text:
Risk Assessment: Parts I-IV
THIS IS THE first in a series of four MichiganScience articles on risk assessment. These articles will be designed to acquaint and provide the reader with information that will allow him or her to understand and evaluate potential risks to human health resulting from exposures to chemicals, including drugs. In other words, this series of papers on risk assessment will not be designed to present the reader with an in-depth treatise on the complexities of risk assessment, but rather will provide a high-level overview of the process. The hope is that enough information will be presented such that the reader, when faced with having to understand and make decisions relative to risk, will have the basic tools necessary to make an informed decision.
The question of whether and to what degree chemicals present in air, food, drinking water, pharmaceuticals, consumer products and occupational settings pose a threat to human health is obviously of enormous social and medical importance. Many chemicals, such as asbestos, arsenic and dioxin, have a bad name. On the other hand, many chemicals have clearly transformed modern life in extremely beneficial ways. We have drugs to prevent and cure disease, pesticides to protect and increase crop production, preservatives to protect our food, as well as plastics, fibers, metals and thousands of other chemicals that enhance the pleasures and safety of life as we know it today.
Assessing potential risk resulting from chemical exposure is a complex scientific process and involves the following four steps:
- Hazard identification: the determination of whether a particular chemical is or is not causally related to particular health effects.
- Dose-response: the determination of the relation between the magnitude of exposure and the probability of occurrence of health effects in question.
- Exposure assessment: the determination of the extent of human exposure from all sources. It includes the population(s) that may be exposed and the pathways of exposure, i.e. the potential for exposure via a particular pathway, such as ingestion, inhalation or skin contact.
- Risk characterization: the description of the nature and often the magnitude of human risk, including all sources of uncertainty implicit in the above steps.[1]
The first step in understanding the risk assessment process is hazard identification, which requires a basic understanding of the field of toxicology. Quite simply, the science of toxicology is defined as the study of the adverse health effects of chemicals (including drugs) on health and of the conditions under which those effects occur.
All chemicals, whether they are man-made or naturally occurring, can be toxic, and therefore have the potential to cause adverse health effects in humans. To assess the toxicity of a chemical, we need to develop an understanding of the dose or concentration that can cause the effect. The hazards of chemicals are not equal. Some chemicals are much more toxic than others. To illustrate, Table 1 presents a conventional rating scheme for lethal doses in humans following oral ingestion. This table clearly shows that toxicity can be rated from practically non-toxic to supertoxic based on the dose. An example of something that is supertoxic is botulinum toxin and something that is practically non-toxic is water.
In addition to dose, we need a fundamental understanding of how much of the chemical to which we are exposed gets into the body, where it goes and what it does, how long it stays in the body and how it leaves. These processes are referred to in toxicology as absorption, distribution, metabolism and elimination (ADME).
There are three primary routes by which a chemical can enter the body: ingestion, inhalation and skin contact. If the chemical is ingested, then it can be absorbed into the body from the stomach. If inhaled, then the chemical can be absorbed from the airways or the lungs. If exposure is by skin contact, then the material must be absorbed through the outer layers of the skin into the underlying blood supply. Quite often, it is observed that the dose required to produce a toxic effect will vary according to the exposure route. Once the toxin is inside the body, the question becomes: Where does it go while it is there? Usually, the material can distribute itself equally throughout the body depending on the blood supply to any given site. However, if the chemical in question happens to be lipophilic (prone to sequester itself in fat tissue), it can stay in the fat for long periods of time and slowly be released back into the blood stream.
As the blood containing the chemical passes through the liver, there are enzymes present that can convert or metabolize the chemical to a different form. The products of metabolism (i.e., metabolites) are generally more soluble in water so that they can be eliminated from the body in the urine. It should be noted, however, that some chemicals can be readily excreted from the body unmetabolized because they are already water-soluble enough when they enter the body. While the process of metabolism is primarily a process to convert a chemical to a form that can be eliminated from the body, cells in the skin, lungs, intestines and kidneys can also play a role in metabolism. This whole process of ADME can be summarized in Figure 1.
While the chemical resides in the body, the question becomes what dose level has the potential to cause harm. Some chemicals can cause damage to organ systems such as the liver, lungs, kidneys, spleen, etc. Other chemicals can cause damage to the reproductive, immune, nervous and other systems and can cause birth defects and cancer. But again, whether or not a chemical causes toxicity is dependent on the dose or concentration of the chemical that makes it into the body. A central paradigm of toxicology comes from Paracelsus (c. 1493-1541), a Swiss physician and alchemist. He is noted for his recognition that "all substances are poisonous, there is none which is not a poison. The right dose differentiates a poison and a remedy." In short, the dose makes the poison.
This brings us to the concept of dose-response. Many individuals have experienced or are familiar with this phenomenon in a mild way (consider the relationship between the amount of alcohol consumed and the various stages of intoxication). It is a well-documented principle of toxicology that for all chemicals, there is a range of doses over which no apparent toxicity can be identified in exposed individuals (No Effect Level, or NOEL) and there is a higher range of doses over which the toxic properties begin to appear. This is shown in Figure 2.
The region of the dose-response curve that makes the transition from "no-toxicity" to "toxicity" is called the threshold. The threshold dose is the dose immediately above which the response (or toxicity) begins to manifest itself. Implied in this concept is the fact that an individual can be exposed to a dose below the threshold for a lifetime and not suffer adverse health effects. However, it must be noted that the actual threshold dose varies from person to person (i.e., inter-individual variation), but there is clearly a "no effect" or sub-threshold range for everyone. In other words, some individuals may be more sensitive than others to the effect of a given chemical.
Finally, toxic effects can be defined as acute, subchronic or chronic, based on duration of exposure. An acute effect is one of very short duration often involving a single exposure at a very high dose. A subchronic exposure is generally viewed as exposure, generally daily, over some period of time less than the whole lifetime. Chronic exposure generally is viewed as a daily exposure lasting over a whole lifetime and beginning at an early age. It should be emphasized, however, that care should be exercised to distinguish subchronic and chronic exposure from subchronic and chronic effects. Subchronic and chronic effects are meant to convey that the adverse effect does not appear immediately after exposure but that the effect occurs after some delay following exposure. In fact, the effects may not appear until close to the end of life (e.g., cancer) even if exposure begins early in life. Furthermore, chronic effects may or may not need chronic exposure to manifest.
In summary, this first article has discussed the process of hazard identification, which is the first step in a human health risk assessment and provides basic information related to how the hazards or toxic properties of chemicals are assessed. The next article in the series will provide an overview of how dose-response and exposure data are used in the risk assessment process. Subsequent articles will deal with the process of risk characterization, risk management, regulatory implications of risk assessment, as well the application of the precautionary principle in protecting human health in the absence of scientific data necessary for assessing risks.
[1] These steps are well-known in the field of toxicology and are described in similar language by a variety of sources. See, for instance, "An SAB Report: Guidelines for Reproductive Toxicity Risk Assessment: Review of the Office of Research and Development's Guidelines for Reproductive Toxicity Risk Assessment by the Environmental Health Committee," U.S. Environmental Protection Agency, http://yosemite.epa.gov/sab/
sabproduct.nsf/DD5DA21FE9F56EB48525719B006A11E1/$File/ehc95014.pdf, p. 8, n. 3.
THIS IS THE second in a series of four MichiganScience articles on risk assessment. These articles will be designed to acquaint and provide the reader with information that will allow him or her to understand and evaluate potential risks to human health resulting from exposures to chemicals, including drugs. In other words, this series of papers on risk assessment will not be designed to present the reader with an in-depth treatise on the complexities of risk assessment, but rather will provide a high-level overview of the process. The hope is that enough information will be presented such that the reader, when faced with having to understand and make decisions relative to risk, will have the basic tools necessary to make an informed decision.
In the first paper of this series, we discussed some of the fundamental elements of risk assessment. The primary focus of the first article was hazard identification, which is the determination of whether a particular chemical is causally related to a particular adverse health effect. We pointed out that all chemicals, whether they are naturally occurring or man-made, can be toxic and, therefore, have the potential to cause adverse health effects in humans. The dose makes the poison, in other words.
This article introduces two additional steps in the risk assessment process - dose response and exposure assessment. Again, this will not be an in-depth presentation of the complexities of these two steps, but rather a high-level overview.
Dose response measures the level of chemical exposure and its impacts. In other words, evaluating the dose-response relationship for a chemical is at the heart of understanding the health risks it may pose.
In order to understand dose and response, we need to understand the conduct of a typical toxicity study. This is how scientists determine at what levels of exposure to a particular chemical it becomes harmful (toxic).
In a toxicity study, multiple groups of experimental animals (ranging from 10 to 60 animals per group) are exposed to or dosed with the chemical.
Because the most common human exposure to chemicals occurs through breathing (inhalation) or eating and drinking (ingestion), these are the two primary routes examined. Very rarely is skin contact evaluated as a route of exposure.
