ATSDR does not currently perform dose-response assessments for carcinogens. This Agency does, however, report values established by other Agencies (e.g., U.S. EPA, IARC).
ATSDR does not currently engage in low-dose modeling efforts or in the development of cancer potency factors (ATSDR 1993).
For substances considered by Health Canada to have no threshold (i.e., mutagens and genotoxic carcinogens), it is assumed that there is some probability of harm to human health at any level of exposure. For these chemicals, Health Canada considers it inappropriate to specify a concentration or dose associated with a negligible or de minimis level of risk (e.g., the1 in a million risk often used by U.S. EPA) by low-dose extrapolation procedures. Rather, potency is expressed as the dose or concentration which induces a 5% increase in the incidence of, or deaths due to, tumours or heritable mutations considered to be associated with exposure. The TD05/TC05 is then compared with exposure levels. If the ratio between exposure and the TD05/TC05 is less than 2 x 10-6, there is little need for further action. If the ratio is 2 x 10-4 or greater, there is a high priority for further action. Values in between are of moderate priority.
In order to compare cancer potencies estimated by different Agencies, TERA chose to express each Agency's potency value as the equivalent of a 1 in a 100,000 risk level. For Health Canada, this required dividing the TD05/TC05 (i.e., a 1 in 20 risk level) by a factor of 5,000 to represent a 1 in a 100,000 risk level. It is noted, however, that unlike the methodology used by U.S. EPA, Health Canada's TD05/TC05 is not based on a confidence limit, but is computed directly from the dose-response curve within or close to the experimental range. Health Canada considered this to be appropriate in view of the stability of the data in the experimental range and to avoid unnecessarily conservative assumptions.
An explanation of IARC's methods is available in the Preamble to the IARC Monographs at http://monographs.iarc.fr/ENG/Preamble/index.php. The Preamble to the Monographs sets out the objective and scope of the evaluation programme, the procedures used when making assessments, and the types of evidence considered and criteria used in reaching the final evaluations.
NSF International currently uses U.S. EPA (2005) dose-response assessment methodology. Earlier documents have used U.S. EPA (1999) draft, U.S. EPA (1996) proposed or U.S. EPA (1986) final guidelines. 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.” For a tumor endpoint, human equivalent doses are first calculated by scaling the applied daily doses to body weight raised to the 0.25 power. The dose-response data are then subject to benchmark dose modeling (U.S. EPA, 2009) to determine the point of departure, which is generally the 95% confidence limit on a dose associated with an estimated 10% increased tumor or related non-tumor response (the LED10). If the weight of evidence suggests that the compound is genotoxic, the dose-response assessment is performed by linear extrapolation from the point of departure to a specific risk level. If there is a plausible mode of action that indicates the tumor or tumor precursor is not produced by a genotoxic mechanism, a margin-of-exposure approach may be used. In this latter case, if the data cannot be modeled, a NOAEL or LOAEL may be used as the point of departure.
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 http://www.rivm.nl/bibliotheek/rapporten/711701006.pdf or at http://www.rivm.nl/en/ (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 http://www.tceq.texas.gov/publications/rg/rg-442.html . This document is a technical guide that details the process of developing Effects Screening Levels (ESLs), Reference Values (ReVs), and Unit Risk Factors (URFs).
U.S. EPA published guidelines for carcinogen risk assessment in 1986 (U.S. EPA, 1986). These guidelines outline procedures for estimating cancer potency. Almost all of the carcinogen assessments on IRIS were based on these 1986 guidelines. In 1996, EPA proposed revisions to the cancer guidelines (U.S. EPA, 1996), and these were further modified in the draft 1999 guidelines (U.S. EPA, 1999), and were then finalized in the 2005 guidelines (U.S. EPA, 2005). Assessments developed between 1996 and approximately 1999 may have used the 1996 proposed guidelines; and assessments developed between approximately 1999 and early 2005 may have used the 1999 draft guidelines. For more details about the evolution of U.S. EPA’s cancer guidelines, please see http://www.epa.gov/cancerguidelines/.
