Reference dose , defined

In the case of noncarcinogenic substances, there exists a threshold this is an exposure with a dose below which there would not be adverse effect on the population that is exposed. This is the reference dose (RfD), and it is defined as the daily exposure of a human population without appreciable effects during a lifetime. The RfD value is calculated by dividing the no observed effect level (NOEL) by uncertainty factors. When NOEL is unknown, the lowest observed effect level (LOEL) is used. NOEL and LOEL are usually obtained in animal studies. The main uncertainty factor, usually tenfold, used to calculate the RfD are the following the variations in interspecies (from animal test to human), presence of sensitive individuals (child and old people), extrapolation from subchronic to chronic, and the use of LOEL instead of NOEL. Noncancer risk is assessed through the comparison of the dose exposed calculated in the exposure assessment and the RfD. The quotient between both, called in some studies as hazard quotient, is commonly calculated (Eq. 2). According to this equation, population with quotient >1 will be at risk to develop some specific effect related to the contaminant of concern. 

The term acceptable is used widely to describe safe levels of intake and is apphed for chemicals to be used in food production such as, e.g., food additives, pesticides, and veterinary dmgs. The term tolerable is applied for chemicals unavoidably present in a media such as contaminants in, e.g., drinking water and food. The term PTWI (Provisional Tolerable Weekly Intake) is generally used for contaminants that may accumulate in the body, and the weekly designation is used to stress the importance of limiting intake over a period of time for such substances. The tolerable intake is similar in definition and intent to terms such as Reference Dose and Reference Concentration (RfD/RfC), which are widely used by, e.g., the US-EPA. For some substances, notably pesticides, the ARID (Acute Reference Dose), is also established, often from shorter-term studies than those that would support the ADI. The ARfD is defined as the amount of a substance in food that can be consumed in the course of a day or at a single meal with no adverse effects. 

The POD is used as the starting point for subsequent extrapolations and analyses. For linear extrapolation, the POD is used to calculate a slope factor, and for nonlinear extrapolation the POD is used in the calculation of a Reference Dose (RfD) or Reference Concentration (RfC). In a risk characterization, the POD is part of the determination of an MOE, defined as the ratio of the POD over an exposure estimate (MOE = POD/Exposure). 

SSLs are risk-based concentrations derived from standardized equations combining exposure information assumptions with US-EPA toxicity data. For the ingestion, dermal, and inhalation pathways, toxicity criteria are used to define an acceptable level of contamination in soil, based on a one-in-a-million (10 individual excess cancer risk for carcinogens and a Hazard Quotient (HQ) of 1 for noncarcinogens. The hazard quotient is defined as the ratio of an exposure estimate over the Reference Dose or Concentration (Section 5.1), i.e., HQ = Exposure/(RfD or RfC). 

There are of course many mathematically complex ways to perform a risk assessment, but first key questions about the biological data must be resolved. The most sensitive endpoint must be defined along with relevant toxicity and dose-response data. A standard risk assessment approach that is often used is the so-called divide by 10 rule . Dividing the dose by 10 applies a safety factor to ensure that even the most sensitive individuals are protected. Animal studies are typically used to establish a dose-response curve and the most sensitive endpoint. From the dose-response curve a NOAEL dose or no observed adverse effect level is derived. This is the dose at which there appears to be no adverse effects in the animal studies at a particular endpoint, which could be cancer, liver damage, or a neuro-behavioral effect. This dose is then divided by 10 if the animal data are in any way thought to be inadequate. For example, there may be a great deal of variability, or there were adverse effects at the lowest dose, or there were only tests of short-term exposure to the chemical. An additional factor of 10 is used when extrapolating from animals to humans. Last, a factor of 10 is used to account for variability in the human population or to account for sensitive individuals such as children or the elderly. The final number is the reference dose (RfD) or acceptable daily intake (ADI). This process is summarized below. 

All of the previously mentioned exposure methods can be used to estimate either chronic exposure (over a period of years) or acute exposure (single day) for the United States population and population subgroups. Both chronic and acute assessments are usually based on a no observed adverse effect level (NOAEL) in an animal species. Acute exposure is defined relative to an acute (single dose) toxicological endpoint (usually a NOAEL) and may be expressed as a margin of exposure (MOE) or as a percentage of an acute reference dose that is based on a NOAEL and an uncertainty factor (see below). 

