Today is Monday, Mar. 27, 2017

Department of Environmental Health

Risk Science Center (RSC)

What is International Toxicity Estimates for Risk (ITER)?

Worldwide, numerous organizations use different terms and approaches to derive chemical toxicity values (CTVs) for their specific applications. Consequently, derived values for the same chemical may differ considerably from one agency to the next. International Toxicity Estimates for Risk (ITER) is composed of human health risk values and cancer classifications for over 735 environmental chemicals from international organizations. The ITER free-internet database presents chemical toxicity values in an easy to compare tabular format. As noted and because many of these chemicals have numerous chemical toxicity values, the database also includes a synopsis explaining the differences in the methods used to derive these values. For risk managers or risk professionals seeking additional information, links to the respective agencies deriving and applying the respective risk values are also provided. ITER contains chemical toxicity values that are applicable for daily (24 hr) average lifetime exposures to environmental chemicals.  By providing a one-stop shop database, ITER provides worldwide assistance to:

  • Reduce unnecessary toxicity testing
  • Promote the concept of communication with one lexicon for risk assessment
  • Make better use of existing chemical risk information

 

Table 1. List of Terminology or
Trademarks Used for chemical toxicity values
(CTVs) 1, 2
Acceptable Daily Intake (ADI)
Cancer Slope Factor (CSF)
Derived Minimal Effect Level (DMEL)
Derived No Effect Level (DNEL)
Effects Screening Levels (ESLs)
Exposure Limits
Maximum Contaminant Level Goals (MCLGs)
Maximum Permissible Risk levels, (MPRs)
Minimal Risk Level (MRL)
Provisional Peer Reviewed Toxicity Value (PPRTV)
Reference Concentration (RfC)
Reference Dose (RfD) 
Risk Value
Single Product Allowable Concentration (SPAC)
Tolerable Concentration (TC)
Tolerable Daily Intake (TDI)
Tolerable Intake (TI) 
Total Allowable Concentration (TAC) 
Toxicity Estimate for Risk
Toxicity Reference Values (TRVs) 
Toxicity Value
1These chemical toxicity values are mostly acronyms for residential or general population
2These only apply for chemicals, not pharmaceuticals

Background

Chemical toxicity values are requisite tools for evaluating toxicity and protecting exposed populations from the adverse health outcomes of environmental chemicals. Unfortunately, the term chemical toxicity value is often used synonymously with general terms such as toxicity estimates, toxicity values, risk value, risk estimate and risk data. This term (chemical toxicity value) may also encompass more specific trademark names such as minimal risk level (MRL), reference dose (RfD), derived no effect level (DNEL), and total allowable concentration (TAC), to name a few (see Table 1 below for additional chemical toxicity value trademarks or names).

Biological, physical and chemical agents contaminate the environment and are the major culprits contributing to disease outcomes. The World Health Organization (WHO) estimates that 24% of global disease in adults, and 33% of disease in children under the age of 5, is caused by environmental exposures (WHO, 2006). One recommendation for reducing the burden from environmental disease includes “more judicious use and management of toxic substances in the home and workplace”. Risk assessment and management of chemicals in the environment requires chemical toxicity values. With 125,000+ chemicals potentially contaminating the environment and thus affecting human health and less than 1000 with chemical toxicity values in the ITER database, the TERA Center has undertaken a new project “ITER +” (pronounced ITER plus) specifically designed to add new, quality chemical toxicity values to ITER.

Back to Top

 

What’s new in ITER?

ITER Updates

December, 2016: 
TCEQ: RfD for CrVI (chromium VI) (CAS RN 18540-29-9) oral cancer and oral noncancer was added to ITER (via ITER+) by Jeanelle Martinez.

NSF International added toxicity values for the following chemicals:

  • 1-Hexanol (CAS RN 111-27-3)
  • Epoxy F (CAS RN 19932-27-5)
  • N-nitrosomorpholine (CAS RN 59-89-2)
  • N-nitrosopiperdine (CAS RN 100-75-4)
  • Tris (2-butoxyethyl) phosphate (CAS RN 78-51-3)
  • Triclosan (CAS RN 3380-34-5)
  • 2,4-Pentanedione (CAS RN 123-54-6)
  • Dibenzoate (CAS RN 120-55-8)
  • Isobornyl methacrylate (CAS RN 7534-94-3)

 

US EPA: Ethylene oxide (CAS RN 75-21-8) cancer inhalation, Ammonia (CAS RN 7664-41-7) noncancer inhalation, and 1,2,4-Trimethylbenzene (CAS RN 95-63-6) noncancer oral and noncancer inhalation were updated on ITER/TOXNET/ by Chijioke Onyema and Jeanelle Martinez.

