Risk assessment of chemical substances
Risk assessment involves the identification, quantification and communication of the risk (and the potential hazard or harm) resulting from a specific activity (for example, the use or occurrence of a chemical). It takes into account the possible harmful effects on individual people, society, or the environment of undertaking the activity (for example, using a chemical in a proposed amount and manner, in light of all of the chemical's possible routes of exposure). This article focuses its discussion on assessing the human health risk of chemical substances.
For many years the terminology and methods used in human risk or hazard assessment were not consistent. This, of course, fostered confusion among scientists and the public about the practice and value of risk assessment. In 1983, the National Academy of Sciences (NAS) published consensus-based terminology and concepts for risk assessments.
Currently, the following terms are used routinely in assessing the risk associated with exposure to chemical substances:
Four fundamental steps in the risk assessment process as defined by the NAS are:
Risk management decisions follow the identification, quantification and communication of risk that are determined by risk assessments. During the regulatory process, risk managers may request that additional research and additional risk assessments be conducted to justify their risk management decisions. As indicated in Figure 1, the risk assessment and risk management processes are intimately related.
This section will describe only the risk assessment process. Risk assessments may be conducted for individual chemicals or for complex mixtures of chemicals. In cases of such complex mixtures as hazardous waste sites, the process of risk assessment itself becomes quite complex. This complexity results from:
- simultaneous exposure to many substances with the potential for numerous chemical and biological interactions
- exposures by multiple media and pathways (e.g., via water, air, and soil)
- exposure to a wide array of organisms with differing susceptibilities (e.g., infants, adults, humans, animals, environmental organisms)
Conducting scientifically sound risk assessments is of great national importance. An error in undercalculating risk probabilities could lead to overexposure of the population. On the other hand, an overcalculation of risk could result in unwarranted costs to the public. As illustrated in Figure 2, the cost to clean-up a hazardous waste site varies greatly with the degree of clean-up required which is determined by risk assessments.
In this initial step, the potential for a xenobiotic (that is, foreign) substance to induce any type of toxic hazard is evaluated. Information is gathered and analyzed in a weight-of-evidence approach. The types of data usually consist of:
- human epidemiology data
- animal bioassay data
- supporting data
Based on these results, one or more toxic hazards (or endpoints) may be identified (for example, cancer, birth defects, chronic toxicity, neurotoxicity). The primary hazard of concern is one for which there is a serious health consequence (such as cancer) that can occur at lower dosages than do other serious toxic effects. The primary hazard of concern will be chosen for the dose-response assessment.
Human epidemiology data are the most desirable and are given highest priority since it avoids the concern for species differences in the toxic response. Unfortunately, reliable epidemiology studies rarely are available. Even when epidemiology studies have been conducted, they usually have incomplete and unreliable exposure histories. For this reason, it is rare that risk assessors can construct a reliable dose-response relationship for toxic effects based on epidemiology studies. More often, the human studies can only provide qualitative evidence that a causal relationship exists.
In practice, animal bioassay data are often the primary data used in risk assessments. Animal studies are well-controlled experiments with known exposures and employ detailed, careful clinical, and pathological examinations. The use of laboratory animals to determine potential toxic effects in humans is a necessary and accepted procedure. It is a recognized fact that effects in laboratory animals are usually similar to those observed in humans at comparable dose levels. Exceptions are attributable primarily to differences in the pharmacokinetics and metabolism of the xenobiotics.
Supporting data derived from cell and biochemical studies may help the risk assessor make meaningful predictions as to likely human response. For example, often a chemical is tested with both human and animal cells to study its ability to produce cytotoxicity, mutations, and DNA damage. The cell studies can help identify the mechanism by which a substance has produced an effect in the animal bioassay. In addition, species differences may be revealed and taken into account.
A chemical's toxicity may be predicted based on its similarity in structure to that of chemical for which the toxicity is known. This is known as a Structure-Activity Relationship (SAR). The SAR has only limited value in risk assessment due to exceptions to the predicted toxicity.
The dose-response assessment step quantitates the hazards which were identified in the hazard evaluation phase. It determines the relationship between dose and incidence of effects in humans. There are normally two major extrapolations required: the first is from high experimental doses to low environmental doses and the second from animal to human doses.
