NON-Cancer Risk Assessment Methodst 


The below explanation of derivation of minimal risk levels (MRLs) developed by ATSDR in their toxicological profiles was extracted from the description provided on ATSDR's web site ( Additional information is provided in Pohl and Abadin (1995). Generally, ITER only presents ATSDR's chronic MRLs. However, there are two situations in which ITER will discuss the intermediate MRL in the synopsis, if ATSDR has not derived a chronic MRL. ITER will discuss ATSDR's intermediate MRL if none of the organizations have derived a chronic risk value. In addition, ITER will discuss ATSDR's intermediate MRL if it is based on the same study as another organization's chronic risk value. 

Following discussions with scientists within the Department of Health and Human Services (HHS) and the EPA, ATSDR chose to adopt a practice similar to that of the EPA's Reference Dose (RfD) and Reference Concentration (RfC) for deriving substance-specific health guidance levels for non-neoplastic endpoints. An MRL is an estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration of exposure. These substance-specific estimates, which are intended to serve as screening levels, are used by ATSDR health assessors and other responders to identify contaminants and potential health effects that may be of concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or action levels for ATSDR or other Agencies. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological information and epidemiologic evaluations of a hazardous substance. During the development of toxicological profiles, MRLs are derived when ATSDR determines that reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a given route of exposure to the substance. MRLs are based on noncancer health effects only and are not based on a consideration of cancer effects. Inhalation MRLs are exposure concentrations expressed in units of parts per million (ppm) for gases and volatiles, or milligrams per cubic meter (mg/m3) for particles. Oral MRLs are expressed as daily human doses in units of milligrams per kilogram per day (mg/kg/day). 

ATSDR uses the no-observed-adverse-effect-level/uncertainty factor approach to derive MRLs for hazardous substances. They are set below levels that, based on current information, might cause adverse health effects in the people most sensitive to such substance-induced effects. MRLs are derived for acute (1-14 days), intermediate (>14-364 days), and chronic (365 days and longer) exposure durations, and for the oral and inhalation routes of exposure. Currently, MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method suitable for this route of exposure. MRLs are generally based on the most sensitive substance-induced end point considered to be of relevance to humans. ATSDR does not use serious health effects (such as irreparable damage to the liver or kidneys, or birth defects) as a basis for establishing MRLs. Exposure to a level above the MRL does not mean that adverse health effects will occur. 

MRLs are intended to serve as a screening tool to help public health professionals decide where to look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that are not expected to cause adverse health effects. Most MRLs contain some degree of uncertainty because of the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, elderly, and nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR uses a conservative (i.e., protective) approach to address these uncertainties consistent with the public health principle of prevention. Although human data are preferred, MRLs often must be based on animal studies because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes that humans are more sensitive than animals to the effects of hazardous substances and that certain persons may be particularly sensitive. Thus, the resulting MRL may be as much as a hundredfold below levels shown to be nontoxic in laboratory animals. When adequate information is available, physiologically based pharmacokinetic (PBPK) modeling and benchmark dose (BMD) modeling have also been used as an adjunct to the NOAEL/UF approach in deriving MRLs.  

Proposed MRLs undergo a rigorous review process. They are reviewed by the Health Effects/MRL Workgroup within the Division of Toxicology and Environmental Medicine; an expert panel of external peer reviewers; the agency wide MRL Workgroup, with participation from other federal agencies, including EPA; and are submitted for public comment through the toxicological profile public comment period. Each MRL is subject to change as new information becomes available concomitant with updating the toxicological profile of the substance. MRLs in the most recent toxicological profiles supersede previously published levels. 

Health Canada

Health Canada has adopted a threshold toxicants approach for substances classified in Groups IV, V, or VI (see Cancer Risk Assessment Methods text for further information on Health Canada cancer classifications). The following is excerpted from Health Canada's "Human Health Risk Assessment for Priority Substances" (1994). Please refer to this text for a more complete discussion.