November, 2016

  • BPA Biomonitoring Equivalent (BE) was added to ITER. This BE is applicable to the US EPA oral RfD. A biomonitoring equivalent (BE) is the concentration or range of concentrations of a chemical in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline value such as a reference dose (RfD) or tolerable daily intake (TDI).

October, 2016
The following pesticides were updated by Chijioke Onyema to reflect IRIS (US EPA) archiving 51 pesticides

  • 2,4-DB, 
  • Acephate, 
  • Amdro,
  • Asulam, 
  • Bayleton, 
  • Benefin, 
  • Bidrin, 
  • Chlorimuron ethyl, 
  • Chlorpropham and 
  • Chlorsulfuron

September, 2016:

  • Bisphenol A (BPA) (CAS ‎80-05-7) oral RfD from NSF International, and TDI from EFSA were added to ITER.
  • Diethyl phthalate (DEP) (CAS 84-66-2) inhalation DNEL was added to ITER/TOXNET

August, 2016: 

  • Alison Pecquet updated profiles for hydrogen cyanide and cyanide salts  based on the updated IRIS profile by US EPA. These include: cyanide (CAS RN 57-12-5), cyanogen (CAS 460-19-5), calcium cyanide (CAS RN 592-01-8), potassium cyanide (151-50-8), sodium cyanide (CAS 143-33-9), and potassium silver cyanide (CAS RN 506-61-6).
  • 2-Ethylhexanol (2-EH) (CAS 104-76-7) oral and inhalation DNELs are on ITER/TOXNET.
  • Diethyl phthalate (DEP) (CAS 84-66-2) inhalation DNEL was accepted for inclusion to ITER/TOXNET, will be public soon
  • Bisphenol A (BPA) (CAS ‎80-05-7) chemical toxicity values were accepted for inclusion to ITER/TOXNET pending revision of the synopsis to explain the differences between the inputs from a) Oral RfD from NSF International, and b) TDI from EFSA
  • BPA Biomonitoring Equivalents (BEs) are being evaluated by the Science Advisory Committee
     


July, 2016
: Helen Goeden, PhD from the Minnesota Department of Health pointed out the following:

  • CAS 39638-32-9 does not seem to have a corresponding entry in IRIS
  • Thallium and related compounds (CAS: 6533-73-9; 7446-18-6; 563-68-8; 10102-45-1; 7791-12-0) values were withdrawn from IRIS.

 

These were updated/fixed in ITER with:

  • IRIS contains Bis(2-chloro-1-methylethyl) ether with CAS RN 108-60-1 that has a synonym the same as CAS RN 39638-32-9; thus changed this (39638-32-9 to 108-60-1) to match IRIS.
  • These thallium compounds were deleted from ITER.


June, 2016
: The chemical toxicity values for TBBPA (Tetrabromobisphenol A) CAS RN 79-94-7 were added to ITER.

May, 2016: ITER/TOXNET now has alerts for US EPA chemical toxicity values that have updated Risk Assessments from the Office of Chemical Safety and Pollution Prevention (OCSPP).

 
Special Alert

 

Up and coming in ITER

Recently IRIS (ORD, US EPA) archived 51 pesticides because the Office of Pesticide Programs (OPP, US EPA) health risk assessment provides current data.  This data is being curated for inclusion in ITER.

Updates are continuous and the TERA Center works to keep this database as current as possible. If you notice anything not current, please let Jeanelle know and it will be addressed immediately.

 

Back to Top

 

What is ITER+?

ITER+ is a collaborative public/private partnership working on a pilot study to further enhance the one-stop shop concept for finding quality chemical toxicity values for environmental chemical exposures. Centralizing authoritative chemical toxicity values from worldwide organizations into a curated, global free access database will foster the prediction of toxicity from environmental chemical exposures. Easily identifying credible values eliminates one of the most significant and time consuming barriers in the use of screening level chemical toxicity values → finding credible values!

