Cancer slope factors (CSF) are used to estimate the risk of cancer associated with exposure to a carcinogenic 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. [1]
Slope factors are also referred to as cancer potency factors (PF).
For carcinogens, it is commonly assumed 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. This toxicity 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. However, some (non-genotoxic) carcinogens may exhibit a threshold whereby doses lower than the threshold do not invoke a carcinogenic response.
When evaluating cancer risks of genotoxic carcinogens, theoretically 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. [2]
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 studies, 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. [2]
High-quality human data (e.g. high quality epidemiological studies) on carcinogens are preferable to animal data. When human data are limited, 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 mean of estimates from all studies may be adopted as the slope. This practice ensures the inclusion of all relevant data. [2]
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. [2]
For each age interval "i", the cancer risk for exposure by a specified pathway is computed as: [3]
Where:
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 (mutations) 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. [4]
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
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. [5]
(see also Risk Equations and Formulas Calculator)
A carcinogen also known as cancerogen is any substance, radionuclide, or radiation that promotes carcinogenesis, the formation of cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise from both natural and synthetic substances. Carcinogens are not necessarily immediately toxic; thus, their effect can be insidious.
Acrylamide (or acrylic amide) is an organic compound with the chemical formula CH2=CHC(O)NH2. It is a white odorless solid, soluble in water and several organic solvents. From the chemistry perspective, acrylamide is a vinyl-substituted primary amide (CONH2). It is produced industrially mainly as a precursor to polyacrylamides, which find many uses as water-soluble thickeners and flocculation agents. Acrylamide is highly toxic, likely to be carcinogenic, but its main derivative polyacrylamide is nontoxic. The possibility that this innocuous polymer contains traces of its hazardous precursor has long attracted attention. Because acrylamide is volatile and hazardous, it is mainly handled as an aqueous solution.
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. 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 (cytotoxicity) or an organ such as the liver (hepatotoxicity). By extension, the word may be metaphorically used to describe toxic effects on larger and more complex groups, such as the family unit or society at large. Sometimes the word is more or less synonymous with poisoning in everyday usage.
A reference dose is the United States Environmental Protection Agency's maximum acceptable oral dose of a toxic substance.Reference doses are most commonly determined for pesticides. The EPA defines an oral reference dose as:
[A]n estimate, with uncertainty spanning perhaps an order of magnitude, of a daily oral exposure to the human population that is likely to be without an appreciable risk of deleterious effects during a lifetime.
Acceptable daily intake or ADI is a measure of the amount of a specific substance in food or drinking water that can be ingested (orally) daily over a lifetime without an appreciable health risk. ADIs are expressed usually in milligrams per kilograms of body weight per day.
The linear no-threshold model (LNT) is a dose-response model used in radiation protection to estimate stochastic health effects such as radiation-induced cancer, genetic mutations and teratogenic effects on the human body due to exposure to ionizing radiation. The model statistically extrapolates effects of radiation from very high doses into very low doses, where no biological effects may be observed. The LNT model lies at a foundation of a postulate that all exposure to ionizing radiation is harmful, regardless of how low the dose is, and that the effect is cumulative over lifetime.
Radiation hormesis is the hypothesis that low doses of ionizing radiation are beneficial, stimulating the activation of repair mechanisms that protect against disease, that are not activated in absence of ionizing radiation. The reserve repair mechanisms are hypothesized to be sufficiently effective when stimulated as to not only cancel the detrimental effects of ionizing radiation but also inhibit disease not related to radiation exposure. This hypothesis has captured the attention of scientists and public alike in recent years.
Mirex was an organochloride that was commercialized as an insecticide and later banned because of its impact on the environment. This white crystalline odorless solid is a derivative of cyclopentadiene. It was popularized to control fire ants but by virtue of its chemical robustness and lipophilicity it was recognized as a bioaccumulative pollutant. The spread of the red imported fire ant was encouraged by the use of Mirex, which also kills native ants that are highly competitive with the fire ants. The United States Environmental Protection Agency prohibited its use in 1976. It is prohibited by the Stockholm Convention on Persistent Organic Pollutants.
Benzotrichloride (BTC), also known as α,α,α-trichlorotoluene, phenyl chloroform or (trichloromethyl)benzene, is an organic compound with the formula C6H5CCl3. Benzotrichloride is an unstable, colorless (to yellowish), viscous, chlorinated hydrocarbon with a penetrating odor. Benzotrichloride is used extensively as a chemical intermediate for products of various classes, i.e. dyes and antimicrobial agents.
Dioxins and dioxin-like compounds (DLCs) are a group of chemical compounds that are persistent organic pollutants (POPs) in the environment. They are mostly by-products of burning or various industrial processes - or, in case of dioxin-like PCBs and PBBs, unwanted minor components of intentionally produced mixtures.
Musk xylene is a synthetic musk fragrance which mimics natural musk. It has been used as a perfume fixative in a wide variety of consumer products, and is still used in some cosmetics and fragrances.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a polychlorinated dibenzo-p-dioxin (sometimes shortened, though inaccurately, to simply 'dioxin') with the chemical formula C12H4Cl4O2. Pure TCDD is a colorless solid with no distinguishable odor at room temperature. It is usually formed as an unwanted product in burning processes of organic materials or as a side product in organic synthesis.