The oral reference dose (Oral RfD) is an estimate of the daily exposure of a person to a contaminant that is likely to be without appreciable risk of a deleterious non-carcinogenic effect during a lifetime (USEPA http //www.epa.gov/iris/). Oral RfD values for POP concentrations in seafood types are presented in Table 16.5, together with the daily intake of POPs from seafood consumed in Singapore. Daily intakes of POPs from seafood are below the oral RfD. The cancer benchmark concentration (Dougherty et al., 2000) represents the exposure concentration at which a lifetime cancer risk equates to one excess cancer death in one million persons. This level is defined as the public health protective concentration in the Congressional House Report to the Food Quality Protection Act of 1996 in the USA. Cancer benchmark concentrations were exceeded for DDTs, heptachlor, and PCBs (See Table 16.5). The cancer hazard ratio is the ratio of the MDI for a specific contaminant relative to the cancer benchmark concentration. The cancer hazard ratio represents the extent to which average daily exposure exceeds the benchmark concentration. The cancer hazard ratio of seafood consumption... 

Example Mercury is a known contaminant of seafood, and regulatory bodies such as the US Food and Drug Administration (FDA) recommend consumption of certain fish on the basis of their ppm levels of methylmercury substances, with a set action level for mercury in seafood of 1 ppm. The US EPA has also set an official reference dose (RfD) for mercury at 0.1 p,gkg per day in humans (corresponding to a blood mercury level of 5.8 p.g 1 or 5.8ppb), which is defined as the amount of mercury an individual (including sensitive subpopulations) can be exposed to on a daily basis over their lifetime without appreciable risk of effects. 

Non-carcinogenic risk is normally characterized in terms of a hazard index defined by the ratio of the estimated intake dose from exposure to the reference dose (RfD). Reference doses depend on the exposure route and may be used with its exposure data. The hazard index is calculated as... 

Contains information on hazard identification and dose - response assessment of over 600 hazardous substances. Covers toxicity, carcinogenicity, chemical and physical properties, and applicable regulations. Includes the reference dose as defined by US EPA, unit risk of exposure by oral and inhalation routes. Produced by the US EPA. (CIS, TOXNET available on CD as part of TOMES Plus by Micromedex and on the EPA Internet website). 

Once a NOAEL (or LOAEL) is provided by the experimental data, the proposed next step by risk assessors is to define a reference dose for developmental toxicity (RfDoT) according to the following equation ... 

The initial process in the application of toxicity (dose-response) data in risk assessment is the extrapolation of findings to establish acceptable levels (AL) of human exposure. These levels may be reference values (inhalation reference concentrations, RfC or oral reference doses, RfD), minimal risk levels (MRL) values, occupational exposure limits, and so on. When the toxicity data are derived from animals, the lowest dose representing the NOAEL (preferably) or the LOAEL defines the point of departure (POD). In setting human RfD, RfC, or MRL values, the POD requires several extrapolations (see [13] and revisions). Extrapolations are often made for interspecies differences, intraspecies variability, duration of exposure, and effect level. Each area is generally addressed by applying a respective uncertainty factor having a default value of 10 their multiplicative value is called the composite uncertainty factor (UF). The UF is mathematically combined with the dose at the POD to determine the reference value ... 

The oral reference dose (oralRfD) is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure of a chemical to the human population (including sensitive subpopulations) that is likely to be without risk of deleterious noncancer effects during a lifetime. For inhala-tional exposure, an inhalation reference concentration (RfC) is defined. 

For humans, the chronic exposure duration assumed for reference dose development is defined by EPA (1989) as lasting between 7 years (approximately 10% of a human lifetime) and a full lifetime. Calculation of an RfD requires use of animal or human toxicity data for a dose or expo.sure corresponding to a no-observed-adversc-effect level (NOAEL) or a lowest-observed-adverse-cffcct level (LOAEL) (EPA, 1989). The NOAEL is the exposure level al which there are no statistically or biologically. significant increases in frequency or severity of adverse... 

A third uncertainty fector of 10 is added if the animal toxicity data do not define the NOAEL conclusively. Eor example, animal toxicity data may define a LOAEL (lowest observed adverse effect level) but not a NOAEL. In such a case, the reference dose might be estimated from the LOAEL by including an additional uncertainty factor of 10 ... 

D.3.1.2 Absorbed Dose and Absorbed Dose Rate. The absorbed dose is defined as the energy imparted by the incident radiation to a unit mass of the tissue or organ. The unit of absorbed dose is the rad 1 rad = 100 erg/gram = 0.01 J/kg in any medium. An exposure of 1 R results in a dose to soft tissue of approximately 0.01 J/kg. The SI unit is the gray which is equivalent to 100 rad or 1 J/kg. Internal and external exposures from radiation sources are not usually instantaneous but are distributed over extended periods of time. The resulting rate of change of the absorbed dose to a small volume of mass is referred to as the absorbed dose rate in units of rad/unit time. 

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