Increasing the number of chemical toxicity values through the ITER+ process will also reduce repetitive toxicity testing costs, and provide an opportunity for upgrading older toxicity values via a high quality systematic and transparent process. For more information on ITER+ click here. For information on the methods used for ITER+ click here.

Back to Top

 

Take a peek: Find your favorite chemical at ITER/TOXNET!

ITER is on TOXNET.  ITER is located in two locations that contain the same information, however, the TOXNET display allows for additional search functions (click here to read a published manuscript describing how to use ITER on TOXNET).  Edits to ITER are uploaded to the TOXNET version of ITER on a weekly basis.

Back to Top

 

Agencies with chemical toxicity values in ITER

  • Agency for Toxic Substances and Disease Registry (ATSDR), Atlanta, GA
  • Health Canada, Canada
  • International Agency for Research on Cancer (IARC), France
  • NSF International, Ann Arbor, Michigan and worldwide
  • US Environmental Protection Agency (US EPA), Washington DC
  • National Institute of Public Health and the Environment (RIVM), Netherlands
  • Independently Peer Reviewed Values (IPRV)
  • Texas Commission on Environmental Quality (TCEQ), Austin, TX

Back to Top

Sponsor a chemical

Support or sponsor a chemical!  Join the expanding, prestigious list of Sponsors. Continuing support is an absolute necessity as the database requires continual updating and software replacement.

Back to Top

Jeanelle Martinez

Current Funding

  • Funding for ITER+ is currently provided by the American Chemistry Council and NSF International.
  • The ITER database is funded by National Library of Medicine, NIH, and NSF International.
  • For more information, contact Jeanelle at Jeanelle.Martinez@uc.edu or (513) 558-7965.
 

Back to Top

Ongoing or recent updates by agency

ATSDR

  • Upcoming: JP-5, JP-8, and Jet A Fuels; and 1 Bromopropane
  • Last update: Feb, 2016. 2,4-Dinitrotoluene (121-14-2), Dinitrotoluene, 2,4/2,6 mixture (2,4/2,6 mix), 2,6-Dinitrotoluene (606-20-2). Final report is available as of Feb., 2016. No changes are necessary in ITER as the chronic MRL was not modified.

 


US EPA

  • Upcoming: 2016 - no new chemical toxicity values available; 51 pesticides archived; 6 in prep for revision; 2015- none available; 2014 - Libby Amphibole asbestos was updated in IRIS.
  • Last updates: Jeanelle Martinez added Libby Amphibole Asbestos to ITER, May 2016. Perchlorate was fixed to reflect ammonium perchlorate. 

 


Health Canada

  • Last update: Melissa Vincent added screening assessment data for Quinoline, July 2016. 

 


IARC

  • Last update: April 2016, Andrea Wullenweber updated classifications for the following chemicals: Benzo[b]fluoranthene; Chlorinated Paraffins, short chain; Benzo[j]fluoranthene; Benzo[k]fluoranthene; Beryllium and compounds; Arsenic, Inorganic; Cadmium, Inorganic; Chromium (VI), Hexavalent; Asbestos; and Benzene. 

 


ITER Peer Review

  • Last update by Jeanelle Martinez, April 2016. The ITER Peer Review for Ammonium Perchlorate was applied to Perchlorate.  
  • January, 2015, 1,4 Dioxane was updated.

 


IPRV (Independently Peer Reviewed Values)

This column contains risk values derived by independent parties whose risk values have undergone peer review through a process outside TERA's ITER Peer Review process. These toxicity values undergo a quality assurance by experts in risk assessment prior to being placed onto ITER/TOXNET.

Upcoming: DNELs for 2-Ethylhexanol (oral and inhalation), and DiethylPhthalate (inhalation) will be added. 

 


NSF International

  • Last update: Nadic methyl anhydride was added in 2013.

 


RIVM

  • Last update: RIVM 2009 - Pentachlorobenzene was updated May 2012.

 

TCEQ

  • Last Update: Cr IV was added August 2014.