Exposure groups can range in number from three to five. One group is the control (non-exposure) group, and another group is exposed to the highest dose the animal can tolerate for the duration of the particular study. The effects of the chemical on the experimental animal are monitored throughout the study, including:
- effects on the amount of food eaten,
- changes in body weight,
- outward signs of effects on the neurological system,
- effects on blood parameters, and
- other key measurements.
The chemical's effects on organ systems are calculated at the end of the study by looking at changes in the weight of the organs and examining any microscopic changes that occur.
After the data are collected and analyzed, the results are plotted graphically (as shown below) where the increasing dose is plotted against increasing severity of response. In general, there is a range of doses below which no response or apparent toxicity occurs in the experimental exposure groups. Conversely, there is a higher range of doses over which the toxic properties begin to appear.
The exposure dose at which the transition between no apparent toxicity and toxicity occurs is referred to as the threshold dose, or No Observed Effect Level (NOEL). Implied in this concept, as noted in the first article, is the fact that an individual can be exposed for a lifetime to a chemical below the threshold and not suffer an adverse effect. It must be noted that even below the threshold, there is likely a sensitive population that responds in some way to the exposure. This is known as inter-individual variation and will be discussed below.
The goal of toxicity studies is to establish a chemical's dose response effects on a specific organ or system, such as the reproductive or central nervous systems. Other studies are designed to assess developmental effects, such as the potential to cause birth defects (teratogens) or the potential to cause cancer (carcinogens).
While most chemicals exhibit a threshold, there are certain classes of compounds for which an argument can be made for no threshold. These compounds (e.g., mutagens and carcinogens) can directly interact with and damage genetic material (DNA) in cells, which can be passed on from one generation of cells to the next. Cells containing such damage are at an increased risk of causing cancer. It should be noted that not all of these cells will become cancerous, but there is an increased probability they will do so. In other words, a single molecule of carcinogen interacting with DNA can potentially lead to cancer. Therefore, it is generally accepted that there is no safe dose or level of exposure for this kind of compound.
There is a complex relationship between dose response and risk assessment:
- Based on the small number of animals used in each dose group in a toxicity study, it is generally accepted that the difference in disease rate or effect needs to be at least 10 percent to be statistically significant.
- The dose response can vary significantly depending on whether the chemical was ingested or inhaled, due to differences in absorption in the gastrointestinal tract and lungs.
- The toxicity of a chemical can be due to the actual chemical itself or a metabolite (molecule formed by a chemical reaction between the foreign chemical and the host body) or potentially a combination of both the chemical and the metabolite.
- The external dose is the actual amount to which an organism is exposed, but what toxicologists really want to know is the internal dose or the amount of chemical that is actually delivered to the target tissue. This obviously will depend on how the chemical is distributed in the body once it is absorbed, how long it stays in the body, how it is metabolized and how it is eliminated from the body (refer to the ADME - absorption, distribution, metabolism and elimination - MichiganScience No. 11).
- Two approaches are available to deal with ADME. The first is physiologically based pharmacokinetic modeling. PBPK models are used to predict internal dose at target organs. They consist of a series of equations representing real biological tissues and physiological processes that additionally simulate the ADME of chemicals that enter the body. The advantage of these models is that they rely on the real physiology of the species in question, which makes them useful for comparing results between different species (interspecies extrapolation). The second approach is biomonitoring, which is the analysis of human body fluids and tissues for purposes of measuring human exposure to chemicals.
In addition to these complexities, there are at least two limitations associated with the use of dose response data in risk assessment. Both of these limitations involve extrapolating data. In essence, this means drawing conclusions about a set of data that cannot be scientifically proven based on information from another data set that has been proven.
For example, toxicologists speak about extrapolating toxicity results obtained in animal experiments to reach conclusions about possible toxicity in human beings. Since animal studies are generally conducted with high doses in order to elicit and understand the toxicity with a limited number of animals, and since human exposure generally occurs at much lower doses (usually below the threshold), estimating an acceptable risk to human health requires extrapolation from effects seen at high doses to potential effects at lower doses. This provides a level of uncertainty to the risk assessment, since there is potentially a part of the human population that may be extremely sensitive to the potential adverse effects.
The second limitation involves trying to estimate potential effects in humans from studies conducted in animals. In other words, we are faced with interspecies extrapolation, which adds another layer of uncertainty when trying to assess the risk to humans. There are many examples of effects that are seen in animals that do not translate to effects in humans (e.g., limonene and renal tumors in rats, see below).
Limonene is a hydrocarbon found in lemon rinds. The compound is employed in cosmetics, cleaning products, food manufacturing, medicines and insecticides.
The use of limonene has the potential to lead to widespread human exposure. However, limonene was shown to cause increases in incidences of nephropathy, renal hyperplasia and renal tumors in laboratory male rats.
It has been shown in studies that administration of limonene to male rats resulted in the accumulation of a low-molecular-weight protein known as alpha-2u-globulin. The protein build-up is followed by kidney disease and an increased incidence of kidney tumors.
It has been shown that the male rat response to alpha-2u-globulin does not occur in female rats or in other animal species such as mice, nor does it occur in humans. In other words, the carcinogenic response to limonene seen in male rats does not occur in other animal species or humans. It is specific to male rats. Therefore, limonene is not considered carcinogenic to humans. This is a clear example of the potential pitfalls in extrapolating adverse results seen on laboratory animals to humans.
From the dose response data, scientists can estimate exposure levels at which adverse responses occur in experimental animals. They also can estimate, at least for chemicals that provoke threshold responses, an exposure level below which most, if not all, humans can be potentially exposed where no adverse effects are expected.
However, there are uncertainties resulting from extrapolations from high dose to low dose and from extrapolating adverse effects seen in animals to humans. The NOEL is the highest dose at which no adverse effects are detected in a hazard identification study. For purposes of a risk assessment, the NOEL is adjusted downward to account for limitations and uncertainties in the available data to arrive at an exposure that is likely to cause no noticeable harmful effects in humans. This is sometimes referred to as reference dose (RfD) or reference concentration (RfC). This approach has been used for years for substances other than those that cause cancer, and it implies that there is a threshold for all other potential adverse affects.
A benchmark dose (BMD) approach has been used as an alternative to address some of the limitations with the use of the NOEL. The BMD is the current approach used by the U.S. Environmental Protection Agency to set an RfD. Unlike a NOEL, the BMD takes into account dose response information by fitting a mathematical model to dose response data. The benchmark dose low (BMDL) is then estimated from this curve.
The BMDL is statistically the 95 percent lower confidence interval of the BMD. Using the BMD approach and then applying appropriate safety or uncertainty factors (see below) to the BMDL to establish a RfD serves as the basis for setting a more scientifically based estimation of a level to protect human health, since this is a conservative estimate of the dose below which humans can be exposed without effect.
In general, the uncertainty factors are used to account for interspecies variation (x10), which allows for extrapolation from animal data to humans and human variability (x10), which takes into account sensitive individuals of the population. The product of these two factors (100) is routinely used in setting what is referred to as the RfD. Therefore, to set the RfD the NOEL or BMDL is divided by 100.
Once we have established the RfD, we need to gather information for the next step in the risk assessment process. This is the level at which humans are potentially exposed. An exposure assessment is the determination of the extent of human exposure from all sources. It includes a determination of the populations that may be exposed (e.g., worker in an industrial setting, children, consumers, general public, etc.). It also is an estimation of the potential for exposure by a particular pathway such as ingestion, inhalation or skin contact.
Humans are exposed to chemicals through indirect contact in a variety of ways, including air, water, food, soils, dusts, cosmetics products, household products and so on. The pathways of exposure can be as simple as direct contact (cosmetics) and some as complex as a contaminant traveling through the air, depositing in the soil of fields where crops are grown, dissolving in the ground water and taken up through the roots of the crops used to feed livestock that is in turn consumed by humans. If the livestock happen to be cattle, for example, then the contaminant could end up in milk from the cattle. In the case of humans, the contaminant could end up in human breast milk if the mother consumes meat from the cow. Furthermore, to make matters more complex, we have potential exposure from the breathing of air and from human contact with soil and dust. By this time, our contaminant of consideration has passed through and into at least 10 media on its way to human exposure. The illustration on the previous page provides an overview of the potential media and exposure pathways for humans living near a chemically contaminated site.
Since all of the above media contain some level of contaminant, it's important to understand the amount of the chemical in each media as well as the amount of each media to which humans are exposed in order to estimate the external exposure level. This is more often than not a very complex and challenging task.
With the right set of tools such as PBPK modeling and biomonitoring, a somewhat reasonable estimate of the internal dose from the estimation of the external dose may be extrapolated. This estimate of external or internal dose can be compared to the RfD to determine whether we are above or below the RfD and whether there is a risk to human health. Of course, the situation is different for non-threshold carcinogens when one uses the human exposure dose to estimate the probability or incremental increase in risk for a lifetime exposure. Likewise, the process for extrapolating dose response for carcinogens is completely different.