Threshold toxicants are those for which the critical effect is not considered to be cancer or a heritable mutation. Where possible, a dose (or concentration) of a chemical substance that does not produce any (adverse) effect [i.e., "no-observed-(adverse)-effect-level" (NO(A)EL)] for the critical endpoint is identified, usually from toxicological studies involving experimental animals, but sometimes from epidemiological studies of human populations. If a value for the NO(A)EL cannot be ascertained, a lowest-observed-(adverse)-effect-level (LO(A)EL) is used. The nature and severity of the critical effect (and to some extent, the steepness of the dose-response curve) are taken into account in the establishment of the NO(A)EL or LO(A)EL.  

An uncertainty factor is applied to the NO(A)EL or LO(A)EL to derive a Tolerable Daily Intake or Tolerable Concentration (TDI or TC), the intake or concentration to which it is believed that a person can be exposed daily over a lifetime without deleterious effect. They are based on non-carcinogenic effects. Short term excursions above these values do not necessarily imply that exposure constitutes an undue risk to health. Ideally, the NO(A)EL is derived from a chronic exposure study involving the most relevant or sensitive species (where possible, determined based on data on species differences in pharmacokinetic parameters or mechanism of action) or on investigations in the most sensitive sub-population (does not include hypersensitive) in which the route of administration is similar to that by which humans are principally exposed. TDIs or TCs are not generally developed on the basis of data from acute or short term studies (unless observed effects in longer term studies are expected to be similar), although they are occasionally based on data from sub-chronic studies in the absence of available information in adequately designed and conducted chronic toxicity studies, in which case an additional factor of uncertainty is included. Exceptionally, another route of exposure may be used where appropriate, incorporating relevant pharmacokinetic data.  

The uncertainty factor is derived on a case-by-case basis, depending principally on the quality of the database. Generally, a factor of 1 to 10 is used to account for intraspecies variation and interspecies variation (these may be subdivided to address separately kinetic and dynamic differences). An additional factor of 1 to 100 is used to account for inadequacies of the database which include but are not necessarily limited to, lack of adequate data on developmental, chronic or reproductive toxicity, use of a LO(A)EL versus a NO(A)EL and inadequacies of the critical study. An additional uncertainty factor ranging between 1 and 5 may be incorporated where there is sufficient information to indicate a potential for interaction with other chemical substances commonly present in the general environment. Other considerations and possible adjustments might be made for essential substances or severe, irreversible effects. Numerical values of the uncertainty factor normally range from 1 to 10,000.  

The value of the TDI or TC is compared to the estimated total daily intake of a chemical substance by the various age groups of the population of Canada and, in some cases, certain high exposure sub-groups or to concentrations in relevant environmental media.  

An alternative approach, which may be used where data permit, involves estimation of the "benchmark dose", a model-derived estimate of a particular incidence level (e.g., 5%) for the critical effect. More specifically, the benchmark dose is the effective dose (or its lower confidence limit) that produces a certain increase in incidence above control levels. The advantages of the benchmark dose are that it takes into account the slope of the dose-response curve, the size of the study groups and the variability in the data in establishment of the true threshold.  

Substances classified as "Possible Carcinogenic to Humans" (Group III) are generally assessed in the above manner. Exceptionally, however, in deriving the TDI or TC an additional uncertainty factor (ranging between 1 and 10) may be incorporated to account for the limited evidence of carcinogenicity.  

NSF International 

NSF International uses the oral reference dose (RfD) methodology as described in Barnes and Dourson (1988), Dourson (1994), and U.S. EPA (2002) for non-cancer risk assessment. Specific implementation of this methodology is described in Annex A of NSF International/American National Standard 60 "Drinking water treatment chemicals – Health effects," and of NSF International/American National Standard 61 "Drinking water system components – Health effects." The LED10 (U.S. EPA, 1995), which is modeled using U.S. EPA (2009) benchmark dose methodology, is favored over the NOAEL in selection of the point of departure if dose-response data on the critical effect can be successfully modeled. Compound specific uncertainty factors are favored over defaults if sufficient data exist for their derivation. The margin-of-exposure approach may also be used.  


An explanation of RIVM's risk assessment methods is available in the following report:  

Janssen, PJCM and GJA Speijers. 1997. Guidance on the Derivation of Maximum Permissible Risk Levels for Human Intake of Soil Contaminants. Report no. 711701006, National Institute of Public Health and the Environment. Bilthoven, The Netherlands. January. Available at or at (click on Search, type "711701006", then click on document). 