Back to Top

 

Risk Assessment Terms and Approaches

As previously noted, numerous organizations globally use different terms and approaches for deriving chemical toxicity values for their specific applications. The following is a brief summary of methods, distinguished by noncancer and cancer approaches, which highlights some of the differences:

Noncancer Risk Assessment Methods

For definition of terms please use the ITER Glossary.

ATSDR

MRLs - (Minimal Risk Levels) developed by ATSDR are an estimate of the daily human exposure to a hazardous substance likely to be without appreciable risk of adverse noncancer health effects over a specified duration of exposure. The MRL may be as much as a hundredfold below levels shown to be nontoxic in laboratory animals. 

For more info on the ATSDR MRL methodology, click here

Back to Top

Health Canada

TDI/TC (Tolerable Daily Intake or Tolerable Concentration), is the intake or concentration of a chemical believed to be without deleterious effects over a lifetime with daily exposure. A noncarcinogenic TDI is developed for  on the basis of a No-Observed-(Adverse)- Effect-Level [NO(A)EL] or Lowest-Observed-(Adverse)Effect-Level [LO(A)EL] in humans or animal species divided by an uncertainty factor (s). For more info on Health Canada "Threshold Toxicants" methodology, click here.

MOE – Margin of exposure is provided in screening assessments of risks to human health. These peer reviewed reports evaluate the most critical effects and conservative effect levels and upper-bounding estimates of exposure. Margins > 1000 are considered adequate as a basis for recommending no further action for substances where the databases on exposure and effects are relatively complete. Margins < 1000, require further consideration and evaluations of limitations and confidence in the exposure and effects databases. For more info on Health Canada MOE methodology, click here.

 

Back to Top

NSF International

RfDs (reference dose) are developed for noncancer oral exposure using US EPA risk assessment guidelines as described in Barnes and Dourson (1988), Dourson (1994), and US EPA (2002). 

TAC - (total allowable concentration)

RSD (risk specific dose) are developed for cancer oral exposure using methods by EPA (US EPA 2005a).

NSF International, an independent, not-for-profit organization, prepares compound specific oral risk assessment documents based on the requirements of Annex A of NSF International/American National Standards 60 "Drinking water treatment chemicals - Health effects" and 61 "Drinking water system components - Health effects". Oral RfDs or cancer risk levels are derived using US EPA risk assessment guidelines. NSF/ANSI standards and oral risk assessment documents prepared by NSF are available on-line at the NSF Bookstore. NSF/ANSI Standards 60 or 61, which include Annex A, are available here. Compound specific oral risk assessment documents prepared by NSF International are available here.

Back to Top

RIVM

MPR (Maximum Permissible Risk) is defined as the TDI or tolerable daily intake of a chemical or an oral concentration that results in 1 in 104 lifetime cancer risk level. The levels are evaluated with either or threshold approach or for genotoxic chemicals the non-threshold approach. Used for human intake of soil contaminants

TDI (Tolerable Daily Intake) were derived using a non-threshold approach and represent the estimated daily intake level that can be ingested by humans during their entire lifetime without resultant adverse effects.

RIVM is the Dutch National Institute for Public Health and the Environment (RIVM). RIVM Risk Assessment methods are from the 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. 

For more info on RIVM MPR methodology, click here.

Back to Top

TCEQ

ReVs (Reference Values) and URFs (Unit Risk Factors) are acute and chronic inhalation Reference Values. These health based values used to evaluate air monitoring data and in the calculation of ESLs.

ESLs (Effects Screening Levels) are chemical specific air concentrations set to protect human health. The concentration of the chemical is not likely to cause adverse health effect and include (accounts for) sensitive populations 

For more info on TVEQs risk assessment methodology, click here.

Back to Top

US EPA

RfD (reference dose) - US EPA defines an estimate with uncertainty of an order of magnitude of a daily oral lifetime exposure to the entire human population without an appreciable risk of deleterious effects.

RfC (inhalation reference concentration) is similarly defined as an estimate with uncertainty of an order of magnitude of a continuous inhalation lifetime exposure to all human populations without an appreciable risk of deleterious effects.
 
For health effects that are not cancer, the US EPA (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.” Uncertainty factors (UFs) are reductions in the dose rate or concentration to account for areas of scientific uncertainty inherent in most toxicity databases.

