Dose-response evaluation

Dose—response evaluation is used in describing the quantitative relationship between the amount of exposure to a substance and the extent of toxic injury or disease. Data may be derived from animal studies or from studies in exposed human populations. Dose—response toxicity relationship for a substance varies under different exposure conditions. The risk of a substance can not be ascertained with any degree of confidence unless... 

Risk characterization is defined as the integration of the data and analysis of the above three components to determine the likelihood that humans wiU. experience any of the various forms of toxicity associated with a substance. When the exposure data are not available, hypothetical risk is characterized by the integration of hazard identification and dose—response evaluation data. 

Dose-Response Evaluation The process of quantitatively evaluating toxicity information and characterizing the relationship between the dose a contaminant administered or received, and the incidence of adverse health effects in the exposed population. From a quantitative dose-respoiise relationship, toxicity values can be derived that are used in the risk characterization step to estimate the likelihood of adverse effects occurring in humans at different exposure levels. 

We can now proceed to demonstrate how scientific information and the regulatory defaults of Table 8.2 can be applied. It is useful and important to separate the dose-response evaluations into those used for substances that produce their toxic effects through threshold mechanisms, as these terms were described or used in Chapters 3 and 6, and those that may involve no-threshold mechanisms. As a practical matter, only carcinogens have, to date, been treated as belonging in the latter category. 

Kirk T, Roache JD, Griffiths RR. Dose-response evaluation of the amnestic effects of triazolam and pentobarbital in normal subjects. J Clin Psychopharmacol 1990 10 161-168. 

The evaluation of dose-response relationships is a critical component of hazard characterization (OECD, 1989 ECETOC, 1992 US , 1997a IPCS, 1999). Evidence for a dose-response relationship is an important criterion in establishing a toxic reproductive effect. It includes the evaluation of data from both human and laboratory animal studies. Because quantitative data on human dose-response relationships are infrequently available, the dose-response evaluation is usually based on the assessment of data from tests performed using laboratory animals. However, if data are available in humans with a sufficient range of doses, dose-response relationships in humans can also be evaluated. 

PB-PK modelling allows further refinement of the dose-response evaluation by partitioning the relationship into pharmacokinetic (exposure vs. tissues dose) and pharmacodynamic (tissue dose vs. toxic response) components. This allows the uncertainties associated with each component to be assessed separately and adds accuracy to the overall animal to man extrapolation. Future developments of PB-PK modelling may allow specific sub-populations such as the newborn or individuals with metabolic variations to be taken into account. However, before this can be done there will need to be considerable growth in the amounts of physiological, pharmacokinetic and pharmacodynamic information available. 

When sufficient data are available, use of the benchmark dose (BMD) or benchmark concentration (BMC) approach is preferable to the traditional health-based guidance value approaches (IPCS, 1999a, 2005 USEPA, 2000 Sonich-Mullin et al 2001). The BMDL (or BMCL) is the lower confidence limit on a dose (the BMD) (or concentration, BMC) that produces a particular level of response or change from the control mean (e.g. 10% response rate for quantal responses one standard deviation from the control mean for a continuous response) and can be used in place of the NOAEL. The BMD/BMC approach provides several advantages for dose-response evaluation 1) the model fits all of the available data and takes into account the slope of the dose-response curve 2) it accounts for variability in the data and 3) the BMD/BMC is not limited to one experimental exposure level, and the model can extrapolate outside of the experimental range. 

Once an assessment has determined that the data indicate human risk potential, the next step is to perform a quantitative evaluation. Here, dose-response data from human and animal reproductive and developmental toxicity studies are analyzed to select LOAELs and NOAELs or to calculate a BMD. The assessment should use quantitative human dose-response data if the data span a sufficient range of exposure. Because data on human dose-response relationships are rarely available, the dose-response evaluation is usually based on an assessment of data from tests performed in experimental animals. 

The dose-response evaluation defines the range of doses that produce reproductive and developmental toxicity, the routes of exposure, the timing and duration of exposure, the species specificity of effects, and any pharmacokinetic or other considerations that might influence comparison with human exposure. Much of the focus is on identification of the adverse effect observed at the LOAEL and the NOAEL for the study. 

Because the literature describes several limitations in the use of NOAELs (Gaylor 1983 Crump 1984 Kimmel and Gaylor 1988), the evaluative process considers other methods for expressing quantitative dose-response evaluations. In particular, the BMD approach originally proposed by Crump (1984) is used to model data in the observed range. That approach was recently endorsed for use in quantitative risk assessment for developmental toxicity and other noncancer health effects (Barnes et al. 1995). The BMD can be useful for interpreting dose-response relationships because it accounts for all the data and, unlike the determination of the NOAEL or LOAEL, is not limited to the doses used in the experiment. The BMD approach is especially helpful when a NOAEL is not available because it makes the use of a default uncertainty factor for LOAEL to NOAEL extrapolation unnecessary. 

