Dose-response relationship measurement

The conceptual foundation of the system is first established by addressing such issues as its focus, dose-response relationships, measures of response, and the applicable risk management paradigm ... 

The dose-response relationship measures the correlation that occurs as one modifies the amount (dose) of a chemical substance to which a living material is exposed and the severity of the effect (response). This is commonly used with pharmaceuticals to determine the most effective amount of medication to be administered to have the desired beneficial effect. If the amount of medicine administered is too small (below the therapeutic level), the intended beneficial effect does not occur if the dose is increased and the amount administered is too large (above therapeutic range) toxicity may become evident. Toxicologists hold that the dose-response relationship applies not only to therapeutic agents but also to all chemical substances, that is, the dose makes the poison . The underlying principal is that the biological effects (beneficial or deleterious) of chemicals are due to the amounts of active material at the site, or sites, of action and that the concentration or the amount of the substance at the site (internal dose) is related to the amount of chemical administered (external dose). 

The aroma of fmit, the taste of candy, and the texture of bread are examples of flavor perception. In each case, physical and chemical stmctures ia these foods stimulate receptors ia the nose and mouth. Impulses from these receptors are then processed iato perceptions of flavor by the brain. Attention, emotion, memory, cognition, and other brain functions combine with these perceptions to cause behavior, eg, a sense of pleasure, a memory, an idea, a fantasy, a purchase. These are psychological processes and as such have all the complexities of the human mind. Flavor characterization attempts to define what causes flavor and to determine if human response to flavor can be predicted. The ways ia which simple flavor active substances, flavorants, produce perceptions are described both ia terms of the physiology, ie, transduction, and psychophysics, ie, dose-response relationships, of flavor (1,2). Progress has been made ia understanding how perceptions of simple flavorants are processed iato hedonic behavior, ie, degree of liking, or concept formation, eg, crispy or umami (savory) (3,4). However, it is unclear how complex mixtures of flavorants are perceived or what behavior they cause. Flavor characterization involves the chemical measurement of iadividual flavorants and the use of sensory tests to determine their impact on behavior. 

If possible, there should be measurement of the toxic effect in order quantitatively to relate the observations made to the degree of exposure (exposure dose). Ideally, there is a need to determine quantitatively the toxic response to several differing exposure doses, in order to determine the relationship, if any, between exposure dose and the nature and magnitude of any effect. Such dose—response relationship studies are of considerable value in determining whether an effect is causally related to the exposure material, in assessing the possible practical (in-use) relevance of the exposure conditions, and to allow the most reasonable estimates of hazard. 

Reproductive Toxicity. No data are available that impHcate either hexavalent or trivalent chromium compounds as reproductive toxins, unless exposure is by way of injection. The observed teratogenic effects of sodium dichromate(VI), chromic acid, and chromium (HI) chloride, adininistered by injection, as measured by dose-response relationships are close to the amount that would be lethal to the embryo, a common trait of many compounds (111). Reported teratogenic studies on hamsters (117,118), the mouse (119—121), and rabbits (122) have shown increased incidence of cleft palate, no effect, and testicular degeneration, respectively. Although the exposures for these experiments were provided by injections, in the final study (122) oral, inhalation, and dermal routes were also tried, and no testicular degeneration was found by these paths. 

Bonithon-Kopp et al. (1986b) investigated another potential marker for lead exposure. Maternal and infant hair lead levels, determined from hair samples taken at birth, were found to be correlated inversely with results on neurobehavioral tests (McCarthy Scales of Children s Abilities) when the children were tested at 6 years of age. Other studies have also reported associations between hair lead levels and behavioral or cognitive test scores, but measures of lead in hair may not accurately reflect internal body burden of lead, and such data should not be used to evaluate internal dose-response relationships (EPA 1986a). 

To study the effect of PGDN on cerebral blood flow, Godin et al. (1995) injected male Sprague-Dawley rats (through a jugular vein cannula) with PGDN at 0.1 to 30 mg/ kg and measured cerebral blood flow with a fiberoptic laser-Doppler flow probe in contact with the brain. Following a small initial drop in cerebral perfusion that lasted 1 min, blood flow rapidly increased and reached a maximum 2 min after injection. The increase in perfusion was correlated with dose, but due to the small number of animals and individual variability, a clear dose-response relationship was not obtained. 