 

  • UFH -- human variability accounts for the variation in human population sensitivity
  • UFA - - accounts for the extrapolation from animal data to the case of humans.
  • UFS - accounts for extrapolating from NOAELs or LOAELs identified from less than chronic exposure to chronic levels.
  • UFL - 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.
  • UFD - database completeness accounts for the inability of any single study to adequately address all possible adverse outcomes.

 

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 EPA equation for 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 Concentration
LOAEL(HEC) = Lowest Observed Adverse Effect Level-Human Equivalent Concentration
BMCL(HEC) = Benchmark Concentration Lower Limit -Human Equivalent Concentration  
For more info on the US EPA RfC/RfD methodology click here.

 

Back to Top

ECHA REACH

DNEL (derived no-effect level): DNELs are defined as the level of exposure above which humans should not be exposed. REACH requires DNELs for chemicals used in quantities of 10 tons or more annually as part of their Chemical Safety Assessment (CSA). DNELs may be necessary for various human populations (e.g. workers, consumers and humans), different routes of exposure (oral, dermal, inhalation), and for different durations (acute and long-term). DNELs for certain subpopulations (e.g. higher sensitivity of children for certain end-points, exposure of children via toys) might also be necessary. Depending on the substance, DNELs may be established for systemic effects, for local effects or both. 

For non-cancer health effects, DNEL derivation proceeds as follows: Step 1: Gather typical toxic dose descriptors (e.g. NOAEL, LOAEL, BMD, BMDL10 or others) from all available and relevant studies on the potential different human health endpoints; Step 2: Identify threshold endpoints of concern (modify to correct starting point as necessary if there are differences in terms of exposure route, units, and/or dimension. Identified with subscript of corr ie NOAELcorr. Step 3: Application of assessment factors (AF) to the selected starting point; to obtain endpoint-specific DNEL(s) for the relevant exposure pattern. Assessment factors are numerical values. They are used to address the differences between the experimental data and the human situation, taking into account the areas of uncertainty and variability  in the extrapolation procedure and in the available data set. They include differences for interspecies, intraspecies, duration of exposure; issues related to dose-response and the quality of whole database.

To derive endpoint-specific DNEL(s) for the relevant exposure the overall AF is applied directly to the corrected (where necessary) dose descriptor(s) in the following manner (exemplified with NOAEL as the dose descriptor):

Endpoint-specific DNEL Formula

Where:
NOAELcorr = No Observed Adverse Effect Level-Corrected (for threshold effects and differences in metabolic rate by allometric scaling) and other interspecies differences.

A description of these methods is available in Guidance on information requirements and chemical safety assessment: Chapter R.8: Characterization of dose [concentration]-response for human health (2012) available here.

For definition of terms please use the ITER Glossary.
For more information on the ECHA DMEL methodology see http://echa.europa.eu

Back to Top

Cancer Risk Assessment Terms and Methods

For definition of terms please use the ITER Glossary.

ATSDR

ATSDR's cancer efforts involve qualitative and quantitative practices Qualitative conclusions regarding carcinogenicity are presented in ATSDR toxicological profiles using a weight-of-evidence approach. This approach relies upon the NTP’s Annual Report on Carcinogens. Conclusions from IARC, US EPA and OSHA are also considered and presented as appropriate. Discrepancies are resolved based on ATSDR's evaluation of data used by different organizations and scientific peer review.
 
ATSDR does not currently engage in modeling efforts or in the development of cancer potency factors (CPFs). Often times, EPA-derived CPFs are employed to estimate cancer risk levels. ATSDR uses these internally in combinations with broader professional judgment to define exposure levels of concern (i.e., those presenting a potentially significant human health hazard). These dose/exposure levels are reported in studies of carcinogenic effects of hazardous substances in the toxicological profiles irrespective of whether a carcinogenic response was observed. The lowest dose levels associated with carcinogenic effects are identified as cancer effect levels (CELs), with the stipulation that such a designation should not be construed to imply the existence of a threshold for carcinogenesis. Also, exposures associated with upper- bound excess risk estimates over a lifetime of exposure (i.e., one case of cancer in 10,000 to one case of cancer in 10,000,000) as developed by EPA are presented.