The exposure route is the way the chemical in question moves into the body. Generally, a given medium will result in only one route of exposure. However, there are cases when a given medium results in multiple routes of exposure. Consider a volatile chemical that is contained in a cosmetic product applied to the skin and some part of the chemical in the product volatilizes into the air. In this case, exposure is by both skin contact and inhalation.
As with other areas of risk assessment, getting a reliable estimate of potential human exposure from environmental and other pathways has its share of uncertainty. Perhaps the major problem is sampling: where to sample, how to take the sample, how to preserve and process the sample, how to analyze the sample, etc.
The obvious goal of sampling the environment is to obtain an accurate representation of the environmental level of the chemical. In other words, we want to have some confidence that the whole actually is represented by the part taken for analysis. Fortunately, this problem can be dealt with by statisticians who devise sampling strategies that allow scientists to know the degree of confidence of the sampling. The same is true for the analysis of the samples. Quality assurance or quality control programs help ensure the scientific integrity of the analytical results.
In the first article in this series, we discussed the process of hazard identification, which is the first step in a human health risk assessment, and provided basic information related to how the hazards or toxic properties of chemicals are assessed. In this article, we have provided an overview of how dose response data are generated from the hazard identification data and how these data are used to estimate a safe level of human exposure or, in the case of carcinogens, how to estimate an incremental increase in the risk of developing cancer resulting from a lifetime of exposure to the chemical.
Next, we have shown the complexities of estimating human exposures from a variety of environmental media and the routes by which humans can be exposed. We have presented information now on three of the steps in the risk assessment process. The next article will focus on how the information from the first three steps in the process is used in the risk characterization. The series will conclude with an article on risk management.
THIS IS THE third in a series of four MichiganScience articles on risk assessment. These articles are designed to acquaint and provide the reader with information that will allow him or her to understand and evaluate potential risks to human health resulting from exposures to chemicals, including drugs. In other words, this series of papers on risk assessment is not designed to present the reader with an in-depth treatise on the complexities of risk assessment, but rather to provide a high-level overview of the process. The hope is that enough information will be presented such that the reader, when faced with having to understand and make decisions relative to risk, will have the basic tools necessary to make an informed decision.
In the first two articles in this series, we discussed three of the four fundamental elements of a risk assessment:
- Hazard Identification, which is the process of determining whether a particular chemical is or is not causally related to particular health effects and involves characterizing the nature and the strength of the evidence of causation.
- Dose-Response, which is the process of characterizing the relationship between the dose of a chemical administered and the incidence or the probability of occurrence of the health effects in question.
- Exposure Assessment, which is the process of measuring or estimating the intensity, frequency and duration of exposure to a chemical from all sources. It includes the population(s) that is (are) potentially exposed and the pathways of exposure (ingestion, inhalation and dermal contact).
In this article, we will touch on the final step in a risk assessment — risk characterization. As before, this will be a high-level overview rather than an in-depth presentation of the complexities of a risk characterization.
Quite simply, risk characterization is the process of estimating the degree of safety associated with exposure to a chemical or the incidence of a human health effect under the conditions of exposure described in the exposure assessment. Risk characterization brings together the exposure and dose-response assessments and includes a description of their uncertainties. For example, what is the risk someone will develop neurological disorders from being exposed to mercury? What is the likelihood someone exposed to benzene in gasoline will develop cancer? For non-cancer-causing chemicals, risk is determined by estimating the margin of exposure (MOE) or hazard quotient (HQ). For cancer-causing chemicals, the risk is a probability and is expressed as a fraction. The risk in both cases is unitless.
The concepts of chemical risk and how they are expressed are sometimes difficult to grasp. People are more familiar with the discussion of risks related to other sorts of activities, such as the annual chance of dying in an automobile resulting for people who drive an average number of miles per year. This risk is about one in 4,000. The risk of dying from lung cancer for individuals who smoke one pack of cigarettes per day beginning at age 15 is about one in 800. The primary difference between these sorts of risks compared to risks associated with chemical exposure is that these risk estimates are much more solid and are derived from years of extensive and substantial statistical data. Risks associated with chemical exposures are filled with uncertainties, which have been described in previous articles.
We have discussed in previous articles the first three steps in the risk assessment process that lead to the final step — risk characterization. The first three steps provide all that is necessary to answer the ultimate risk questions: What type of toxicity is expected in the exposed population (neurotoxicity, birth defects, reproductive effects, cancer, etc.), and what is the risk of it occurring in the exposed population?
A key component of the risk characterization is an analysis of the uncertainties. The two critical areas of uncertainty are the relevance to humans of the animal toxicity findings (hazard assessment) and the dose-response relations at the human levels typically associated with the chemical in question (high-dose to low-dose extrapolation). These uncertainties are generally dealt with by applying uncertainty factors to the NOEL (no observed effect level) or BMDL (benchmark dose low) to establish an RfD (reference dose), for ingestion, or RfC (reference concentration), for inhalation. The uncertainty factors are usually 10 for animal to human extrapolation and 10 for high-dose to low-dose extrapolation. In the case where a NOEL was not determined in a toxicity study and the LOEL (lowest observed effect level) has to be used in the dose-response assessment, a third uncertainty factor of 10 is used.
So, how does this whole process work? Let's assume we have chemical X that is subjected to a complete hazard assessment using the ingestion (oral) route of exposure. The results of the study showed that this chemical has liver toxicity in repeated dose studies and a reproductive effect in female rats in a standard study to assess male and female reproductive effects. Both effects occurred in a dose-related manner as shown below.
Dose-response function with a no-effect region
The most sensitive endpoint for chemical X is liver damage, where endpoint is defined as an effect observed in a toxicity study. The apparent NOEL for the liver damage is 100 mg of X/kg body weight (BW) and the apparent NOEL for the reproductive effect is 1,000 mg of X/kg BW, making the liver effect the most sensitive endpoint. Using an uncertainty factor of 100 gives an RfD of 1 mg of X/kg BW and 10 mg of X/kg BW for the liver and reproductive effects, respectively. An exposure assessment showed that the intake of chemical X by humans from all sources and by all routes of exposure is 0.5 mg of X/kg BW.
Having the hazards indentified, the dose-response relationship evaluated, and the potential human exposure dose or intake, we can assess whether the level at which humans are exposed are safe or without appreciable risk of adverse non-cancer health effects over a specified period of time. This can be accomplished in one of two ways, which yield different answers but in reality are comparable. The first approach is to divide the NOEL by estimated daily human exposure determined in the exposure assessment. Remember that the NOEL will not have the uncertainty factors (100) applied to it. In the case of our chemical X, the MOEs (margins of exposure) would be:
Liver Effect:
MOE = (NOEL)/estimated human exposure = (100 mg X/kg BW)/(0.5 mg X/kg BW = 200
Reproductive Effect:
MOE = (NOEL)/estimated human exposure = (1000 mg X/kg BW)/(0.5 mg X/kg BW = 2000
Since the MOEs are greater than 100, human exposure to 0.5 mg X/kg BW is judged to be safe or without appreciable risk if exposed to this level everyday for a specified duration of time (generally a lifetime). The second approach is to use the RfD, which has the uncertainty factors of 100 applied to the NOEL and to calculate what is called a Hazard Quotient (HQ). The HQ is calculated by dividing the estimated human exposure dose by the calculated RfD. The HQs for chemical X are:
Liver Effect:
HQ = estimated human exposure/RfD = (0.5 mg X/kg BW)/(1.0 mg X/kg BW) = 0.5
Reproductive Effect:
HQ= estimated human exposure/RFD = (0.5 mg X/kg BW)/(10 mg X/kg BW) = 0.05
For each effect for chemical X, the HQ is less than 1.0, which indicates that the 0.5 mg of X/kg human exposure by all routes and sources is without appreciable risk. It needs to be noted that this is not an expression of probability of an individual suffering and adverse health effect but serves more as a guide of what would be considered a safe level of exposure or an absence of risk.
In the first two articles in this series and the first part of the current article, we focused primarily on a discussion of the approach to assessing risks to human health from chemicals demonstrating a threshold effect in the hazard identification studies. We mentioned that the approach to assessing the risks from exposure to chemicals classified as carcinogens is different. The reason for this difference is that chemicals that cause cancer are considered to have no threshold, because they are generally considered to interact with and damage genetic material (DNA) in cells, which can be passed on from one generation of cells to the next. It is considered that a single molecule of carcinogen interacting with DNA can potentially lead to cancer, and because of this, it is generally accepted that there is no safe dose or level of exposure for these kinds of compounds. The dose-response for a carcinogen is considered linear especially in the low-dose region of the dose response curve, which means for every incremental increase in dose there is an increase in response. Benchmark dose modeling is used on the actual dose-response data to estimate the BMD and the BMDL (sometimes referred to as the ED10 and LED10), which is the dose corresponding to a specified increase in the probability of a specified response or effect. The BMD (or ED10) is usually the estimated dose corresponding to an increase of 10 percent (or increase of 0.1 in probability) of the specified response relative to the probability of that same response at zero dose. The BMDL (or LED10) is statistically the 95 percent lower confidence interval of the BMD (or ED10). This estimated point on the dose response curve is sometimes referred to as the Point of Departure (POD).
