Cancer slope factor
Encyclopedia
Cancer slope factors are used to estimate the risk of cancer
associated with exposure to a carcinogen
ic or potentially carcinogenic substance. A slope factor is an upper bound, approximating a 95% confidence limit, on the increased cancer risk from a lifetime exposure to an agent by ingestion
or inhalation
.
This estimate, usually expressed in units of proportion (of a population) affected per mg of substance/kg body weight
-day, is generally reserved for use in the low-dose region of the dose-response relationship
, that is, for exposures corresponding to risks less than 1 in 100.
of carcinogens is referred to as being "non-threshold" because there is believed to be essentially no level of exposure that does not pose some probability of producing a carcinogenic response, therefore, there is no dose that can be considered to be risk-free.
When evaluating cancer risks, an effect threshold cannot be estimated. For chemicals that are carcinogens, a two-part evaluation to quantify risk is often employed in which the substance first is assigned a weight-of-evidence classification, and then a slope factor is calculated.
, the development of a slope factor generally entails applying a model to the available data set
and using the model to extrapolate from the relatively high doses administered to experimental animals (or the exposures noted in epidemiologic studies) to the lower exposure levels expected for human contact in the environment.
of estimates from all studies may be adopted as the slope. This practice ensures the inclusion of all relevant data.
Where:
s) in DNA
. It is also the default choice for carcinogens when there are insufficient data to demonstrate that the mode of action of the chemical is nonlinear. The RSD is often calculated based on a one-in-a-million extra risk (10−6 risk) or a one-in-a-hundred-thousand risk (10−5 risk) for other-than highly exposed individuals. The term "extra" in the definition of the RSD refers to a risk from environmental exposure to the chemical of interest above the background risk that is always present.
The formula to calculate the RSD for a chemical based on a one-in-a-million extra risk (10−6 risk) is: RSD = 0.000001 / CSF
(see also Risk Equations and Formulas Calculator)
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
associated with exposure to a carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
ic or potentially carcinogenic substance. A slope factor is an upper bound, approximating a 95% confidence limit, on the increased cancer risk from a lifetime exposure to an agent by ingestion
Ingestion
Ingestion is the consumption of a substance by an organism. In animals, it normally is accomplished by taking in the substance through the mouth into the gastrointestinal tract, such as through eating or drinking...
or inhalation
Inhalation
Inhalation is the movement of air from the external environment, through the air ways, and into the alveoli....
.
This estimate, usually expressed in units of proportion (of a population) affected per mg of substance/kg body weight
Body weight
The term body weight is used in daily English speech as well as in the contexts of biological and medical sciences to describe the mass of an organism's body. Body weight is measured in kilograms throughout the world, although in some countries it is still measured in pounds or stones and pounds...
-day, is generally reserved for use in the low-dose region of the dose-response relationship
Dose-response relationship
The dose-response relationship, or exposure-response relationship, describes the change in effect on an organism caused by differing levels of exposure to a stressor after a certain exposure time...
, that is, for exposures corresponding to risks less than 1 in 100.
Toxicity Assessments for Carcinogenic Effects
For carcinogens, the assumption is often made that a small number of molecular events may evoke changes in a single cell that can lead to uncontrolled cellular proliferation and eventually to a clinical diagnosis of cancer. The toxicityToxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
of carcinogens is referred to as being "non-threshold" because there is believed to be essentially no level of exposure that does not pose some probability of producing a carcinogenic response, therefore, there is no dose that can be considered to be risk-free.
When evaluating cancer risks, an effect threshold cannot be estimated. For chemicals that are carcinogens, a two-part evaluation to quantify risk is often employed in which the substance first is assigned a weight-of-evidence classification, and then a slope factor is calculated.
Generating a Slope Factor
When the chemical is a known or probable human carcinogen, a toxicity value that defines quantitatively the relationship between dose and response (i.e., the slope factor) is calculated. Because risk at low exposure levels is difficult to measure directly either by animal experiments or by epidemiologic studiesEpidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...