 

For more info on the ATSDR cancer methodology, click here.

Back to Top

Health Canada

TC05 - Tumorigenic Concentration (05) is the concentration in air (expressed in mg/cu.m) associated with a 5% increase in incidence or mortality due to tumors. The TC05 is not based on the confidence limit but rather, is computed directly from the curve. Health Canada calculates TC05s for compounds classified in Groups I and II basing these values on tumors observed in epidemiological studies (generally) in occupationally exposed human populations, or those considered relevant to humans as observed in bioassays in experimental animals. The estimates of potency are generally restricted to effects for which there has been a statistically significant increase in incidence and a dose-response relationship, characterized by appropriate mathematical models (e.g. multistage). The Health Canada TC05 can be divided by a suitable margin, to provide a benchmark against which the adequacy of intake can be judged, with respect to potential carcinogenicity.

Health Canada classifies chemicals into six categories with regard to carcinogenicity based on a modification of the scheme used by IARC. The following is excerpted from Human Health Risk Assessment for Priority Substances (Health Canada, 1994):

Group I: Carcinogenic to Humans. Data from adequate epidemiological studies indicate that there is a causal relationship between exposure to a substance and an increased incidence of cancer in humans.

Group II: Probably Carcinogenic to Humans. Data from epidemiological studies are inadequate to assess carcinogenicity. However, there is sufficient evidence of carcinogenicity in animal species.

Group III: Possibly Carcinogenic to Humans. This includes chemicals for which data from epidemiological studies are inadequate, or which indicate an association between exposure and human cancer but alternative explanations such as chance, bias or confounding cannot be excluded. 

Group IV: Unlikely to be Carcinogenic to Humans. Four subgroups in Group IV describe the data in humans and laboratory animals that would result in this classification. This includes chemicals for which there is no evidence of carcinogenicity in adequate epidemiological studies or data are inadequate. There is some evidence of carcinogenicity in well -designed and well-conducted carcinogenicity bioassays in animals, but the results are limited or can be confidently ascribed to species-specific mechanisms of toxicity and/or metabolism which do not appear to be operative in humans.

Group V: Probably Not Carcinogenic to Humans.  Three subgroups; includes chemicals for which there is no evidence of carcinogenicity in sufficiently powerful and well-designed epidemiological studies; there is no evidence or inadequate data on carcinogenicity in laboratory animals.

Group VI: Unclassifiable with Respect to Carcinogenicity in Humans. Three subgroups; describe the data in humans and laboratory animals that would result in a classification in this Group. This includes chemicals for which data from epidemiological and/or animal studies are inadequate or not available.

For more information on Health Canada risk assessment methods, click here.

Back to Top

IARC

IARC divides carcinogens into four different groups based on evaluation of whole body of evidence:

Group 1 is cancer causing in humans. These are chemicals deeded as carcinogenic to humans based on either sufficient evidence of carcinogenicity in humans or less sufficient evidence of carcinogenicity in humans but sufficient evidence of cancer causing in experimental animals.

Group 2A is probably carcinogenic to humans.  This grouping is for chemicals with limited evidence of carcinogenicity in humans and sufficient evidence from experimental animals.

Group 2B is possibly carcinogenic to humans. In general chemicals have limited evidence of cancer causing in humans and less sufficient evidence from experimental animals.

Group 3 is not classifiable as to its carcinogenicity to humans. This category is used most commonly for chemicals where the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals.

Group 4 is probably not carcinogenic to humans. This group is used where evidence suggests a lack of carcinogenicity in humans and in experimental animals.

An explanation of IARC's methods is available in the Preamble to the IARC Monographs, available here.

Back to Top

NSF International

NSF International currently uses the US EPA (2005) weight of evidence narrative approach to cancer classification. The conclusion reached by NSF is included as part of the hazard assessment in a weight of evidence evaluation and cancer characterization section of the oral risk assessment document. If the US EPA or another internationally recognized organization such as the NTP, ATSDR, Health Canada, IARC or other members of the World Health Organization has also classified the chemical, that classification will be included in the risk comparisons and conclusions section of the NSF document, with discussion if the classifications differ. The US EPA and NSF International classifications may occasionally differ if new data have been evaluated by one of the organizations.