The procedures used to extrapolate from high to low doses are different for assessment of carcinogenic effects and non-carcinogenic effects. Carcinogenic effects are not considered to have a threshold and mathematical models are generally used to provide estimates of carcinogenic risk at very low dose levels.
Noncarcinogenic effects (e.g., neurotoxicity) are considered to have dose thresholds below which the effect does not occur. The lowest dose with an effect in animal or human studies is divided by Safety Factors to provide a margin of safety.
Cancer Risk Assessment
Cancer risk assessment involves two steps. The first step is a qualitative evaluation of all available epidemiology studies, animal bioassay data, and biological activity (e.g., mutagenicity). The substance is classified as to carcinogenic risk to humans based on the weight of evidence. If the evidence is sufficient, the substance may be classified as a definite, probable or possible human carcinogen.
The second step is to quantitate the risk for those substances classified as definite or probable human carcinogens. Mathematical models are used to extrapolate from the high experimental doses to the lower environmental doses.
The two primary cancer classification schemes are those of the Environmental Protection Agency (EPA) and the International Agency for Research on Cancer (IARC). The EPA and IARC classification systems are quite similar.
The EPA's cancer assessment procedures have been used by several Federal and State agencies. For example, the Agency for Toxic Substances and Disease Registry (ATSDR) relies on EPA's carcinogen assessments. A substance is assigned to one of six categories as shown below:
The basis for sufficient human evidence is an epidemiology study that clearly demonstrates a causal relationship between exposure to the substance and cancer in humans. The data is determined to provide limited evidence of harm to humans if there are alternative explanations for the observed effect. The data is considered to be inadequate evidence of harm in humans if no satisfactory epidemiology studies exist.
An increase in cancer in more than one species or strain of laboratory animals, or in more than one experiment, is considered sufficient evidence in animals. Also, data from a single experiment can be considered sufficient animal evidence if there is a high incidence or unusual type of tumor induced. Normally, however, a carcinogenic response in only one species, strain, or study, is considered as only limited evidence in animals.
When an agent is classified as a Human or Probable Human Carcinogen, it is then subjected to a quantitative risk assessment. For those designated as a Possible Human Carcinogen, the risk assessor can determine on a case-by-case basis whether a quantitative risk assessment is warranted.
The key risk assessment parameter derived from the EPA carcinogen risk assessment is the cancer slope factor. This is a toxicity value that quantitatively defines the relationship between dose and response. The cancer slope factor is a plausible upper-bound estimate of the probability that an individual will develop cancer if exposed to a chemical for a lifetime of 70 years. The cancer slope factor is expressed as mg/kg/day.
EPA uses the Linearized Multistage Model (LMS), illustrated in Figure 3, to conduct its cancer risk assessments. It yields a cancer slope factor, known as the q1* (pronounced Q1-star) which can be used to predict cancer risk at a specific dose. It assumes linear extrapolation with a zero dose threshold from the upper confidence level of the lowest dose that produced cancer in an animal test or in a human epidemiology study.
Other models that have been used for cancer assessments include:
Estimated drinking water concentrations for chlordane that will cause a lifetime risk of one cancer death in a million persons, derived from different cancer risk assessment models, vary as illustrated below:
PB-PK models are relatively new and are being employed when biological data are available. They quantitate the absorption of a foreign substance, its distribution, metabolism, tissue compartments, and elimination. Some compartments store the chemical (bone and adipose tissue) whereas others biotransform or eliminate it (liver or kidney). All these biological parameters are used to derive the target dose and comparable human doses.
Non-carcinogenic Risk Assessment
Historically, the Acceptable Daily Intake (ADI) procedure has been used to calculate permissible chronic exposure levels for humans based on non-carcinogenic effects. The ADI is the amount of a chemical to which a person can be exposed each day for a long time (usually lifetime) without suffering harmful effects. It is determined by applying safety factors (to account for the uncertainty in the data) to the highest dose in human or animal studies which has been demonstrated not to cause toxicity ('no observed adverse effect level', or NOAEL).
The EPA has slightly modified the ADI approach and calculates a reference dose (RfD) as the acceptable safety level for chronic non-carcinogenic and developmental effects. Similarly, the ATSDR calculates Minimal Risk Levels (MRLs) for noncancer end points.
