Chronicity factor, defined

COPD includes chronic bronchitis and emphysema. Chronic bronchitis is defined clinically as a chronic productive cough for at least 3 months in each of two consecutive years in a patient in whom other causes have been excluded.1 Emphysema is defined pathologically as the presence of permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis.1 The major risk factor for both conditions is cigarette smoking, and many patients share characteristics of each condition. Therefore, new consensus guidelines have moved away from using these subsets and instead focus on chronic airflow limitation. 

Tension-type headache (TTH) is the most common primary headache disorder. It is often underrepresented in clinical practice, as many patients do not present for care.6 The term tension-type headache is used to describe all headache syndromes in which muscle contraction is the most significant factor in the pathogenesis of pain. The 1-year prevalence of TTH in the population ranges from 30% to 90%.6 It is more common in adult females. Environmental factors, as opposed to genetic predisposition, play a more central role in their development. Tension-type headaches can be further divided into episodic or chronic the mean frequency of attacks is 3 days per month in episodic disorders, and chronic TTH is defined as 15 or more attacks in a 1-month period.7 The estimated prevalence of chronic TTH is less than 5%.6 Some researchers believe that chronic TTHs represent a continuum of headache severity with migraine headache.8 When severe headaches are difficult to differentiate clinically, treatment should initially target TTH. 

This gives an example of fate modeling in which the risks of an insect growth inhibitor, CGA-72662, in aquatic environments were assessed using a combination of the SWRRB and EXAMS mathematical models.. Runoff of CGA-72662 from agricultural watersheds was estimated using the SWRRB model. The runoff data were then used to estimate the loading of CGA-72662 into the EXAMS model for aquatic environments. EXAMS was used to estimate the maximum concentrations of CGA-72662 that would occur in various compartments of the defined ponds and lakes. The maximum expected environmental concentrations of CGA-72662 in water were then compared with acute and chronic toxicity data for CGA-72662 in fish and aquatic invertebrates in order to establish a safety factor for CGA-72662 in aquatic environments. 

Bronchial asthma is defined as a chronic inflammatory disease of the lungs it affects an estimated 9 to 12 million individuals in the U.S. Furthermore, its prevalence has been increasing in recent years. Asthma is characterized by reversible airway obstruction (in particular, bronchospasm), airway inflammation, and increased airway responsiveness to a variety of bronchoactive stimuli. Many factors may induce an asthmatic attack, including allergens respiratory infections hyperventilation cold air exercise various drugs and chemicals emotional upset and airborne pollutants (smog, cigarette smoke). 

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

WHO/IPCS (1994, 1996, 1999) did not consider an extrapolation factor for duration of exposure specifically, but the uncertainty related to this element is included in a broader defined additional factor addressing the adequacy of the overall database (Section 5.9). The US-EPA (1993) has adopted the 10-fold factor to account for the uncertainty involved in extrapolating from less than chronic NOAELs to chronic NOAELs. This default value has later on been reconfirmed (US-EPA 2002) when only a subchronic duration smdy is available to develop a chronic reference value no chronic reference value is derived if neither a subchronic nor a chronic smdy is available. For systemic effects, ECETOC (2001) recommended a default assessment factor of 6 for extrapolation from subacute (28 days) to chronic exposure, and a factor of 2 from subchronic (90 days) to chronic exposure. For local effects, no additional assessment factor is needed for duration of exposure extrapolation for substances with a local effect below the threshold of cytotoxicity. KEMl (2003) suggested that extrapolation from subchronic to chronic exposure should be based on the distribution of NOAEL ratios reported by Vermeire et al. (2001) with an assessment factor of 16 covering 95% of the substances compared and for extrapolation from subacute to chronic exposure, with an assessment factor of 39 covering 95% of the substances. 

Baird et al. (1996) suggested a probabilistic alternative to the practice used by the US-EPA to derive RfDs from a NOAEL and application of UFs. The probabilistic approach expresses the human population threshold for a given substance as a probability distribution of values, rather than a single RfD value, taking into account the major sources of scientific uncertainty in such estimates. The approach was illustrated by using much of the same data that US-EPA used to justify their RfD procedure. For the four key extrapolations that were considered necessary to define the human population threshold based on animal data (interspecies, interindividual, LOAEL-to-NOAEL, and subchronic-to-chronic), the proposed approach used available data to define a probability distribution of each adjustment factor, rather than using available data to define point estimates of UFs. 

Recent investigations into intracellular events have begun to define the postsynaptic events through which TCAs appear to exert their effects (Morinobu et ah, 1995). One of the observations made was down-regulation of transcription factors for early gene products such as c-Fos. C-Fos is normally produced in response to periods of stress. In research with rats, TCAs as well as other antidepressants have been shown to decrease the expression of c-Fos in areas of frontal cortex after chronic but not acute treatment. Other psychotropic medications (e.g., cocaine and haloperidol) with similar acute effects on norepinephrine/serotonin neurotransmission have not shown this same chronic effect. It has been speculated that the decreased production of c-Fos is the end product of a cascade of events stimulated by increased norepinephrine levels (Morinobu et ah, 1995). 

A poor diet is a major contributing factor to the etiology of chronic diseases such as heart disease and cancer.However, defining what constitutes a healthy diet remains contentious, as it is difficult to definitively ascribe beneficial and detrimental properties to the... 

An important outcome of the JECFA evaluation is the establishment of an ADI for a food additive. The ADI is based on the available toxicological data and the no adverse effect level in the relevant species. JECFA defines the ADI as an estimate of the amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk (8). JECFA utilizes animal data to determine the ADI based on the highest no-observed-adverse-effect level (NOAEL), and a safety factor is applied to the NOAEL to provide a margin of safety when extrapolating animal data to humans. JECFA typically uses safety factors of 50, 100, or 200 in the determination of an ADI. The NOAEL is divided by the safety factor to calculate the ADI. The food additive is considered safe for its intended use if the human exposure does not exceed the ADI on a chronic basis. This type of information may potentially be used to help assess the safety of a pharmaceutical excipient that is also used as a food additive, based on a comparison of the ADI to the estimated daily intake of the excipient. 

The financial cost of performing studies to define these toxicities increases according to their duration and complexity further, the rarer the occurrence of the effect anticipated, the greater will be the number of animals required for its detection. These several factors combine to ensure that very few chronic toxicity data are available for chemicals that fail to occupy key commercial or environmental positions. 

National Council on Alcoholism and Drug Dependence and the American Society of Addictive Medicine defines alcoholism as a chronic disease influenced by genetic, psychological, and environmental factors. Alcoholism is described as a loss of control over drinking—a preoccupation with drinking despite negative consequences to one s physical, mental, and emotional makeup as well as one s work and family life. 

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

Contrast-induced nephropathy has been defined as an increase in serum creatinine of at least 25% or an absolute increase in serum creatinine of at least 0.5 mg/dL within 48 to 72 hours of iodinated contrast administration and is associated with significant morbidity and mortality (75). Important risk factors include diabetes mellitus, chronic renal insufficiency, administration of large volumes of high osmolar contrast agents, and intravascular volume depletion. Numerous pharmacologic preventive measures have been studied, but consistent benefits have not been demonstrated. In a recent large retrospective study, preprocedural statin therapy was independently associated with a lower risk of contrast nephropathy and nephropathy requiring dialysis (76). 

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