The dose-response curve for a carcinogen is assumed to be linear from the POD down to zero dose. The slope of the extrapolated linear curve is referred to as the potency of the carcinogen, which reflects the lifetime cancer risk associated with one unit of average daily lifetime dose. The slope of the extrapolated curve is the rise of the line — the increased risk shown on the vertical axis — for each unit increase in dose, shown on the horizontal axis) (below).
Dose Response Relationship, Carcinogens
The more potent the carcinogen, the steeper the slope compared to less potent carcinogens.
Since there is essentially no safe dose with carcinogens, one has to estimate a level of risk that would be considered acceptable. This is a probability that lifetime exposure to a chemical, under specified conditions of exposure, will lead to an excess cancer risk, which generally ranges from 1/10,000 to 1/1,000,000 and means that one in 10,000 or one in 1 million people exposed is expected to develop cancer. It is important to note again that this is a probability and there is no way to identify which, if any, of the 10,000 to 1,000,000 people exposed will develop cancer. To calculate excess lifetime cancer risk, the estimate of human exposure dose is multiplied by the potency factor.
So how does this work? If, for example, a population of individuals is exposed to 0.0014 mg of a cancer-causing chemical per kg BW per day for a lifetime and the potency factor is 0.006 risk per mg BW per day, then the excess lifetime cancer risk is:
Risk = (0.0014) x (0.006) = 0.000008
This means, then, that eight people out of 1 million experiencing an average intake of the carcinogen each day for a full lifetime will develop cancer over that lifetime, or in other words, the human population would need to have the exposure level reduced to 0.00017 mg of this cancer-causing chemical in order to give an excess lifetime cancer risk of one in 1 million people exposed.
In summary, we have in three articles led the reader through the four steps of a risk assessment:
- Hazard Identification
- Dose-Response Assessment
- Exposure Assessment
- Risk Characterization
We have attempted to show at a very high level how the process works for both non-carcinogens and carcinogens. It must be reinforced that these articles were a very general overview of each step in the process. While the actual process may be more complex, these articles provide the basic tools to evaluate information presented in news media or other sources. All that needs to be done is a little investigative work to gather some of the basic data needed to perform independent risk assessments of particular chemicals. The next article in this series will focus on how regulatory agencies such as the U.S. Food and Drug Administration and U.S. Environmental Protection Agency use risk assessment to manage risk and set levels of exposure to chemicals in an attempt to protect public health.
THIS IS THE fourth and final MichiganScience article on risk assessment. These articles have been designed to acquaint and provide the reader with information that will allow him or her to understand and evaluate potential risks to human health resulting from exposure to chemicals, including drugs. In other words, this series on risk assessment was not designed to present the reader with an in-depth treatise on the complexities of risk assessment, but rather to provide a high level overview of the process. The hope was that enough information would be presented so that the reader, when faced with having to understand and make decisions relative to risk, would have the basic tools necessary to make an informed decision.
In the first three articles, we discussed the four basic steps in a risk assessment:
- Hazard Identification
- Dose-Response Relationships
- Exposure Assessment
- Risk Characterization
In the last article, we provided examples of a risk characterization for both a threshold chemical and a nonthreshold chemical (i.e. carcinogen) and discussed the uncertainties in the whole process. An expanded view of the risk assessment process would include a provision for additional data to enhance the overall process or to reduce the uncertainties in the final risk assessment number (see Figure 1). Also shown in Figure 1 is risk management, which is the focus of this article. The entirety of the process outlined in Figure 1 is in essence the process of risk analysis.
Figure 1: Risk Analysis
A risk assessment simply cannot draw a distinct line between safe and unsafe. Safety is by its nature an inverse relationship of hazard. If the concept of safety is meant to simply mean the absence of risk resulting from exposure to chemicals, then this is nearly impossible to prove, because to do so requires proof that risk does not exist. Please recall from the earlier articles that it was pointed out that everything has a hazard or is toxic. It is best summed up, to paraphrase Paracelsus, as, "The dose makes the poison."
We can divide chemicals into three broad categories:
- The enormous number of naturally occurring chemicals that reach us primarily through food.
- Industrial chemical products that are produced for specific purposes.
- Industrial pollutants - chemical byproducts of fuel use, of the chemical industry and of most other types of manufacturing (Rodericks).
If the goal is to be absolutely safe, or without risk, from these products, especially industrial chemicals or the polluting byproducts, then a wholesale banning would be necessary. This would require turning the calendar back 200 years or more (Rodericks). Therefore, the process of risk assessment is necessary to understand scientifically what the risk is from exposure from these sources and what is an acceptable level of exposure that would be without appreciable risk.
Once the scientific process is complete and the risks and uncertainties identified, decisions need to be made on how to manage the risk. This is perhaps the thorniest step in the overall process in the risk assessment paradigm. The risk assessor or those charged with protecting public health must make management decisions based on an evaluation of public health, economic, social and political consequences of a regulatory action. They must weigh competing priorities of individual freedoms, groups of individuals (i.e. the population as a whole), environmental groups, industry, etc. That is to say, judgments of acceptability of risky activities are not just a matter of numbers but draw on judicial, regulatory and political mechanisms through which societal choices are made and enforced. Some fundamental factors that must be considered in the management process are voluntariness, equity, procedural legitimacy, treatment of uncertainty and perceptions.
Voluntary vs. involuntary exposure is one key determinant in assessing risk acceptability. In a society that values individual liberties, the risk an individual is willing to take may be higher than a quantitatively similar risk that is imposed on an individual by another party. As a classic example, an individual can smoke cigarettes in the privacy of his or her home, creating a health risk for him or herself, and yet be forbidden to smoke in public, where this individual would impose a much smaller risk (via secondhand smoke inhalation) on others.
A second consideration in the management of risk concerns the fairness and equity of the distribution of risks and benefits. The concept of equity of risk is complicated by the fact that a risk management analysis that appears to be fair and equitable may turn out to be inequitable (though not perhaps unfair). This is very akin to the famous utilitarian dictum: "The needs of the many outweigh the needs of one."
Legal acceptability of risk is based on the answer to a fundamental question posed by society, regulators and industry, which is: How can disputes over risk be adjudicated and policy decisions made in the absence of adequate scientific information and knowledge about causal mechanisms? A critical issue, therefore, is "proof" in cases where it is not clear whether a risk is being imposed or where the magnitude of the suspected risk created by an exposure is highly uncertain. This will be discussed further below.
Uncertainties in the risk assessment process have been discussed in previous articles in this series. Uncertainty in the risk assessment process simply cannot be eliminated, and risk assessment and risk management cannot be clearly separated for uncertain risks. The decision of when to stop collecting data and to act is a risk management problem (Figure 1), while expressing the uncertainty at the time of transition from research to management is part of the risk assessment process.
Individual perception of risk cannot be ignored, but often these perceptions regarding risk are changeable, unreliable and overly sensitive to impressions. Many times, an individual's perception of risk is influenced by special interest groups that have an agenda and can make broad statements that may be true on the surface but are devoid of the fundamental concepts of dose and response. In other words, they may neglect to state that while a material is hazardous, the level at which exposure takes place may be in the range at which no appreciable risk occurs (i.e., exposure is devoid of risk or is at a level to which an individual may be exposed for some duration of time without an impact on health). Therefore, a risk may be perceived as large when in reality the risk to human health is negligible.
So how does one approach the task of risk management? There is a great propensity on the part of regulatory agencies and those who practice public policy to require numerical standards for judging what risks are acceptable. For non-cancer-causing chemicals, numerical thresholds are of great value. They reduce ambiguity and debate for the most part. The reason for this is that it is far easier to compare numbers than to evaluate the complexity of social decision processes.
One common approach to the risk management decision process is to conduct a cost-risk-benefit analysis when chronic health risks of an activity are known (Rodericks). The common practice in this approach is to evaluate risk control measures in the terms of dollars spent per statistical life saved. Balancing the costs against the benefits of risk control measures is clearly necessary for an efficient allocation of resources. To implement fully the cost-risk-benefit analysis approach, it is essential to develop more realistic measurements of the benefits from risk reduction than the conventional one of expected number of statistical lives saved. When risks are uncertain, a different set of issues must be confronted that essentially centers on the high costs of risk research, costs of risk control and uncertain benefits of possible risk reductions resulting from control measures.