The critical toxic effect used in the calculation of an ADI, RfD, or MRL is the serious adverse effect which occurs at the lowest exposure level. It may range from lethality to minor toxic effects. It is assumed that humans are as sensitive as the animal species unless evidence indicates otherwise.
In determining the ADIs, RfDs or MRLs, the NOAEL is divided by safety factors (uncertainty factors) in order to provide a margin of safety for allowable human exposure.
When a NOAEL is not available, a 'lowest observed adverse effect level' (LOAEL) can be used to calculate the RfD. An additional safety factor is included if an LOAEL is used. A Modifying Factor of 0.1-10 allows risk assessors to use scientific judgment in upgrading or downgrading the total uncertainty factor based on the reliability and quality of the data. For example, if a particularly good study is the basis for the risk assessment, a modifying factor of <1 may be used. If a poor study is used, a factor of >1 can be incorporated to compensate for the uncertainty associated with the quality of the study.
A dose-response curve for non-carcinogenic effects is illustrated in Figure 4, which also identifies the NOAEL and LOAEL. Any toxic effect might be used for the NOAEL/LOAEL so long as it is the most sensitive toxic effect and considered likely to occur in humans.
The Uncertainty Factors or Safety Factors used to derive an ADI or RfD are:
The modifying factor is used only in deriving EPA Reference Doses. The number of factors included in calculating the ADI or RfD depend upon the study used to provide the appropriate NOAEL or LOAEL.
The general formula for deriving the RfD is:
The more uncertain or unreliable the data becomes, the higher will be the total uncertainty factor that is applied. An example of an RfD calculation is provided below. A subchronic animal study with a LOAEL of 50 mg/kg/day was used. Thus the uncertainty factors are: 10 for human variability; 10 for an animal study; 10 for less than chronic exposure; and 10 for use of an LOAEL instead of a NOAEL.
In addition to chronic effects, RfDs can also be derived for other long-term toxic effects, including developmental toxicity.
While ATSDR does not conduct cancer risk assessments, it does derive Minimal Risk Levels (MRLs) for noncancer toxicity effects (such as birth defects or liver damage). The MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects over a specified duration of exposure. For inhalation or oral routes, MRLs are derived for acute (14 days or less), intermediate (15-364 days), and chronic (365 days or more) durations of exposures.
The method used to derive MRLs is a modification of the EPA's RfD methodology. The primary modification is that the uncertainty factors of 10 may be lower, either 1 or 3, based on scientific judgment. These uncertainty factors are applied for human variability, interspecies variability (extrapolation from animals to humans), and use of a LOAEL instead of NOAEL. As in the case of RfDs, the product of uncertainty factors multiplied together is divided into the NOAEL or LOAEL to derive the MRL.
Risk assessments are also conducted to derive permissible exposure levels for acute or short-term exposures to chemicals. Health Advisories (HAs) are determined for chemicals in drinking water. HAs are the allowable human exposures for one day, ten days, longer-term, and lifetime durations. The method used to calculate HAs is similar to that for the RfD's using uncertainty factors. Data from toxicity studies with durations of length appropriate to the HA are being developed.
For occupational exposures, Permissible Exposure Levels (PELs), Threshold Limit Values (TLVs), and National Institute for Occupational Safety and Health (NIOSH) Recommended Exposure Levels (RELs) are developed. They represent dose levels that will not produce adverse health effects from repeated daily exposures in the workplace. The method used to derive is conceptually the same. Safety factors are used to derive the PELs, TLVs, and RELs.
Animal doses must be converted to human dose equivalents. The human dose equivalent is based on the assumption that different species are equally sensitive to the effects of a substance per unit of body weight or body surface area.
Historically, the Food and Drug Administration (FDA) used a ratio of body weights of humans to animals to calculate the human dose equivalent. EPA has used a ratio of surface areas of humans to animals to calculate the human dose equivalent. The animal dose was multiplied by the ratio of human to animal body weight raised to the 2/3rd power (to convert from body weight to surface area). FDA and EPA have agreed to use body weight raised to the 3/4th power to calculate human dose equivalents in the future.
The last step in risk assessment is to express the risk in terms of allowable exposure to a contaminated source. Risk is expressed in terms of the concentration of the substance in the environment where human contact occurs. For example, the unit risk in air is risk per mg/m3 whereas the unit risk in drinking water is risk per mg/L.
