assessment information, are used determine the most sensitive endpoint. Available data are then used to define the dose at which there is no observed effect (NOEL, no observed effect level) and the shape of the dose/response curve. It may be necessary to perform additional studies to define the dose/response curve. The ED50 is defined as the effective dose at which 50% of the subjects respond.
If the hazard assessment indicates that the compound is potentially hazardous, the next step is to evaluate the various possibilities for exposure. What is the most likely route of exposure: oral, inhalation, or skin? How much absorption is expected from the different routes of exposure? Information is also needed on amount, duration, and frequency of exposure. Is exposure occurring in the home, workplace, school, or other areas? This information helps to define the population of concern. Exposure information may also be important for designing appropriate studies on hazard assessment and certainly for the next step of establishing dose/response relationships.
The final step is to take all the information from hazard assessment, exposure assessment, and dose/response assessment and summarize it in a risk characterization for the chemical substance. Any uncertainties in the data set or missing information must be evaluated. While all efforts are made to minimize professional judgment by having robust data, it is often the case that not enough of the right information is available. Recommendations must still be made as to an acceptable level of exposure for a given population, the goal being to ensure the even the most sensitive individuals are protected from any adverse effects. The dose thought to ensure protection is called a reference dose (RfD) or acceptable daily intake (ADI). Note the word safe is NOT used, only the avoidance of adverse effects.
In the simplest terms, risk is the product of two factors: hazard and exposure (i.e. hazard x exposure = risk). In real risk assessments, all hazards may not be known and exposure is often difficult to quantify precisely. As a result, the calculated risk may not accurately reflect the real risk. The accuracy of a risk assessment is no better than the data and assumptions upon which it is based.
"The daily intake of a chemical, which during an entire lifetime appears to be without appreciable risk on the basis of all known facts at the time."
- World Health Organization, 1962
There are of course many mathematically complex ways to perform a risk assessment but first, key questions about the biological data must be resolved. The most sensitive endpoint must be defined along with relevant toxicity and dose/response data. A standard risk assessment approach that is often used is the so-called divide by 10 rule. Dividing the dose by 10 applies a safety factor to ensure that even the most sensitive individuals are protected. Animal studies are typically used to establish a dose/response curve and the most sensitive endpoint. From the dose/response curve a NOAEL dose, or no observed adverse effect level, is derived. This the dose at which there appears to be no adverse affects in the animals studies at a particular endpoint which could be cancer, liver damage, or a neurobehavioral effect. This dose is then divided by 10 if the animal data is in any way thought to be inadequate. For example, there may be a great deal of variability, there were adverse effects at the lowest dose, or only tests of short-term exposure to the chemical were conducted. An additional factor of 10 is used when extrapolating from animals to humans. Last, a factor of 10 is used to account for variability in the human population or to account for sensitive individual such as children or the elderly. The final number is the reference dose (RfD) or acceptable daily intake (ADI). This process is summarized below.
Animal Dose Response Data: NOAEL (No Observed Adverse Effect Level)
Divide by 10 (Account for inadequate animal data)
Divide by 10 (Animal-to-human extrapolation)
Divide by 10 (Human variability or individual sensitivity)
Reference Dose (RfD) or Acceptable Daily Intake (ADI)
Safety factors are typically used in a risk assessment to define an acceptable dose for food additives and pesticides. It is very important to ensure that an artificial sweetener such as aspartame, which is commonly consumed by all age groups as well as pregnant women, have a large margin of safety. In contrast, consider a compound such as lead. The risk of lead exposure to the developing child is well known but there has been no safety factor applied to blood lead levels of concern.
Risk management is the political or social process of deciding how the benefits balance the associated risks. Risk management is also concerned with how the public perceives risk and how we judge and perform our own risk assessments. An example of risk management was the decision to remove lead from gasoline. After a great deal of research it was demonstrated that low levels of lead exposure are harmful to the developing nervous system. It was then determined that the benefits of removing lead from gasoline were greater than the costs. A program was developed to gradually phase out lead from gasoline, design new engines not requiring lead, and replace old cars.
An individual's perception of risk is sometimes very different from a risk assessment based on a more objective analysis of the data. For example, individuals often rank nuclear power as a high risk but most experts give it a low risk rank. The following table characterizes some of the factors that influence perception of risk.
Characteristics of Risk
(Adapted from Kraus and Slovic (1988))
"When an activity raises threats of harm to the environment or human health, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically."
- Wingspread Statement on the Precautionary Principle, Jan. 1998
The risk assessment and risk management approach used in United States places a heavy reliance on the certainty of the data. The precautionary principle emphasizes that there is always some uncertainty and that decisions should be based on recognizing the possibility of harm. When in doubt, a cautious approach should be taken until adequate data are available to show that there is little potential for harm. Action to reduce exposure to hazardous agents should begin even if there is some uncertainty in the data. In other words, some uncertainty in the data should not be used as an excuse for inaction. This approach is being given more consideration in Europe than in the United States. The approach gains credibility when one considers how its application years ago would have prevented the tragic effects of lead in gasoline and paint.
Concerned by the shortcomings of risk assessment, a growing body of scientists is advocating a precautionary approach to risks that are not fully understood. The precautionary principle has been applied to issues related to toxicology, public health and sustainable development, and use of the environment (Cairns (2003; Goldstein (2001), and is an established global principle (Rio Declaration, 1992).