Below is a brief description of EPA dose-response procedures based on the 1986 guidelines and an explanation of how TERA expresses the results on ITER for comparison purposes. This is followed by a brief description of the 2005 guidelines.
Description of 1986 Guidelines
Two extrapolations are generally necessary when using animal data. The first step is extrapolation from animals to humans. According to the 1986 guidelines, this extrapolation is done by estimating a human equivalent oral dose, by scaling the daily applied doses to body weight raised to the 0.66 power. Second, one needs to extrapolate from the high doses used in animal studies to the generally lower doses of interest for environmental exposure. Risk at low exposure levels generally cannot be measured directly (either by animal experiments or by epidemiologic studies). Therefore, a number of mathematical models and procedures have been developed for use in extrapolating from high to low doses. Under EPA's 1986 cancer risk assessment guidelines, the linearized multistage model was generally chosen as the default model for extrapolation to low doses. Multistage models are exponential models approaching 100% risk at high doses, with a shape at low doses described by a polynomial function. The multistage model is fit to the tumor dose-response data, and an upper bound for the risk is estimated by incorporating an appropriate linear term into the statistical bound for the polynomial. At sufficiently small exposures, any higher-order terms in the polynomial will contribute negligibly, and the graph of the upper bound will appear to be a straight line. The slope of this line (formerly called the potency) is called the slope factor. Its units are (proportion of individuals with tumors)/mg/kg-day.
For the oral route, EPA calculates both a slope factor and a unit risk. As described above, the oral slope factor expresses the risk per mg/kg-day. The unit risk is a numerically equivalent term that is expressed as the risk associated with a drinking water concentration of 1 ug/L (with assumptions being made that an adult weighs 70 kg and drinks 2 L/day). For the route of inhalation, EPA does not provide a slope factor, but rather expresses the risk only in terms of a unit risk. The units for the inhalation unit risk are risk per 1 ug/m3. In other words, it is the risk associated with an air concentration of 1 ug/m3 (assuming a 70 kg adult breathes 20 cubic meters/day).
In order to compare cancer potencies estimated by different Agencies, TERA chose to express each Agency's potency value as the equivalent of a 1 in a 100,000 risk level. Thus, TERA calculates risk specific doses (RSDs) from EPA's oral slope factors and risk specific concentrations (RSCs) from EPA’s inhalation unit risks. Specifically, for oral slope factors, TERA converts the EPA risk estimate to a concentration at the 1 in 100,000 (E-5) risk level by dividing 1E-5 by the unit risk [in units of “per (ug/m3)”] and then by another 1000 to convert to mg/cu.m to determine a risk specific concentration (RSC) (in units of “mg/ m3”). Similarly, TERA converts the EPA oral slope factors to a dose at the 1 in 100,000 (E-5) risk level by dividing 1E-5 by the slope factor [in units of “per (mg/kg-day”] to determine a risk specific dose (RSD) (in units of “mg/kg-day”).
In setting standards for carcinogens, EPA generally considers a de minimis (e.g., less than or equal to 1 in a million) risk to be an acceptable goal. Using the output from the linearized multistage model, EPA often determines the oral intake or inhalation concentration that is associated with a risk of 1 in a million as a goal for setting limits on exposure. Risk management issues may lead to the setting of intakes/concentrations that are higher or lower.
Description of 2005 Guidelines
The 2005 cancer guidelines (U.S. EPA, 2005) differ significantly from the 1986 guidelines. When animal studies are used, the estimation of a human equivalent dose utilizes toxicokinetic models when available, and if not, the default for oral doses is to scale the daily applied doses to body weight raised to the 0.75 power. The default dose scaling methodology for inhalation follows that developed for derivation of reference concentrations (RfCs), estimating the relative animal and human respiratory deposition of particles, and the relative internal dose or dose to the respiratory region of gases, depending on the chemical and physical properties of the gas.