, the development of a slope factor generally entails applying a model to the available data set
Data set
A data set is a collection of data, usually presented in tabular form. Each column represents a particular variable. Each row corresponds to a given member of the data set in question. Its values for each of the variables, such as height and weight of an object or values of random numbers. Each...
and using the model to extrapolate from the relatively high doses administered to experimental animals (or the exposures noted in epidemiologic studies) to the lower exposure levels expected for human contact in the environment.
Data Sets
High-quality Human data on carcinogens is preferable to animal data. When no clear choice is possible, the most sensitive species is given the greatest emphasis. Occasionally, in situations where no single study is judged most appropriate, yet several studies collectively support the estimate, the geometric meanGeometric mean
The geometric mean, in mathematics, is a type of mean or average, which indicates the central tendency or typical value of a set of numbers. It is similar to the arithmetic mean, except that the numbers are multiplied and then the nth root of the resulting product is taken.For instance, the...
of estimates from all studies may be adopted as the slope. This practice ensures the inclusion of all relevant data.
Weight-of-Evidence Classification for Carcinogens
Slope factors are typically calculated for potential carcinogens in classes A, B1, and B2. Quantitative estimation of slope factors for the chemicals in class C proceeds on a case-by-case basis. The slope factor is used in risk assessments to estimate an upper-bound lifetime probability of an individual developing cancer as a result of exposure to a particular level of a potential carcinogen. Slope factors should always be accompanied by the weight of-evidence classification to indicate the strength of the evidence that the agent is a human carcinogen.- A = Human carcinogen
- B1 = indicates that limited human data are available.
- B2 = indicates sufficient evidence in animals and inadequate or no evidence in humans.
- C = Possible human carcinogen
- D = Not classifiable as to human carcinogenicity
- E = Evidence of non-carcinogenicity for humans
Calculation of Cancer Risk
For each age interval "i", the cancer risk for exposure by a specified pathway is computed as:Where:
- C = Concentration of the chemical in the contaminated environmental medium (soil or water) to which the person is exposed. The units are mg/kg for soil and mg/l for water.
- IRi = Intake rate of the contaminated environmental medium for age bin "i". The units are mg/day for soil and l/day for water.
- BWi = Body weight of the exposed person for age bin "i".
- EFi = Exposure frequency for age bin "i" (days/year). This describes how often a person is exposed to the contaminated medium over the course of a typical year.
- EDi = Exposure duration for age bin "i" (years). This describes how long a person is exposed to the contaminated medium over the course of their lifetime.
- AT = Average days. This term specifies the length of time over which the average dose is calculated. For quantifying cancer risk a "lifetime" of 70 years is used (ie, 70 years times 365 days/year).
- SF = Cancer slope factor (mg/kg-day)-1
- ADAF = Age-dependant adjustment factor for age bin "i" (unitless)
Risk Specific Dose (RSD)
The Cancer Slope Factor is used to derive the Risk Specific Dose (RSD)(mg/kg-day) for direct-acting carcinogenic agents, those that cause chemical changes (mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s) in DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. It is also the default choice for carcinogens when there are insufficient data to demonstrate that the mode of action of the chemical is nonlinear. The RSD is often calculated based on a one-in-a-million extra risk (10−6 risk) or a one-in-a-hundred-thousand risk (10−5 risk) for other-than highly exposed individuals. The term "extra" in the definition of the RSD refers to a risk from environmental exposure to the chemical of interest above the background risk that is always present.
The formula to calculate the RSD for a chemical based on a one-in-a-million extra risk (10−6 risk) is: RSD = 0.000001 / CSF
Potency Factor
The CSF is also called a "potency factor" and is used to calculate the Incremental Lifetime Cancer Risk by multiplying the CSF by the chronic daily intake (CDI). The CDI is the dose over a lifetime and is expressed in mg/kg-day.(see also Risk Equations and Formulas Calculator)