An explanation of TCEQ's methods is available in the publication entitled, TCEQ Guidelines to Develop Toxicity Factors” Available at . This document is a technical guide that details the process of developing Effects Screening Levels (ESLs), Reference Values (ReVs), and Unit Risk Factors (URFs). 


EPA defines the oral reference dose (RfD) as “an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.” The inhalation reference concentration (RfC) is similarly defined as “an estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.” The estimation of RfDs and RfCs lies squarely in the area of hazard identification and dose response assessment as defined by the National Academy of Sciences (NAS, 1983) report on risk assessment in the federal government. 

The oral RfD and inhalation RfC are useful reference points for gauging the potential effects of other doses. Doses at the RfD (or less) or concentrations at the RfC (or less) are not likely to be associated with any health risks, and are, therefore, assumed likely to be protective and of little regulatory concern. In contrast, as the amount and frequency of exposures exceeding the RfD or RfC increases, the probability that adverse effects may be observed in a human population also increases. However, it cannot be stated categorically that all doses below the RfD or RfC are acceptable and that all doses in excess of the RfD or RfC are unacceptable. The probability of an effect, the percentage of people affected, and the severity of the risk usually increases as the oral dose or inhalation concentration increases. Therefore, small exceedances of the RfD or RfC will generally result in risk to only the most sensitive individuals in the population, and larger exceedances are generally required before most people are affected. In addition, while exposures at or below the RfD or RfC are protective for sensitive people for most chemicals, such exposures may carry some risk for a sensitive individual for some chemicals. Moreover, the precision of the RfD or RfC depends in part on the overall magnitude of the composite uncertainty and modifying factors used in its calculation. The precision at best is probably one significant figure and more generally an order of magnitude, base 10. As the magnitude of this composite factor increases, the estimate becomes even less precise. 

The basic assumption in the development of an RfD or RfC is that a threshold exists in the dose rate at or above which an adverse effect will be evoked in an organism. EPA and others consider this assumption to be well-founded. I t is supported by known mechanisms of toxicity of many compounds, which show that a known physiologic reserve must be depleted and/or the repair capacity of the organism must be overcome before toxicity occurs (Klaassen, 2001). 

For health effects that are not cancer, the U.S. Environmental Protection Agency (EPA, 2002, 2005) and others first identify the critical effect(s), which is “the first adverse effect, or its known precursor, that occurs to the most sensitive species as the dose rate of an agent increases.” Human toxicity data adequate for use in the estimation of RfDs or RfCs are seldom available, but if they are available, they are used in the selection of this critical effect. The use of human data has the advantage of avoiding the problems inherent in interspecies extrapolation.  

After the critical effect(s) has been identified, EPA generally selects from an overall review of the literature an exposure level (e.g., dose rate for oral studies in mg/kg-day, or air concentration for inhalation studies in mg/m3) that represents the highest level tested at which the critical effect(s) was not demonstrated. This level, the No Observed Adverse Effect Level (NOAEL), is the key datum gleaned from the toxicologist's review of the chemical's entire database and is the first component in the estimation of an RfD or RfC. If a NOAEL is not available, the Lowest Observed Adverse Effect Level (LOAEL) is used. It is not considered appropriate, however, to derive an RfD or RfC from a frank effect, such as lethality. As an alternative to the NOAEL or LOAEL, a benchmark dose (BMD) may be used in this part of the assessment. Advantages and disadvantages of NOAELs and BMDs are described elsewhere (U.S. EPA, 1995). 

In the absence of appropriate human data, animal data are closely scrutinized. Presented with data from several animal studies, EPA and others first seek to identify the animal model that is most relevant to humans, based on the most defensible biological rationale, for instance using comparative pharmacokinetic data. In the absence of a clearly most relevant species, however, EPA and others generally choose the critical study and species that shows an adverse effect at the lowest administered dose. This is based on the assumption that, in the absence of data to the contrary, humans may be as sensitive as the most sensitive experimental animal species. 