Response data from effects of the agent on carcinogenic processes (i.e., nontumor data) are analyzed along with tumor incidence data. Tumor incidences and precursor effects may be combined to extend the dose-response curve below the tumor data. A biologically based or case-specific dose response model to relate dose and response data in the range of empirical observation may be used when data are sufficient. When this is not the case, standard default procedures are used to fit a curve to the data and to calculate the lower 95% confidence limit on a dose associated with an estimated 10% increased tumor or relevant nontumor response (LED10). The LED10 then serves as a point of departure for extrapolating outside the observable range. Depending on the mode(s) of action of the agent, low-dose extrapolation from the LED10 is done using a linear approach, a nonlinear approach, or both. Linear extrapolation to low doses is used when the mode of action data indicates that the agent is DNA-reactive and has direct mutagenic activity, or if the human exposure or body burden is high and near doses associated with key precursor events. Linear extrapolation is also used as a default when there are insufficient data to evaluate mode of action. For linear extrapolation, a straight line is drawn from the point of departure to zero dose, zero response, corrected for background. The slope of the line expresses the extra risk per unit dose. This risk can be converted to the risk specific dose or risk specific concentration, as described for the 1986 guidelines. A nonlinear extrapolation is used when there a tumor mode of action supporting nonlinearity applies, and the chemical does not demonstrate mutagenic effects consistent with linearity. Alternatively, a nonlinear extrapolation may also be used when the data support a nonlinear mode of action, and there is a suggestion of mutagenicity, but the data justifies the conclusion that mutagenicity is not operative at low doses. The guidelines present criteria (based on a modification of the Hill criteria for evaluation of epidemiology data) for evaluation of potential modes of action. When the nonlinear extrapolation is used, an RfD- or RfC-like value is derived using standard methods. Mode of action analysis is critical to the 2005 draft guidelines. This emphasis will bring new research on carcinogenic processes to bear in assessments.
The 2005 guidelines also include supplemental guidance for assessing susceptibility from early-life exposure to carcinogens. This guidance states that particular attention should be paid to the potential for higher potency from early-life exposure. Mode of action data should also be evaluated for age-specific differences. If chemical-specific data are available to evaluate the age-specific potency, those data should be used. If chemical-specific data are not identified, but the chemical acts via a mutagenic mode of action, age-dependent adjustment factors are used.
ATSDR. 1993. ATSDR Cancer Policy Framework. U.S. Department of Health and Human Services. January. Available at http://www.atsdr.cdc.gov/cancer.html
Health Canada. 1994. Human Health Risk Assessment for Priority Substances. Environmental Health Directorate. Canadian Environmental Protection Act. Health Canada, Ottawa, 1994.
NSF/ANSI Standard 60. 2009. Drinking Water Treatment Chemicals - Health Effects. NSF International, Ann Arbor, MI. Available for a fee at http://www.techstreet.com/standards/NSF/60_2009?product_id=1628365
NSF/ANSI Standard 61. 2009. Drinking Water System Components - Health Effects. NSF International, Ann Arbor, MI. Available for a fee at http://www.techstreet.com/standards/NSF/61_2009?product_id=1656646
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 http://www.epa.gov/NCEA/bmds/index.html
U.S. EPA (Environmental Protection Agency). 2005. Guidelines for Carcinogen Risk Assessment. Washington, DC, National Center for Environmental Assessment. EPA/630/P-03/001b. NCEA-F-0644b. Available at http://www.epa.gov/cancerguidelines.
US. EPA (Environmental Protection Agency). 1999. Draft Revised Guidelines for Carcinogen Risk Assessment (External Draft, July 1999). Risk Assessment Forum, Washington, DC. NCEA-F-0644. Available at http://epa.gov/cancerguidelines/draft-guidelines-carcinogen-ra-1999.htm
U.S. EPA (Environmental Protection Agency). 1996. Proposed Guidelines for Carcinogen Risk Assessment. EPA/600/P-92/003C. 61 Federal Register pp 17960-18011. April 23, 1996. Available at http://www.epa.gov/raf/publications/pdfs/propcra_1996.pdf
U.S. EPA (Environmental Protection Agency). 1986. Guidelines for Carcinogen Risk Assessment. Risk Assessment Forum, Washington, DC. EPA/630/R-00/004. Available at http://epa.gov/cancerguidelines/guidelines-carcinogen-risk-assessment-1986.htm