It should be clear from the above discussion that one of the most challenging areas in statutory interpretation of risk assessment and risk management is the problem of setting cutoff levels or acceptable levels of exposure for risk regulators. The consistency and effectiveness of risk management decision-making might be enhanced if agencies had a systematic approach for determining whether specific risks are "de minimis" — that is, too trivial to warrant an expenditure of resources to assess or control them.[1]
Determining a de minimis risk level is essentially a pragmatic decision tool for distinguishing between trivial and nontrivial risks. In general, the de minimis approach is accomplished by establishing a risk cutoff level greater than zero. If a hazard is greater than the de minimis level, it becomes the object of possible regulation, up to and including a ban on the use of the chemical. If, however, the level falls below the de minimis level, it is excluded from further consideration. Ideally, a de minimis risk level would distinguish between small risks that are more costly to regulate than to tolerate and large risks that are more costly to tolerate than to regulate.
The de minimis approach is certainly consistent with current health and safety statutes and with regulatory agency efforts to establish insignificant risk levels in the evaluation of suspected hazardous chemicals. The fact that they are labeled insignificant risk levels rather than de minimis levels is not important. The logic underlying both is the same. For an example of this approach, let's refer back to the third article in this series, in which we evaluated chemical X and discovered that it had a reproductive effect with a NOEL or BMDL of 100 mg/kg/day. We applied a 100-fold uncertainty factor to the NOEL or BMDL and established an RfD of 1 mg/kg/day. The RfD established for this reproductive effect could, in essence, be considered the de minimis level below which there is an insignificant risk of a reproductive effect in women if exposed below this level for a lifetime.
On the other hand, how would we handle a nonthreshold chemical (i.e., a carcinogen)? Some argue, as stated in previous articles in this series, that there is no safe level of exposure to a carcinogen (i.e., the no-threshold hypothesis). What is true is that under the no-threshold hypothesis any exposure to a carcinogen increases the probability of cancer occurring, but it does not mean that any exposure to a carcinogen will cause cancer. Short of banning all carcinogens, if the above were true, regulators take the position that the "safe level" for exposure to a carcinogen is defined as the dose or exposure that produces no more than a specified and very low level of excess lifetime risk — generally 1/1,000,000, or one excess cancer in 1 million people exposed, which is sometimes expressed as 10-6. What does this mean? If we assume there are 300 million people in the United States, for example, exposed daily for their full lifetime to a concentration of a carcinogen that caused risk, then the number of extra cancer cases created over a 70-year lifespan would be (300 million people) x (1/1,000,000 extra lifetime risk per person) = 300 extra cancer cases during a lifetime, or an average of 300 ÷ 70 = four to five extra cases per year for an average lifespan of 70 years. Since the actual number of cases associated with 10-6 risk is probably lower than but certainly not more than the four to five extra cases per year, it would appear that a 10-6 risk level is an appropriate definition of protective of human health and that exposure below a level of one in a 1 million extra lifetime risk could be the de minimis level.
The Precautionary Principle
While the above approach seems reasonable to manage risk even with the uncertainties that are ever-present in the risk assessment process, there is a significant movement to manage risks in a much different approach, which is the use of the "precautionary principle." The precautionary principle, as it relates to environmental hazards, was proposed in January of 1998 at the Wingspread Conference held at the headquarters of the Johnson Foundation in Racine, Wis. At the conclusion of the three-day conference, a diverse group of scientists, philosophers, lawyers and environmental activists issued a statement calling for governments, corporations and scientists to adopt the precautionary principle:
"When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically. In this context the proponent [e.g. chemical manufacturer] of an activity, rather than the public, should bear the burden of proof [of a lack of harm]."
The precautionary principle is an extrapolation of the motto "better safe than sorry." While there is precaution involved in traditional risk assessment (note the 100-fold uncertainty factor used in the first de minimis risk calculation above), the precautionary principle is meant to address situations with higher degrees of scientific uncertainty about how and whether particular harms might be caused. The principle is intended for cases concerning potentially irreparable harm, such as birth defects or species loss.
Because the precautionary principle is applied in instances where scientific evidence and causality are not "fully established," critics observe that the principle may be invoked based on less-than-plausible risks and used to ban, rather than reduce exposure to, a process or product. The European Commission, which implements legislation passed by the European Union, "stresses that the precautionary principle may only be invoked in the event of a potential risk and that it can never justify arbitrary decisions. Hence, the precautionary principle may only be invoked when the three preliminary conditions are met — identification of potentially adverse effects, evaluation of the scientific data available and the extent of scientific uncertainty" (European Commission Communication).
In summary, this four-part MichiganScience series on risk assessment has attempted to provide the reader with a high level overview of the process of assessing risk to human health and the environment resulting from chemical exposures. It has tried to convey the complexities of the process and the uncertainties associated with this process, as well as to provide some insights into the most complex part of the process: risk management. This is by no means the complete picture. After these processes are complete comes the task of trying to communicate the risk to the general public, so they can understand and accept the safe exposure levels that are set.
[1] The term "de minimis" is derived from the Latin maxim "De minimis non curat lex," which means, "The law does not concern itself with trifles."
References and Further Reading
Rodericks, J.V., "Calculated Risks: The toxicity of human health risks of chemicals in our environment," Cambridge University Press, New York, N.Y., 1994.
National Academy Press, "Science and judgment in risk assessment," National Academy Press, Washington, D.C., 1994.
Paustenbach, D.J. (ed), "The risk assessment of environmental and human health hazards: A textbook of case studies," John Wiley and Sons, New York, N.Y., 1989.
"Europa: Summaries of EU Legislation: The precautionary principle," European Union, http://europa.eu/legislation_summaries/ consumers/consumer_safety/l32042_en.htm (accessed May 16, 2010).


text:
We Found 2
Lyndonville, VT Foreclosed Homes For Salefor You.
There are a few listings for "searched location". Try expanding the map to find listings nearby. Or save this location to get notified when new homes are listed!
Page 1 of 1
Sort by: Closest Match
Location data not available
1 to 2 of 2 Results
1 to 2 of 2 ResultsLocation data not available

subset: commoncrawl


text:
Paul Ince insists securing npower Championship survival will be his primary target after being confirmed as Blackpool's new manager.
Last season's beaten play-off finalists won three out of three at the start of the current campaign to establish themselves as the early pacesetters, only for patchy form thereafter and the managerial departures of Ian Holloway and Michael Appleton to all but end their promotion ambitions.
The Seasiders lie 14th in the table ahead of the midweek fixtures, 10 points shy of the play-off places and six above the relegation zone, with Ince more interested in the latter statistic. He told Sky Sports News: "To be fair we're not going to catch (Championship leaders) Cardiff, but what we do know is that in the short-term we've got to try and get as many points as we can."
He added: "Once we get to 50, 52 points and get that safety net then we can start looking upwards. We're under no illusions about how tough this job is going to be but we have got fantastic spirit, fantastic fans and great prospects going forward."
Ince agreed a one-year rolling contract at Bloomfield Road in line with the established policy of chairman Karl Oyston. This approach became an increased source of friction between Oyston and Holloway towards the end of the outspoken Bristolian's tenure, but Ince is unconcerned by such details at present.
"Sometimes it doesn't really matter how long the contract is for, it can be six, seven years but if you're not getting the job done you're not going to keep it," said the 45-year-old former England midfielder, who is back in management for the first time since leaving Notts County by mutual consent in April 2011.
"The terms of the contract are not really important to me. What is important is getting back into football at Blackpool and taking this club forward."
The main source of intrigue surrounding Ince's appointment is his son Tom's status as Blackpool's star player.
Liverpool and Reading both tabled bids during the January transfer window for the highly-rated England Under-21 winger, who has 17 goals in 33 appearances this season.
"I'll always do what's best for Thomas in football, as I will for any other player at Blackpool," Ince Snr added. "His contract does end at the end of the season, we do have an option on him and I'll have to discuss it with his mum as to whether we can take that up."


text:
I speak out every day about my HIV status. I tell a large number of people my story. I want them to know my name and of my many experiences. Some people thank me. Others despise my exposure. They tell me it's no one's business but my own, what I have done and what STD [sexually transmitted disease] I have. However, I'm honest and have no problem telling the world that I have sex with men on occasion and that I'm HIV positive.
They ask, "Are you proud of your HIV status? Do you take pride in you incurable infectious disease?"
Out of sheer defense, I say, "YES!"
I know that I have nothing to hide no matter how America may accept me. I'm very honest, truthful and forthright about who I am and what I do. I LOVE MYSELF ... I don't expose myself for attention or fame. I always wanted to become famous, but not because of a disease. I said I wanted to help others ... Am I?
I think back to when I first began to tell my story and why. I was scared and alone, I had only my sister's support and a few friends. I felt completely isolated and hurt. I really wanted to speak about my life just as any other family member at family events. I disclosed my bi-sexuality to my family at the age 13 so I never shied away from speaking out. It was very uncomfortable not being able to share intimate parts of my life with those that mattered most to me.