The goal of precautionary assessment (PA) is to move beyond risk assessment and allow communities and individual to incorporate their knowledge, values, and ethics into a more comprehensive evaluation of a hazardous condition. The PA combines the philosophy and ethics of the precautionary principle with the standard scientific evaluation of the hazards. Precautionary assessment contains three basic elements: a) community and social issues, b) exposure, and c) hazard and toxicity. Each element is broken down into a series of questions that are scored numerically and summed to produce a summary score for each element. The PA is designed to help place the knowledge available within the context of the community. In contrast to the traditional risk assessment, the PA is a more comprehensive approach to evaluating the human and environmental health risks. Overall, the PA can be considered a more reasonable, rational, and responsible approach to evaluating risk of chemicals. A detailed discussion of the PA and spreadsheet are available here (Gilbert, 2006). Other authors have also discussed alternative decision-making approaches to risk assessment, for example O'Brien (2000).
Slide Presentation and Online Material
• A Small Dose of Risk Assessment presentation material and references. Website contains presentation material related risk assessment.
European, Asian, and International Agencies
• UK Department of Health (DOH). Guidance on a strategy for the risk assessment of chemical carcinogens. [accessed August 24, 2009] The Department of Health has published information and research outcomes on risk and public health. [accessed August 24, 2009]
• International Programme on Chemical Safety (IPCS). Health Impacts of Chemicals. Information on global risk assessment issues. [accessed August 24, 2009]
• EnviroLink: The Online Environmental Community. "The EnviroLink Network is a nonprofit organization founded in 1991. EnviroLink maintains a database of thousands of environmental resources and provides internet services to nonprofit organizations. [accessed August 24, 2009]
• World Health Organization (WHO) Organization for Economic Co-operation and Development. Chemicals Assessment. "OECD assists member countries developing in and harmonizing methods for assessing such risk." [accessed August 24, 2009]
• National Institute for Environmental Studies. Center for Environmental Risk Research. The center aims to provide policy responsive research on improving assessment methods for environmental risk. (English and Japanese) [accessed August 24, 2009]
North American Agencies
• US Environmental Protection Agency (EPA). National Center for Environmental Assessment (NCEA). NCEA goals are to apply "science to improve risk assessment and environmental decision making." [accessed August 24, 2009]
• US Environmental Protection Agency (EPA). Risk Assessment. NCEA goals are to apply "science to improve risk assessment and environmental decision making." [accessed August 24, 2009]
• US National Cancer Institute (NCI). Breast Cancer Risk Assessment Tool. An interactive tool designed by scientists at the National Cancer Institute (NCI) to estimate a woman's risk of developing invasive breast cancer. [accessed August 24, 2009]
• California Office of Environmental Health Hazard Assessment (OEHHA). Risk Assessment. "OEHHA is responsible for developing and providing risk managers in state and local government agencies with toxicological and medical information relevant to decisions involving public health." [accessed August 24, 2009]
• American Conference of Governmental Industrial Hygienists (ACGIH). "The ACGIS community of professionals advances worker health and safety through education and the development and dissemination of scientific and technical knowledge. [accessed August 24, 2009]
• Toxicology Excellence for Risk Assessment (TERA). TERA is a nonprofit [501(c)(3)] corporation that works to "protect public health developing, reviewing, and communicating risk assessment values and analyses." [accessed August 24, 2009]
• Society for Risk Analysis (SRA). "SRA provides an open forum for all those who are interested in risk analysis. Risk analysis is broadly defined to include risk assessment, risk characterization, risk communication, risk management, and policy relating to risk." [accessed August 24, 2009]
• Harvard Center for Risk Analysis (HCRA). HCRA focuses on "using decision science to empower informed choices about risks to health, safety, and the environment." [accessed August 24, 2009]
• The Science & Environmental Health Network. Precautionary Principle. SEHN advocates the wise application of science to protecting the environment and public health. [accessed August 24, 2009]
A Guide to Health Risk Assessment. California Environmental Protection Agency, Office of Environmental Health Hazard Assessment. [accessed August 24, 2009]
The Precautionary Principle In Action A Handbook. Science and Environmental Health Network, Joel Tickner, Carolyn Raffensperger, and Nancy Myers. [accessed April 10, 2003]
Cairns, John, Jr. (2003). "Interrelationships between the Precautionary Principle, Prediction Strategies, and Sustainable Use of the Planet". Environmental Health Perspectives 111, 7 (2003).
Goldstein, Bernard D. (2001). "The Precautionary Principle Also Applies to Public Health Actions". American Journal of Public Health 91, 9 (2001): 1358-1361.
Rio Declaration on Environment and Development. Stockholm, Sweden: United Nations, 1992.
Nielsen, E., Ostergaard, G. and J. C. Larsen. Toxicological Risk Assessment of Chemicals: A Practical Guide. New York: Informa HealthCare, 2008.
O'Brien, M. Making Better Environmental Decisions: An Alternative to Risk Assessment. Cambridge: MIT Press, 2000.
Gilbert, S.G. (2006) Precautionary Assessment: Getting Out of the Risk Assessment Box.