Uncertainty factors (UFs) are reductions in the dose rate or concentration to account for areas of scientific uncertainty inherent in most toxicity databases. The choice of appropriate uncertainty and modifying factors reflects a case-by-case judgment by experts and should account for each of the applicable areas of uncertainty and any nuances in the available data that might change the magnitude of any factor. 

U.S. EPA has several publications that describe its use of uncertainty factors (UF) in estimating RfDs and RfCs (e.g., Dourson, 1994; EPA, 2002, 2005). EPA considers five areas of uncertainty in developing RfDs and RfCs. The default value for these factors is 10, but factors of 3 (a half-log of 10, rounded to one significant figure), or 1 are routinely used when partial data are available for these areas of uncertainty (Dourson et al., 1996). EPA's UF for intrahuman variability (designated as H) is intended to account for the variation in sensitivity among the members of the human population. EPA's UF for experimental animal to human extrapolation (designated as A) is intended to account for the extrapolation from animal data to the case of humans. Both of these uncertainty factors can be considered to have components of both toxicokinetics and toxicodynamics, and either component can be replaced by data, when available. More information about this approach, termed chemical-specific adjustment factors (CSAFs) is provided in IPCS (2005). EPA is also in the process of developing its own guidelines addressing this approach. As an example of this type of approach, the use of dosimetric adjustments to the experimental animal NOAEL or LOAEL to estimate the Human Equivalent Concentration (HEC) in the development of RfCs addresses much of the kinetic differences between the experimental animal species and humans. Therefore, a 3-fold, rather than a 10-fold factor is used. EPA's subchronic-to-chronic UF (designated as S) is intended to account for extrapolating from NOAELs or LOAELs identified from less than chronic exposure to chronic levels. EPA's UF for LOAEL-to-NOAEL extrapolation (designated as L) is applied when an appropriate NOAEL is not available to serve as the basis for a risk estimate, and extrapolation from an experimental LOAEL is necessary. An uncertainty factor of 3 is typically used when extrapolating from a minimal LOAEL. EPA's database completeness (designated as D) is intended to account for the inability of any single study to adequately address all possible adverse outcomes (Dourson, 1994; EPA, 2002, 2005).

Older EPA assessments occasionally also used an additional factor, referred to as a modifying factor (MF), as an occasional, necessary adjustment in the estimation of an RfC or RfD to account for areas of uncertainty not explicitly addressed by the usual factors. The value of the MF is greater than zero and <10, but it should generally be developed on a log 10 basis (i.e., 0.3, 1, 3, 10) since its precision is not expected to be any greater than the standard UFs. The default value for this factor is 1. Current EPA assessments consider the issues addressed in the context of the MF to fall under the five standard UFs, typically under the database UF. 

The RfD is composed of the NOAEL or LOAEL or BMD divided by the composite UF, calculated as the product of all individual UFs (and MF, if relevant).
The following equation is used: 

RfD = NOAEL or LOAEL or BMDL / (UF).  

The equation that EPA uses to determine the value of the RfC is:  
RfC = NOAEL(HEC) or LOAEL(HEC) or BMCL(HEC) (mg/m3) / (UF)   where:  

NOAEL(HEC) = No Observed Adverse Effect Level-Human Equivalent  

LOAEL(HEC) = Lowest Observed Adverse Effect Level-Human Equivalent  

BMCL(HEC) = Benchmark Concentration Lower Limit -Human Equivalent  

The "Human Equivalent Concentration" designation reflects the incorporation of dosimetric considerations in the development of an RfC. In determining the dosimetric adjustments between the experimental animal specie and humans, one first determines whether the agent was a particle or a gas (vapor). The approach for dosimetric adjustments for gases is determined by the gas category. Gases are categorized by their target effects and the chemical/physical properties (all of which relate to the mode of action). For particles, the dosimetric adjustments take into account the differences in deposition to different regions of the respiratory tract in the experimental animal specie and humans. These differences depend on the particle size, inhalation rate, and respiratory tract dimensions. Dosimetric adjustments are also available to account for differences between occupational and continuous general population exposures. For a comprehensive understanding of this method the interested reader is referred to U.S. EPA (1994), Jarabek (1994), or Jarabek (1995). 