I think I'm so open because I come from a big family (a REALLY BIG FAMILY), and we didn't have many secrets. My family feels: "A family that prays together will stay together" and "A family that cares will share the good times as well as the hardships."
When I told my family I was HIV positive ... they threw me a "STAY HEALTHY" party. They cooked, they brought me gifts and information about the virus. I knew that I was truly loved. I guess I'm one of the lucky ones who just come from continued acceptance.
After my flash back, I notice that I do have PRIDE -- not specifically POZ PRIDE but SELF PRIDE. The PRIDE that has brought me out of denial, and out of depression, into a state of love and empowerment.
I will continue to be non-judgmental in my life and the lives of others!
"He who conceals his disease cannot expect to be cured." -- Ethiopian Proverb
Read Tree's blog, Tree House Talk (All Strength No Shade).


text:
Over 30 million late model used auto and truck parts at your fingertips
Search Online Top US Salvage Yards' Inventories...
Used Lada Parts - Knoxville (TN) Yard... Call Toll Free 1-866-612-9798
Used Lada parts in Alcoa,TN area
if you live in , our Alcoa yard can service your needs of used Lada parts. Our Alcoa warehouse specializes in providing replacement Lada parts for late-model cars/trucks. This local Tennessee salvage yard offers high quality OEM recycled Lada parts and motors at great discount prices. If your Lada car or pickup-truck needs to have its bumper, headlight, engine or transmission replaced, we can find you a certified replacement one. Our Alcoa Tennessee store offers lowest price guarantee and up to 3 years warranty on selected Lada used parts and engines. Our wrecking yard is located at Alcoa, Tennessee 37701 and can arrange a free delivery right to your door.
Note, our Alcoa,TN area doesn't carry the Lada parts at this time


text:
New I-9 Form, effective January 22, 2017
by, 11-17-2016 at 02:10 PM (14893 Views)
By Bruce Buchanan, Sebelist Buchanan Law
On November 14, 2016, the USCIS finally issued the new I-9 form, effective January 22, 2017. The current I-9 form continues to be in effect; however, during the interim period before January 22, 2017, an employer may use either the current 2013 version or the 2017 version. The new I-9 form has an expiration date of August 31, 2019.
The most significant change is to make the downloadable I-9 form into a smart form. What does a smart form mean? It is not an electronic I-9 form. The downloadable I-9 form, using an Adobe reader, has been enhanced with error checking which is designed to prevent the most common mistakes. An example is if you fail to fully complete section 1 of the I-9 form, you will receive an alert that you did not enter data into all of the required fields.
Employers filling out the smart I-9 version must still print the form, obtain signatures, monitor reverifications and updates. Second, if you use the smart form and make a mistake, your company will be held to the same standard of review when faced with an Immigration and Customs Enforcement (ICE) inspection.
With the addition of the smart form, there are three types of I-9 forms: paper, smart, and electronic.
Some of the other changes are:
(1) Replacing the Other Names Used field in Section 1 with Other Last Names Used. This will avoid employees writing their nicknames in this field;Although most of the changes may not appear significant, I would advise employers to seek legal advice from an immigration attorney as to compliance with the new I-9 form.
(2) Modifying Section 1 to request certain employees to enter either their I-94 number or foreign passport information, rather than both;
(3) Requiring you designate whether the employees number is an Alien (A) number or USCIS number, if using the smart form (however the numbers are the same though the more recent green cards refer to the number as USCIS);
(4) Requiring N/A be entered instead of blanks in certain fields;
(5) Replacing the word date to todays date, next to signature boxes (this may help some people from entering their birthdate or from backdating the signature);
(6) Providing a box for employees to check if they did not use a preparer or translator;
(7) Modifying the I-9 form by adding a supplemental third page if using multiple preparers and/or translators;
(8) Adding an area in Section 2 to enter additional information for TPS extensions, OPT STEM extensions and H-1B portability to avoid having to note this information in the margins of the I-9 form; and
(9) Increasing the pages of instructions from 6 to 15.


text:
Many cotton producers in the South accept too much stinkbug damage when it can be easily and inexpensively avoided, says Ron Smith, Auburn University Extension entomologist.
"We must consider the long life cycle of the stinkbug," says Smith. "The adult stinkbug likely will be in the field for almost the entire growing season, and no other cotton insect pest has such a long life cycle."
Stinkbugs have become a major insect pest of Southern cotton, primarily due to a low spray environment, he says. "In Alabama, we're hardly spraying cotton at all. We averaged less than two sprays last year. And some of those are worm sprays with materials that won't kill bugs," he says.
This trend, he adds, likely will continue, especially in the Coastal Plains area of the Southeast, including south Alabama and about 1 million acres in Georgia. This area also has mild winters, he continues, which contribute to the increase in stinkbugs.
"We knew this would happen based on growers' experiences in the Carolinas after boll weevil eradication. It's actually a greater problem than we imagined because of the lack of winterkill in our region. In areas such as Baldwin County, Ala., farmers can't even grow corn without applying stinkbug controls. Stinkbugs will destroy the stalks," says Smith.
Growers need to be more conscious of thresholds when treating for stinkbugs, he says. "Consultants are reporting that our thresholds are way out of line — that we're waiting too late before spraying. And part of this may be due to the stinkbug's long life cycle. It takes about 30 to 35 days for the stinkbug to develop into an adult, and the adults can live for two months. In other words, when stinkbugs get into cotton, they don't need to go anywhere else because they can feed on the bolls.
"And, basically, they're only a problem in cotton during the boll set period. That would begin in July and continue until the youngest bolls are about 25 days old. At that point, they're almost too hard for a stinkbug to do much damage."
Surveying for stinkbugs isn't easy, notes Smith. One method is to look for stinkbugs using the drop cloth method.
"You can lay down a drop cloth and beat the plants to see if the stinkbugs drop off. But stinkbugs are very sensitive to noise, and this method can scare them away. So, if you're sampling with this method, you need to walk a distance and get away from your last sample to find the next one. You've just about got to sneak up on them. If you disturb the cotton or make noise, they'll move."
The most accurate method for detecting stinkbugs is by slicing quarter-sized bolls, says the entomologist. A boll of this size still is soft and is most preferred by stinkbugs, he says.
"You need to look for calloused areas on the inside of the boll wall, deteriorating areas inside the boll or yellow-stained lint. All of these are symptoms indicating that part of that boll is going to rot before harvest."
The reason for slicing bolls is that not all bolls with outside damage also will have internal damage, says Smith. On the other hand, some bolls that appear to have internal stinkbug damage will show no evidence of damage on the outside.
Stinkbugs often don't damage the entire boll, says Smith, and only one or two locks may be damaged.
"Many consultants in the coastal areas are going strictly by physical sightings. If they sight multiple stinkbugs in a field, they feel they have a problem. Stinkbugs aren't easy to see. And, if you see several, there are many more that you're not seeing."
Stinkbugs, says Smith, do not clump early after hatching but instead clump for several weeks as they're going through immature instars, he says.
"They don't fly — they only crawl, and they'll pretty much stay in the same general area before dispersing."
Stinkbugs also can move into cotton from adjacent crops, says Smith. They can come out of wheat early in the growing season, from corn at mid-season and from peanuts later in the year. If cotton matures on time, peanuts probably won't be a problem, he adds. In addition, there can be three or more generations of stinkbugs per year.
Almost everyone, says Smith, uses the same threshold for sliced boll damage — 15 to 20 percent damage. "That may seem like a lot of bolls, but it's not all of the bolls in the field. It's just the ones that are quarter-sized in diameter during that particular week."
Smith says he disagrees with the other threshold measurement used by most states when sampling for immature or adult stinkbugs.
"Most states are using one per 6 row feet. If you calculate the number of row feet in an acre, this threshold translates into about 2,000 stinkbugs per acre. I don't think anyone with a reasonable knowledge of stinkbug damage would want to allow 2,000 stinkbugs per acre, especially considering the pest may live for two months. So, we're using one stinkbug per 20 row feet as our threshold in Alabama.
"Our growers need to be triggering quicker for stinkbug sprays. Basically, the damage is done from about the third week of bloom to maturity. That's a time period during which we're not so concerned with beneficial insects. We feel that many growers in Alabama are waiting too late before spraying for stinkbugs in an attempt to conserve beneficial insects. Once you spray for stinkbugs, you should get about two-plus weeks of control before another treatment is needed."
The stinkbug, says Smith, is one of the most inexpensive cotton insect pests to treat, with controls costing $3.50 to $4 per acre. "We can achieve nearly 100 percent control for the $3.50 to $4 per acre. At this price, we shouldn't be afraid to spray for stinkbugs."
Weather also can play a role in stinkbug damage, he says. "If we have a wet, humid fall, more of these stinkbug-damaged bolls will rot. If we have a perfect fall, we'll see less rot from stinkbug damage."