Back to Top

RIVM

CR(inhal): The cancer risk from inhalation exposure, CR(inhal) is the 1 in 10,000 (E-4) lifetime excess cancer risk following exposure by inhalation (expressed in microgram/cu.m), as derived by RIVM. For comparison purposes on ITER, this value has been converted to a 1 in 100,000 (E-5) risk level, and has also been converted to milligrams/cu.m. 

CR(oral):The cancer risk from oral exposure, CR(oral) is the 1 in 10,000 (E-4) lifetime excess cancer risk following oral exposure (expressed in microgram/kg bw-day), as derived by RIVM. For comparison purposes on ITER, this value has been converted to a 1 in 100,000 (E-5) risk level, and has also been converted to milligrams/kg-day. 

Back to Top 

TCEQ

SFo (Slope Factor) represents the carcinogenic potency of a chemical and is based on data concerning chronic cancer effects.  SFo values are based on the most sensitive adverse health effect relevant to humans from oral exposure. Derivation of SFo values begins with a toxicity assessment involving hazard identification and dose-response assessment based on the chemical’s mode of action. SFo values are used to calculate health-protective cleanup levels for the TCEQ’s remediation program.

URFs (chronic inhalation Unit Risk Factor (URF) values) express cancer potency in terms of risk per unit air concentration (e.g., risk per μg/m3) assuming continuous environmental lifetime exposure. They are calculated using TCEQ publication RG-442 Hazard Characterization and Exposure-Response Assessment Using Epidemiology Data Revised 2015 195 linear low-dose extrapolation when the carcinogenic MOA is mutagenic or the MOA is unknown

An explanation of TCEQ's methods is available in the publication entitled, TCEQ Guidelines to Develop Toxicity Factors”, available here.

Back to Top

US EPA

Slope Factor (SF): EPA defines slope factor on IRIS as the slope of the dose-response curve in the low-dose region. An upper bound (i.e., the 95% upper confidence limit) on this slope is used instead of the slope itself because it is a statistically more stable number. The units of the slope factor are usually expressed as 1/(mg/kg-day).

Unit Risk
: EPA defines unit risk on IRIS as the upper-bound excess lifetime cancer risk estimated to result from continuous (oral or inhalation) exposure to an agent at a concentration of 1 ug/L in water, or 1 ug/cu.m in air.

WOE (Weight-of-evidence) for carcinogenicity: This is a narrative for carcinogenicity that explains what is known about an agent's human carcinogenic potential and the conditions that characterize its expression. A WOE highlights the key issues and decisions that were the basis for the evaluation of the agent's potential hazard. The WOE characterizes the extent to which the available data support the hypothesis that an agent causes cancer in humans. Under EPA's 1986 risk assessment guidelines, the weight of evidence is described by categories “A through E,” with Group A for known human carcinogens through Group E for agents with evidence of non-carcinogenicity. 

The approach outlined in EPA's guidelines for carcinogen risk assessment (2005) provides five standard hazard descriptors:

  • Carcinogenic to humans
  • Likely to be carcinogenic to humans
  • Suggestive evidence of carcinogenic potential
  • Inadequate information to assess carcinogenic potential
  • Not likely to be carcinogenic to humans.

 

In 1986, the US EPA published general guidelines to be used by Agency scientists in developing and evaluating risk assessments for carcinogens (US EPA, 1986). Earlier US EPA assessments on IRIS were based on the 1986 guidelines. For more details about the evolution of US EPA’s cancer guidelines, please see here (PDF).

Back to Top

IPRV

RSC (Risk Specific Concentration): The risk value of a chemical in mg/cu.m that is associated with a specified excess lifetime cancer risk, usually an upper 95% confidence limit. In ITER, all RSCs are calculated by TERA from the organization's unit risk or TC05 and represent the risk at a 1 in 100,000 (E-5) level.
 
RSD (Risk Specific Dose): The risk value of a chemical in mg/kg-day that is associated with a specified excess lifetime cancer risk, usually an upper 95% confidence limit. In ITER, the RSDs for the US EPA and Health Canada are calculated from the organization's slope factor or TD05, respectively, and represent the 1 in 100,000 (E-5) risk level. NSF International calculates a human equivalent dose at the 105 risk level that is then used to calculate the TAC in drinking water.