Finally, EPA (2005) provides a statement of confidence in its noncancer risk estimates for each chemical on its Integrated Risk Information System (IRIS). High confidence indicates a judgment that additional toxicity data are not likely to change the RfC or RfD (Barnes and Dourson, 1988). Low confidence for an RfD indicates that at least a single, well-conducted, subchronic mammalian bioassay by the appropriate route is available. A low confidence RfC means that at least a single, well-conducted, subchronic mammalian bioassay that identified a NOAEL and included evaluation of the respiratory tract is available. For such a minimum database, the likelihood that additional toxicity data may change the RfC or RfD is greater. Medium confidence indicates a judgment somewhere between these former two choices.  Additional information on methods for developing RfDs and RfCs is provided in U.S. EPA (2002). 

Barnes, D.G., and M.L. Dourson. 1988. Reference Dose (RfD): Description and Use in Health Risk Assessments. Regulatory Toxicology and Pharmacology, 8:471-486. 

Klaassen, C, Ed. 2001. Casarett and Doull's Toxicology: The Basic Science of Poisons. McGraw-Hill, Medical Publishing Division, New York, NY. pp. 64-78; 92-93. 

Dourson, M.L., 1994. Methodology for establishing oral reference doses (RfDs). In: Risk Assessment of Essential Elements. W. Mertz, C.O. Abernathy, and S.S. Olin (editors), ILSI Press Washington, D.C., pages 51-61.

Dourson, M.L., S.P. Felter and D. Robinson. 1996. Evolution of science-based uncertainty factors in noncancer risk assessment. Reg. Tox. Pharmacol., 24: 108-120. Available at  

Health Canada. 1994. Human Health Risk Assessment for Priority Substances. Environmental Health Directorate. Canadian Environmental Protection Act. Health Canada, Ottawa, 1994. 

IPCS (International Programme on Chemical Safety). 2005. Final Guidance Document for the Use of Data in Development of Chemical Specific Adjustment Factors (CSAFs) for Interspecies Differences and Human Variability: Guidance Document for Use of Data in Dose/Concentration- Response Assessment, (Harmonization Project Document 2), World Health Organization, Geneva. Available at  

Jarabek, A.M. 1994. Inhalation RfC methodology: Dosimetric adjustments and dose-response estimation of noncancer toxicity in the upper respiratory tract. Inhal. Tocicol. 6(suppl):301-325. 

Jarabek, A.M. 1995. Interspecies extrapolation based on mechanistic determinants of chemical disposition. Human and Ecological Risk Assessment. 1(5):641-662. 

NAS (National Academy of Sciences). 1983. Risk Assessment in the Federal Government: Managing the Process. National Academy Press, Washington, DC. 

NSF/ANSI Standard 60. 2009. Drinking Water Treatment Chemicals - Health Effects. NSF International, Ann Arbor, MI. Available for a fee at

NSF/ANSI Standard 61. 2009. Drinking Water System Components - Health Effects. NSF International, Ann Arbor, MI. Available for a fee at 

Pohl, H.R. and H.G. Abadin. 1995. Utilizing uncertainty factors in minimal risk levels derivation. Regulatory Toxicology and Pharmacology. 22:180-188. 

U.S. EPA (Environmental Protection Agency). 2009. Benchmark Dose Software Version 2.1.1. National Center for Environmental Assessment, Office of Research and Development. Available at  

U.S. EPA (Environmental Protection Agency). 2005. Integrated Risk Information System (IRIS). Available at IRIS guidance documents and individual chemical files.

U.S. EPA (Environmental Protection Agency). 2002. A Review of the Reference Dose and Reference Concentration Processes. U.S. EPA, Risk Assessment Forum, Washington, DC, EPA/630/P-02/002F, 2002. Available at  

U.S. EPA (Environmental Protection Agency). 1995. The use of the benchmark dose approach in health risk assessment. Risk Assessment Forum. Office of Research and Development. Washington, D.C. EPA/630/R-94/007.

U.S. EPA (Environmental Protection Agency). 1994. Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry. Office of Health and Environmental Assessment. Washington, DC. EPA/600/8-90-066F, October.