Phosphate insecticides are most effective on stinkbugs, he says. These include Bidrin, methyl parathion and the encapsulated methyl parathion Penncap-M. These products, says Smith, will give 95-plus percent control of stinkbugs. Pyrethroids do an adequate job, with about 80 percent control of the Southern green stinkbug.
e-mail: [email protected].


text:
Brand Names: Meridia
Generic Name: sibutramine (Pronunciation: si BUE tra meen)
- What is sibutramine (Meridia)?
- What are the possible side effects of sibutramine (Meridia)?
- What is the most important information I should know about sibutramine (Meridia)?
- What should I discuss with my healthcare provider before taking sibutramine (Meridia)?
- How should I take sibutramine (Meridia)?
- What happens if I miss a dose (Meridia)?
- What happens if I overdose (Meridia)?
- What should I avoid while taking sibutramine (Meridia)?
- What other drugs will affect sibutramine (Meridia)?
- Where can I get more information?
What is sibutramine (Meridia)?
Sibutramine was withdrawn from the U.S. market in October 2010.
Sibutramine affects chemicals in the brain that affect weight maintenance.
Sibutramine is used together with diet and exercise to treat obesity that may be related to diabetes, high cholesterol, or high blood pressure.
Sibutramine may also be used for other purposes not listed in this medication guide.
Meridia 10 mg
blue/white, imprinted with MERIDIA, 10
What are the possible side effects of sibutramine (Meridia)?
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.
Stop using sibutramine and call your doctor at once if you have a serious side effect such as:
- fast, pounding, or uneven heartbeats;
- new or worsening shortness of breath;
- agitation, hallucinations, fever, tremor, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, dilated pupils;
- very stiff (rigid) muscles, high fever, sweating, confusion, feeling like you might pass out;
- easy bruising or bleeding (nosebleeds, bleeding gums, or any bleeding that will not stop);
- dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, seizure);
- chest pain or heavy feeling, pain spreading to the arm or shoulder, general ill feeling; or
- sudden numbness or weakness (especially on one side of the body), problems with vision, speech, or balance.
Less serious side effects may include:
- dry mouth, upset stomach;
- changes in appetite;
- constipation, stomach pain;
- headache, back pain, joint pain;
- feeling nervous, dizzy, or depressed;
- flu symptoms, runny or stuffy nose, sore throat, cough;
- warmth, redness, or tingly feeling under your skin;
- trouble sleeping (insomnia); or
- mild skin rash.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What is the most important information I should know about sibutramine (Meridia)?
Sibutramine was withdrawn from the U.S. market in October 2010.
Do not use sibutramine if you have taken an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) in the last 14 days. Serious, life threatening side effects can occur if you use sibutramine before the MAO inhibitor has cleared from your body.
You should not take sibutramine if you are allergic to it, or if you have severe or uncontrolled high blood pressure, an eating disorder (anorexia or bulimia), if you are taking stimulant diet pills, or if you have a history of coronary artery disease, stroke, or heart disease.
Before taking sibutramine, tell your doctor if you have glaucoma, high blood pressure, liver or kidney disease, depression, underactive thyroid, seizures, a bleeding disorder, a history of gallstones, or if you are older than 65 or younger than 16.
Tell your doctor about all prescription and over-the-counter medications you use, especially antidepressants, cold or allergy medication, narcotic pain medicine, or migraine headache medicines.
Tell your doctor if you do not lose at least 4 pounds after taking the medication for 4 weeks along with a low calorie diet.
What should I discuss with my healthcare provider before taking sibutramine (Meridia)?
Do not use sibutramine if you have taken an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) in the last 14 days. Serious, life threatening side effects can occur if you use sibutramine before the MAO inhibitor has cleared from your body.
You should not take this medication if you are allergic to sibutramine, or if you have:
- severe or uncontrolled hypertension (high blood pressure);
- an eating disorder (anorexia or bulimia);
- a history of coronary artery disease (atherosclerosis);
- a history of heart disease (congestive heart failure, heart rhythm disorder);
- a history of heart attack or stroke; or
- if you are taking stimulant diet pills.
If you have any of these other conditions, you may need a sibutramine dose adjustment or special tests:
- glaucoma;
- high blood pressure;
- liver disease;
- kidney disease;
- depression;
- underactive thyroid;
- epilepsy or seizure disorder;
- a bleeding or blood clotting disorder;
- a history of gallstones; or
- if you are older than 65 or younger than 16.
FDA pregnancy category C. It is not known whether sibutramine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using sibutramine.
It is not known whether sibutramine passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.
Do not give this medication to anyone younger than 16 years old.
How should I take sibutramine (Meridia)?
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Sibutramine is usually taken once daily. Follow your doctor's instructions.
Your doctor may occasionally change your dose to make sure you get the best results.
Sibutramine can be taken with or without food.
You should lose at least 4 pounds during the first 4 weeks of taking sibutramine and eating a low calorie diet. Tell your doctor if you do not lose at least 4 pounds after taking the medication for 4 weeks.
Your blood pressure and pulse will need to be checked often. Visit your doctor regularly.
Sibutramine should not be taken for longer than 2 years.
Store at room temperature away from moisture, heat, and light.
Do not share sibutramine with another person. Keep the medication in a place where others cannot get to it.
What happens if I miss a dose (Meridia)?
Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.
What happens if I overdose (Meridia)?
Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.
Overdose symptoms may include headache, dizziness, and fast heart rate.
What should I avoid while taking sibutramine (Meridia)?
Sibutramine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.
Do not take any other prescription or over-the-counter weight-loss products without your doctor's advice.
Avoid taking cough and cold or allergy medications while taking sibutramine.
Avoid drinking alcohol while taking sibutramine.
What other drugs will affect sibutramine (Meridia)?
Before using sibutramine, tell your doctor if you regularly use other medicines that make you sleepy (such as cold or allergy medicine, sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by sibutramine.
Ask your doctor before taking any decongestants, cough medicine, or other diet pills.
The following drugs can interact with sibutramine. Tell your doctor if you are using any of these:
- lithium (Lithobid, Eskalith, and others);
- tryptophan or L-tryptophan;
- ketoconazole (Nizoral);
- an antibiotic such as erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin);
- an antidepressant such as citalopram (Celexa), desvenlafaxine (Pristiq), duloxetine (Cymbalta), fluoxetine (Prozac, Sarafem, Symbyax), paroxetine (Paxil), sertraline (Zoloft), venlafaxine (Effexor), and others;
- ergot medicine such as dihydroergotamine (D.H.E. 45, Migranal Nasal Spray), ergonovine (Ergotrate), ergotamine (Ergomar), or methylergonovine (Methergine).
- migraine headache medicine such as sumatriptan (Imitrex) or zolmitriptan (Zomig); or
- narcotic pain medication such as fentanyl (Actiq, Duragesic, Fentora, Onsolis), meperidine (Demerol), pentazocine (Talwin).
This list is not complete and other drugs may interact with sibutramine. Tell your doctor about all medications you use. This includes prescription, over the counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.
Where can I get more information?
Your pharmacist can provide more information about sibutramine.
Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.
Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.
Copyright 1996-2013 Cerner Multum, Inc. Version: 5.02. Revision date: 12/15/2010.
Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.


text:
Healthy Eating to Decrease StressSkip to the navigation
Topic Overview
You can handlestressbetter when you are as healthy as possible, so eating nutritiously is a good defense against stress. The tips below focus on using nutrition to reduce the symptoms of stress. For more information about eating right, see the topic Healthy Eating.
- Avoid or limit caffeine. Coffee, tea, some sodas, and chocolate contain caffeine. Caffeine causes you to feel "wound up," which can make stressful situations seem more intense. If you drink a lot of caffeine, reduce the amount gradually. Stopping use of caffeine suddenly can cause headaches and make it hard to concentrate.
- If you drink alcohol, do so in moderation. If you are feeling very stressed, you might be turning to alcohol for relief more often than you realize. If you drink, limit yourself to 2 drinks a day for men and 1 drink a day for women.
- Make mealtimes calm and relaxed. Try not to skip meals or eat on the run. Skipping meals can make stress-related symptoms worse. You may get a headache or a tight, tense feeling in your stomach. Eating on the run can cause indigestion. Use mealtime to relax, enjoy the flavor of your meal, and reflect on your day.
- Avoid eating to relieve stress. Some people turn to food to comfort themselves when they are under stress. This can lead to overeating and guilt. If this is a problem for you, try to replace eating with other actions that relieve stress, such as taking a walk, playing with a pet, or taking a bath.
Related Information
ByHealthwise Staff
Primary Medical Reviewer Kathleen Romito, MD - Family Medicine
Adam Husney, MD - Family Medicine
Specialist Medical Reviewer Christine R. Maldonado, PhD - Behavioral Health
Current as ofDecember 7, 2017
- Top of Page
Next Section:Related Information
Previous Section:Topic Overview
- Top of Page
Next Section:Credits
Previous Section:Related Information
- Top of Page
Current as of: December 7, 2017
This information does not replace the advice of a doctor. Healthwise, Incorporated, disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use. Learn how we develop our content.