Back to Top

ECHA REACH 

DMEL (derived minimal effect level): DMELs are defined as a reference risk level considered being of very low concern. DMELs can be seen as a tolerable level of effects, and it should be noted that it is not a level where no potential effects can be foreseen. No DNEL can be derived for non-threshold mutagens/carcinogens as it is assumed that a no-effect-level cannot be established for these substances (either because there is no threshold or the threshold level cannot be determined). In such cases, and assuming that there are data allowing it, the registrant should develop a DMEL.

For non-threshold mutagens/carcinogens, DMEL derivation proceeds with the following steps: Step 1:  If no thresholds are identified one can assume a nonthreshold in relation to mutagenicity, genotoxicity, and genotoxic carcinogenicity, although a dose-response relationship may be shown under experimental conditions. Selection of relevant dose-descriptor(s) either T25, BMD10 or BMDL10 for the endpoint of concern Step 2: Modification, when necessary, of relevant dose descriptor(s) per endpoint to the correct starting point (i.e., correct the unit of exposure) and when necessary, of assessment factors/high to low dose risk extrapolation factor to the correct starting point to obtain endpoint-specific DMEL(s) for the relevant exposure pattern (duration, frequency, route and exposed human population); Step 3: Use either the ‘Linearized’ approach or the EFSA ‘Large Assessment Factor’ approach to derive DMEL values representing exposure levels where the likelihood that effects (cancer) are avoided is appropriately high and of low concern from a public health point of view. 

Linearized approach: The linear approach is used when there is an absence of sufficient information on modes of action or when mode of action information indicates that the dose-response curve at low dose is or is expected to be linear. The BMD10 i.e. the Benchmark-dose representing a 10% response should be used in certain cases in addition to the T25 when data are adequate for modeling purposes.

Large Assessment Factor approach: This method is used for threshold dose response relationship between tumor formation and exposure; formally similar to the overall assessment factor approach applied for threshold effects in deriving DNELs. It is a linear approach used when there is an absence of sufficient information on modes of action or when mode of action information indicates that the dose-response curve at low dose is or is expected to be linear. The BMD10corr or the benchmark-dose representing a 10% response should be used in certain cases in addition to the T25, when data are adequate for modeling purposes.

DMEL Formula

Possibilities exist for deriving a DMEL for a non-threshold carcinogen/mutagen, without adequate cancer data, but are not presented here. A description of these methods is available in APPENDIX R. 8-6 in Guidance on information requirements and chemical safety assessment: Chapter R.8: Characterization of dose [concentration]-response for human health (2012) available here.

For definition of terms please use the ITER Glossary.
For more information on the ECHA DMEL methodology see http://echa.europa.eu

Back to Top

 

ITER Glossary

For additional health effect terminology we recommend visiting ITER Glossary.

Back to Top

References 

ATSDR. 1993. ATSDR Cancer Policy Framework.  US Department of Health and Human Services. January.  Available here.
 
Health Canada.  1994. Human Health Risk Assessment for Priority Substances.  Environmental Health Directorate. Canadian Environmental Protection Act.  Health Canada, Ottawa.
 
NSF/ANSI Standard 60.  2009.  Drinking Water Treatment Chemicals - Health Effects.  NSF International, Ann Arbor, MI.  Available for a fee here.
 
NSF/ANSI Standard 61.  2009.  Drinking Water System Components - Health Effects.  NSF International, Ann Arbor, MI.  Available for a fee here.
 
US EPA (Environmental Protection Agency). 2009. Benchmark Dose Software Version 2.1.1. National Center for Environmental Assessment, Office of Research and Development. Available here.
 
US 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 here.
 
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 here.
 
US 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 here.

US EPA (Environmental Protection Agency).  1986. Guidelines for Carcinogen Risk Assessment. Risk Assessment Forum, Washington, DC. EPA/630/R-00/004.  Available here.

Wullenweber, A. et al.  2008.  Resources for global risk assessment: The International Toxicity Estimates for Risk (ITER) and Risk Information Exchange (RiskIE) databases.  Toxicology. Appl. Pharmacology.  doi:10.1016/j.taap.2007.12.035

Back to Top