Effect of Dose and Duration of Exposure on Toxicity. No studies were located where -hexane concentration was measured in workplace air before workers became ill, so no dose-response relationship can be defined for human neurotoxicity as the result of -hexane exposure. Information on duration of exposure leading to toxicity is available from some case series reports. An occupational exposure caused sensory disturbances in the lower extremities after approximately 2 months (Herskowitz et al. 1971). A case of peripheral neuropathy after 7 months of exposure was reported among press-proofing workers in Taipei (Wang et al. 1986) a serious case resulting in quadriplegia after 8 months of exposure was reported among sandal workers in Japan (Yamamura 1969). Based on case reports, it can be estimated... 

Ideal for studying the dose-response relationship for QT interval prolongation taking into account all the pharmacological properties of a compound The dog model is one of the most widely used anesthetized rabbits (especially female rabbits) have also been proposed for high sensitivity It provides complementary information with respect to in vitro tests (activity of metabolites, measurement of plasma drug concentrations, calculation of the volume of distribution) Possibility to induce experimental TdP... 

Phenol can also be measured in the urine after oral exposure, although a dose-response relationship between oral exposure to phenol and phenol in the urine has not been established. In persons not exposed to phenol or benzene, the total phenol concentration in the urine does not exceed 20 mg/L and is usually <10 mg/L (ACGIH 1998). 

Exposure. Measurement of total phenol in the urine is the most useful biomarker following inhalation exposure to phenol (ACGIH 1991). The test is nonspecific and should not be used when workers are exposed to benzene, to household products, or to medications containing phenol. Dermal exposure may also result in overestimation of inhalation exposure. In persons not exposed to phenol or benzene, the total phenol concentration in the urine does not exceed 20 mg/L and is usually <10 mg/L (ACGIH 1991). Phenol can also be measured in the urine after oral exposure, although a dose-response relationship between oral exposure to phenol and phenol in the urine has not been established. Benzene metabolism yields not only phenol, 1,4-dihydroxybenzene, and their sulfates and glucuronides, but also the benzene-... 

Pharmacokinetics has played a crucial and somewhat unusual role in the assessment of health risks from methylmercury. Some of the epidemiology studies of this fish contaminant involved the measurement of mercury levels in the hair of pregnant women, and subsequent measurements of health outcomes in their offspring (Chapter 4). Various sets of pharmacokinetic data allowed estimation of the level of methylmercury intake through fish consumption (its only source) that gave rise to the measured levels in hair. In this way it was possible to identify the dose-response relationship in terms of intake, not hair level. Once the dose-response relationship was established in this way, the EPA was able to follow its usual procedure for establishing an RfD (which is 0.1 ag/(kg b.w. day)). 

We designed our studies to establish potency, onset and duration of physiological and cognitive effects, dose/response relationships, and methods of treatment. For compounds of greatest interest, we measured the relative effectiveness by various routes of administration. 

Heagle and associates found a reduction in yield of sweet com and soybean after exposure to ozone at 0.10 ppm for 6 h/day over much of the growing season. These exposures were carried out in field chambers set over soybean plots in the field. They suggested that a threshold for measurable effects on these crops would lie between ozone (oxidant) concentrations of 0.05 and 0.10 ppm for 6 h/day. These values are realistic in terms of growing-season averages in the eastern United States. More of these studies could help to clarify dose-response relationships for economically important crops. Table 11-5 summarizes these long-term, chronic studies. 

S Dose levels in vivo It is necessary to define the dose-response relationship of any adverse effects observed. The onset and duration of effects should be measured. Because there are differences in sensitivity between species, the doses chosen need to exceed those used for therapy. The ICH guideline states that the highest dose tested should be a dose that produces moderate adverse effects, for example, dose-limiting pharmacodynamic effects or other toxicities. Such effects should not be so severe that they confoimd the interpretation of the results being sought. Safety pharmacology studies... 

An important qualification must be made. While a biomarker may be of proven value in establishing whether a drug has the desired effect in patients or healthy volunteers (see Section 4.6.3) and for evaluation of the dose-response relationship, a biomarker may not be a surrogate for the clinical endpoint. Thus, suppression of testosterone after an initial rise will give an almost immediate endpoint for the effect of GnRH analogues in prostate cancer but the relationship breaks down later in the disease. Measures of blood glucose control are vital... 

The first step in these studies has been the search for the shortest fragment of the ACTH chain that is essential for (maintenance of) activity. Next, changes in the peptide backbone and modification of the side-chains of the amino acid residues have been studied. As a test system the delay of extinction of an active avoidance response in rats as measured in a pole-jumping test after subcutaneous administration has been used (7 ) this assay method gives a graded dose-response relationship which allows the estimation of an ED50 and thus potency ratio s. The heptapeptide ACTH--(4-10) has been used as the reference peptide (8 ). For a more extensive review see ref. 9. 

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