To learn more about Healthwise, visit Healthwise.org.
© 1995-2018 Healthwise, Incorporated. Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.


text:
In the city that never sleeps there is always something new and amazing to discover. The list of activities is mind-boggling, not to mention exciting. Bike rides through Central Park, shopping in Times Square, the view from the 86th floor of the Empire State Building or eating your way through some of the many historic cafés, diners and five star restaurants. However you choose to explore the city do so with an open mind, you won't regret it!
Address New York, USAwork Phone: +1 (0)610 952 6245work Email: [email protected]INTERNET Visit Website


text:
The first feature length movie to focus on high school students forming a GSA.
Plot: Recently relocated from San Francisco to conservative suburbia by her lesbian mothers, Tru struggles like all teens to fit in and find love, but her quest is complicated by sexual politics, closed minds, and closeted friends as she seeks to establish her school's first Gay-Straight Alliance.
Cast: Najarra Townsend, Bruce Vilanch, Matthew Thompson, Alec Mapa, Jasmine Guy, Alexandra Paul, Cynda Williams, Jane Lynch, David Kopay
Director: Stewart Wade
See: More movie clips on Youtube
Buy: Get the "Tru Loved" DVD at Brownbag Productions and 10 percent of proceeds go to GSA Network when you select us as the beneficiary.
Coming Soon: Stage version of Tru Loved the play, along with a GSA Action and Campaign Guide. Check back soon!
Other Video Clips:
|Audience reactions to Tru Loved
Alec Mapa speaks about GSAs
Jane Lynch speaks about Tru Loved


text:
Professional AV Solutions
If the region in the support menu is incorrect, please select the
correct region below so we can provide appropriate contact information.
Flat Panel
Select Manufacturer
Don't see your model #?
If you don't know if this mount is compatible with your equipment use the MountFinder
Compatibility Check below.
Select Brand:
Products Compatible with


text:
SEATTLE — A newborn baby who died of whooping cough last week in King County was the first pertussis death in Washington since August 2011 and occurred even though the number of new cases in the epidemic is one-tenth of last spring's rate.
The Seattle-King County Health Department withheld details about Thursday's death for the family's privacy, but said it's a reminder that mothers and family members should be immunized to protect babies from pertussis.
There have been 4,658 cases of the disease in Washington this year through Saturday, said state Health Department spokesman Tim Church. That's the highest number since 1941.
With that many cases it's almost surprising there hasn't been a death until now.
"It's tragic to have a death," Church said Tuesday. "But with this number of cases it's not unexpected."
There were a total of two pertussis deaths in Washington in 2011 and two in 2010.
Health Secretary Mary Selecky declared this year's outbreak an epidemic April 3 and the number of cases peaked in May at more than 250 a week. Since then the number of new cases declined to about 25 a week in December — still at an epidemic level and about twice what would be considered normal in previous years.
"We're glad to see it's dropping, but it's more than we want to see," Church said.
Whooping cough mostly affects children, and 57 percent of the 2012 cases have been in school-age children, ages 5 to 18, who typically have a chronic cough with the "whooping" sound.
The disease is most severe in infants. Some infants are unable to cough. They may turn bluish and have trouble feeding. Nearly 400 cases have been in children under the age of 1. Of those more than 70 were hospitalized, the Seattle-King County Health Department reported.
Nationally, there have been more than 35,000 pertussis cases through mid-November and 16 deaths, mostly infants, according to the Centers for Disease Control and Prevention.
It takes a four-shot series of vaccine shots to immunize a baby in the first 18 months. That's when babies risk catching the disease from adults and why adults are encouraged to have booster shots.
Women should revaccinate with every pregnancy because some protection is passed from mother to child, the Seattle-King County department said.
"Assuring that all family members and other close contacts are up-to-date with the pertussis vaccine provides additional security or a 'cocoon' around vulnerable babies," the department said.
The disease is relatively mild in adults. Anyone with a cough should avoid infants.
-- The Associated Press


text:
Working with Students
Working with Students
The following is meant as a general guide for faculty and staff working with students with disabilities and provides information regarding arranging academic accommodations and communicating effectively. Remember, the AEC staff is here to support you. Please feel free to contact a AEC counselor with any questions or concerns you may have.
Communicating with Students with Disabilities
When students request an appointment to discuss any disability or accommodations related issues, encourage students to meet with you during office hours. Meeting in a more relaxed, one on one setting allows plenty of time to discuss matters in a private, comfortable, reduced distraction environment.
Treat students with disabilities as you would other students, speaking directly to the student in a normal tone and volume. Avoid making assumptions about a student's capabilities; students will make you aware if they require assistance or require a different mode of communication. Refer to the U.S. Department of Labor's disability etiquette publication or "Fast Facts for Faculty" for further information working with students with disabilities.
Under legal mandates and University policy governing confidentiality, faculty members are committed to confidentiality regarding information disclosed to them personally, on the test accommodation forms, or by other means of written or verbal communication. Confidentiality protection also applies to information gained through contacts with the AEC. Legally, students are not required to disclose the nature of their disability or to submit copies of disability documentation to other University departments or personnel after registering with the AEC.
Working with Students Using Testing Accommodations
For many students, well-executed accommodations mean the difference between success and failure. The following tips will assist you in partnering with the AEC to provide test accommodations on behalf of your students.
Accommodation forms must be signed by the professor at least five school days prior to the exam date. After signing a test accommodation form, the student is required to return the form to the AEC office.
Rescheduling an exam can only be done with the professor's approval. The professor may contact the AEC by phone for a verbal approval, memo, or email.
Professors are welcome to accommodate students themselves if they are able to provide the same prescribed accommodations as the AEC and the environment is conducive to testing (i.e., private room, muted phone, no traffic or conversations) can provide. If you are providing accommodations yourself, allow the student to see the testing area or accommodations (i.e., hardware/software, accessible furniture) ahead of time to determine whether they are effective.
As you will likely encounter students who use adaptive technology, alternative media, or testing services, you are encouraged to set up a time to tour the AEC's Testing Room in IS 223 or Center for Accessible Technology (CAT) in the MLK Library.
When working with those students who are Deaf or Hard of Hearing, you will be provided a copy of the Important Guidelines from the Interpreter/Captioner (PDF).
- For further information regarding testing accommodations, see the test accommodation webpage.
If you are presented with a Notetaker Request Memorandum, please check the memo for the method of securing a notetaker: 1) general announcement in-class, or 2) confidentially.
If confidentiality is the preferred method, AEC ask you speak directly with a fellow classmate to request assistance as a notetaker. When speaking with the potential notetaker it is important to be aware of your surroundings to maintain confidentiality; only state the requesting student's name when the fellow classmate agrees to be a notetaker.
If the preferred method is a general announcement in-class the AEC has provided you with language to assist in making the announcement; you will find this language in the Notetaker Request memo:
"A student in this class is in need of a notetaker. If you take clear, legible notes and are interested in being a notetaker, come up after class to meet the student. Notetakers are eligible for priority registration for the following semester.
AEC ask that you make an announcement to your classes during the first, second and third class meetings once the student presents you with the Notetaker Request Memo. If a fellow student does not volunteer after the second/third request contact AEC immediately for assistance. Volunteers should meet with the registered AEC student to receive priority registration information and make arrangements to exchange notes.
Classroom Concerns
If you are presented with a Notetaker Request Memorandum, please make an announcement to your classes during the first, second and third class meetings announcing the need for a student notetaker for students with disabilities. Volunteers should meet with the registered AEC student to receive priority registration information and make arrangements to exchange notes. The memo contains the following announcement:
"A student in this class is in need of a notetaker. If you take clear, legible notes and are interested in being a notetaker, come up after class to meet the student. Notetakers are eligible for priority registration for the following semester. A student taking notes on a laptop is prefered."
Referring Students to the AEC
Contrary to disability legislation governing secondary schools, disability laws at the postsecondary level forbid university faculty and staff from asking a student whether he or she has a disability. Therefore, should you suspect that a student may be struggling in your class due to a learning disability or could otherwise benefit from AEC services, present your concerns to the student using the following 5-step method:
- State what you have observed in the student's academic performance or classroom behavior: "I have noticed that essays seem difficult for you. Perhaps there is some difficulty expressing yourself in writing."
- Express a strength you have noticed: "I can tell that this class is important to you because you have good attendance and participation."
- State your motivation and concerns: "I'm concerned that your knowledge of the course materials is not being demonstrated in your written work and exams. Your success is important to me."
- Share a personal anecdote with the student: "I had an Economics course in college that was really difficult; I ended up having to retake the course to pass it."
- Invite the student to visit Admin 110 (AEC) to meet with someone: "There is an office on campus that performs various educational tests to identify areas of learning strength and weakness and provides academic services and accommodations for students who are eligible."