For carcinogens, the media risk estimates are calculated by dividing cancer slope factors by 70 kg (average weight of man) and multiplying by 20 m3/day (average inhalation rate of an adult) or 2 liters/day (average water consumption rate of an adult).
Exposure assessment is a key phase in the risk assessment process since without an exposure, even the most toxic chemical does not present a threat. All potential exposure pathways are carefully considered. Contaminant releases, their movement and fate in the environment, and the exposed populations are analyzed.
Exposure assessment includes three steps:
- characterization of the exposure setting (e.g., point source)
- identification of exposure pathways (e.g., groundwater)
- quantification of the exposure (e.g., µg/L water)
The main variables in the exposure assessment are:
- exposed populations (general public or selected groups)
- types of substances (pharmaceuticals, occupational chemicals, or environmental pollutants)
- single substance or mixture of substances
- duration of exposure (brief, intermittent, or protracted)
- pathways and media (ingestion, inhalation, and dermal exposure)
All possible types of exposure are considered in order to assess the toxicity and risk that might occur due to these variables.
The risk assessor first looks at the physical environment and the potentially exposed populations. The physical environment may include considerations of climate, vegetation, soil type, groundwater and surface water. Populations that may be exposed as the result of chemicals that migrate from the site of pollution are also considered.
Subpopulations may be at greater risk due to a higher level of exposure or because they have increased sensitivity (infants, elderly, pregnant women, and those with chronic illness).
Pollutants may be transported away from the source. They may be physically, chemically or biologically transformed. They may also accumulate in various media. Assessment of the chemical fate requires knowledge of many factors including:
- organic carbon and water partitioning at equilibrium (Koc)
- chemical partitioning between soil and water (Kd)
- partitioning between air and water (Henry's Law Constant)
- solubility constants
- vapor pressures
- partitioning between water and octanol (Kow)
- bioconcentration factors
These factors are integrated with the data on sources, releases and routes of the pollutants to determine the exposure pathways of importance.
Exposure pathways may include:
Since actual measurements of exposures are often not available, exposure models may be used. For example, in air quality studies, chemical emission and air dispersion models are used to predict the air concentrations to downwind residents. Residential wells downgradient from a site may not currently show signs of contamination. They may become contaminated in the future as chemicals in the groundwater migrate to the well site. In these situations, groundwater transport models may estimate when chemicals of potential concern will reach the wells.
This final stage in the risk assessment process involves prediction of the frequency and severity of effects in exposed populations. Conclusions reached concerning hazard identification and exposure assessment are integrated to yield probabilities of effects likely to occur in humans exposed under similar conditions.
Since most risk assessments include major uncertainties, it is important that biological and statistical uncertainties are described in the risk characterization. The assessment should identify which components of the risk assessment process involve the greatest degree of uncertainty.
Potential human carcinogenic risks associated with chemical exposure are expressed in terms of an increased probability of developing cancer during a person's lifetime. For example, a 10-6 increased cancer risk represents an increased lifetime risk of 1 in 1,000,000 for developing cancer. For carcinogenicity, the probability of an individual developing cancer over a lifetime is estimated by multiplying the cancer slope factor (mg/kg/day) for the substance by the chronic (70-year average) daily intake (mg/kg-day).
For non-carcinogenic effects, the exposure level is compared with an ADI, RfD or MRL derived for similar exposure periods. Three exposure durations are considered: acute, intermediate, or chronic. For humans, acute effects are considered those that arise within days to a few weeks, intermediate effects are those evident in weeks to a year, and chronic effects are those that become manifest in a year or more.
In some complex risk assessments such as for hazardous waste sites, the risk characterization must consider multiple chemical exposures and multiple exposure pathways. Simultaneous exposures to several chemicals, each at a subthreshold level, can often cause adverse effects by simple summation of injuries.
The assumption of dose additivity is most acceptable when substances induce the same toxic effect by the same mechanism. When available, information on mechanisms of action and chemical interactions are considered and are useful in deriving more scientific risk assessments.
Individuals are often exposed to substances by more than one exposure pathway (e.g., drinking of contaminated water, inhaling contaminated dust). In such situations, the total exposure will usually equal the sum of the exposures by all pathways.
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