Chromium toxicity refers to any poisonous toxic effect in an organism or cell that results from exposure to specific forms of chromium—especially hexavalent chromium. Hexavalent chromium and its compounds are toxic when inhaled or ingested. Trivalent chromium is a trace mineral that is essential to human nutrition. There is a hypothetical risk of genotoxicity in humans if large amounts of trivalent chromium were somehow able to enter living cells, but normal metabolism and cell function prevent this.
Heterocyclic amines are a group of chemical compounds, many of which can be formed during cooking. They are found in meats that are cooked to the "well done" stage, in pan drippings and in meat surfaces that show a brown or black crust. Epidemiological studies show associations between intakes of heterocyclic amines and cancers of the colon, rectum, breast, prostate, pancreas, lung, stomach, and esophagus, and animal feeding experiments support a causal relationship. The U.S. Department of Health and Human Services Public Health Service labeled several heterocyclic amines as likely carcinogens in its 13th Report on Carcinogens. Changes in cooking techniques reduce the level of heterocyclic amines.
PhIP (2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is one of the most abundant heterocyclic amines (HCAs) in cooked meat. PhIP is formed at high temperatures from the reaction between creatine or creatinine, amino acids, and sugar. PhIP formation increases with the temperature and duration of cooking and also depends on the method of cooking and the variety of meat being cooked. The U.S. Department of Health and Human Services National Toxicology Program has declared PhIP as "reasonably anticipated to be a human carcinogen". International Agency for Research on Cancer (IARC), part of World Health Organization, has classified PhIP as IARC Group 2B carcinogen. There is sufficient evidence in experimental animals, as well as in vitro models, for the carcinogenicity of PhIP.
4-Methylimidazole is a heterocyclic organic chemical compound with molecular formula H
3C–C
3H
3N
2 or C
4H
6N
2. It is formally derived from imidazole through replacement of the hydrogen in position 4 by a methyl group. It is a slightly yellowish solid.
Astronauts are exposed to approximately 50-2,000 millisieverts (mSv) while on six-month-duration missions to the International Space Station (ISS), the Moon and beyond. The risk of cancer caused by ionizing radiation is well documented at radiation doses beginning at 100mSv and above.
Exposure to ionizing radiation is known to increase the future incidence of cancer, particularly leukemia. The mechanism by which this occurs is well understood, but quantitative models predicting the level of risk remain controversial. The most widely accepted model posits that the incidence of cancers due to ionizing radiation increases linearly with effective radiation dose at a rate of 5.5% per sievert; if correct, natural background radiation is the most hazardous source of radiation to general public health, followed by medical imaging as a close second. Additionally, the vast majority of non-invasive cancers are non-melanoma skin cancers caused by ultraviolet radiation. Non-ionizing radio frequency radiation from mobile phones, electric power transmission, and other similar sources have been described as a possible carcinogen by the WHO's International Agency for Research on Cancer, but the link remains unproven.
Radiation is a moving form of energy, classified into ionizing and non-ionizing type. Ionizing radiation is further categorized into electromagnetic radiation and particulate radiation. Electromagnetic radiation consists of photons, which can be thought of as energy packets, traveling in the form of a wave. Examples of electromagnetic radiation includes X-rays and gamma rays. These types of radiation can easily penetrate the human body because of high energy. Radiation exposure is a measure of the ionization of air due to ionizing radiation from photons. It is defined as the electric charge freed by such radiation in a specified volume of air divided by the mass of that air. Medical exposure is defined by the International Commission on Radiological Protection as exposure incurred by patients as part of their own medical or dental diagnosis or treatment; by persons, other than those occupationally exposed, knowingly, while voluntarily helping in the support and comfort of patients; and by volunteers in a programme of biomedical research involving their exposure. Common medical tests and treatments involving radiation include X-rays, CT scans, mammography, lung ventilation and perfusion scans, bone scans, cardiac perfusion scan, angiography, radiation therapy, and more. Each type of test carries its own amount of radiation exposure. There are two general categories of adverse health effects caused by radiation exposure: deterministic effects and stochastic effects. Deterministic effects are due to the killing/malfunction of cells following high doses; and stochastic effects involve either cancer development in exposed individuals caused by mutation of somatic cells, or heritable disease in their offspring from mutation of reproductive (germ) cells.
Threshold dose is the minimum dose of drug that triggers minimal detectable biological effect in an animal. At extremely low doses, biological responses are absent for some of the drugs. The increase in dose above threshold dose induces an increase in the percentage of biological responses. Several benchmarks have been established to describe the effects of a particular dose of drug in a particular species, such as NOEL(no-observed-effect-level), NOAEL(no-observed-adverse-effect-level) and LOAEL(lowest-observed-adverse-effect-level). They are established by reviewing the available studies and animal studies. The application of threshold dose in risk assessment safeguards the participants in human clinical trials and evaluates the risks of chronic exposure to certain substances. However, the nature of animal studies also limits the applicability of experimental results in the human population and its significance in evaluating potential risk of certain substances. In toxicology, there are some other safety factors including LD50, LC50 and EC50.
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