The UEL for reproductive and developmental toxicity is derived by applying uncertainty factors to the NOAEL, LOAEL, or BMDL. To calculate the UEL, the selected UF is divided into the NOAEL, LOAEL, or BMDL for the critical effect in the most appropriate or sensitive mammalian species. This approach is similar to the one used to derive the acute and chronic reference doses (RfD) or Acceptable Daily Intake (ADI) except that it is specific for reproductive and developmental effects and is derived specifically for the exposure duration of concern in the human. The evaluative process uses the UEL both to avoid the connotation that it is the RfD or reference concentration (RfC) value derived by EPA or the ADI derived for food additives by the Food and Drug Administration, both of which consider all types of noncancer toxicity data. Other approaches for more quantitative dose-response evaluations can be used when sufficient data are available. When more extensive data are available (for example, on pharmacokinetics, mechanisms, or biological markers of exposure and effect), one might use more sophisticated quantitative modeling approaches (e.g., a physiologically based pharmacokinetic or pharmacodynamic model) to estimate low levels of risk. Unfortunately, the data sets required for such modeling are rare. 

A quantitative approach was taken to evaluate the effect of various concentrations of water extracts of the two crosslinked solids and individual liquid components on cell growth of L-929 cells in vitro. Both cells and adhesive materials were prepared as described above. For this assay, dilutions of an aqueous extract of the solids were prepared for a dose-response evaluation. The following weight per volume ratios were used 4,000, 500, 100, 50, 4, 3, 2, 1 fig per 20-mL water. Extraction was performed for 4 hr at 60 °C followed by 20 hr at room temperature. Supernatants were transferred to clean containers. The negative control consisted of sterile, triple distilled water, and the positive control was 40 mg/mL dextran sulfate. 

Hassan PC, Sproule BA, Naranjo CA, Herrmann N. Dose-response evaluation of the interaction between sertraline and alprazolam in vivo. J Clin Psychopharmacol 200020(2) 150-8. 

In general, data from studies in humans are preferred to animal data for purposes of hazard and dose-response evaluation. 

In the absence of human data, or when the available human data are insufficiently quantitative or are insufficiently sensitive to rule out risks, animal data will be used for hazard and dose-response evaluation. 

The extrapolations from mouse-to-man described in earlier chapters are primarily qualitative in nature, not quantitative. In the context of dose—response evaluations, quantitative extrapolation might concern, for example, estimation of the size of the minimum toxic dose in humans based on observations of the size of that dose in rodents or monkeys. This is trickier, by far, than the type of qualitative extrapolation involved in limited statements such as observations of nervous system toxicity in Fischer strain rats are applicable to human beings. The twin problems of Interspecies and High-to-Low Dose Extrapolations each has several sets of associated issues, so we shall deal with them one at a time, in as simple a way as possible. 

Because we know that the nature, severity, and risk of toxicity vary with dose, the next step in a risk assessment is the dose—response evaluation. For each of the established forms of toxicity caused by the chemical of interest, what is the quantitative relationship between dose and risk of toxicity in the range of doses that have been or might be experienced by human beings ... 

These three steps — hazard evaluation, dose-response evaluation, and human exposure evaluation - provide all that is necessary to... 

The U.S. EPA applies an alternative dose-response evaluation of carcinogens using a low-dose, linear model (EPA 2005). The linear extrapolation is applied under two circumstances (1) when there are data to indicate that the dose-response curve has a linear component below the point of departure or (2) as a default for a tumor site where the mode of action is not established. For a linear extrapolation, a straight line is drawn from the point of departure to the origin. The slope of the line, known as the slope factor, is an upper-bound estimate of risk per increment of dose that can be used to estimate risk probabilities for different exposure levels. The slope factor is equal to 0.01/LEDoi, for example, if the LEDqi is used as the point of departure. The lower hmit on effective doscoi (LEDoi) is the 95% lower confidence hmit of the dose of a chemical needed to produce an adverse effect in 1% of those exposed to the chemical, relahve to control. If, however, there are sufficient data to ascertain that a chemicaTs mode of action supports modeling at low doses, a reference dose or concentrahon may be developed in lieu of a cancer slope factor. 

The second step, termed dose-response evaluation, involves Identifying the observed quantitative relationship between exposure and risk, and extrapolating from the conditions of exposure for which data exist to other conditions of Interest( ). This step almost always Involves high-to-low dose extrapolation and frequently Involves extrapolation from experimental animals to humans. This step requires the assumption that dose-response relations do not simply disappear at the detection limit of our experimental or epidemiologic systems. It also requires that a biologically plausible... 

Handley, D.A. Tinkelman, D. Noonan, M. Rollins, T.E. Snider, M.E. Caron, J. Dose-response evaluation of levalbuterol versus racemic albuterol in patients with asthma. J. Asthma 2000, 37, 319-327. 

If ingested at a concentration of 0.15 mg/kg bw/day, DON is able to cause vomiting in swine, while it has been estimated that levels up to 1—2 mg/kg in the diet can cause partial feed refusal in livestock, mainly pigs. Unfortunately, an accurate acute dose—response evaluation in humans has not been reported so far. However, it has been possible to ascribe the induction of acute gastroenteritis to vomiting in both mammals and humans to... 

Thus, the distinction between the hazard (an inherent toxic property of a chemical that may or may not be manifested, depending on exposure potential) and risk (the consequences of being exposed to a hazardous chemical at a particular exposure level) is critical (Purchase, 2000). Each component of a risk assessment—hazard identification, dose-response evaluation, and exposure assessment—is essential for evaluating the potential risks associated with the use of a substance such as a nanomaterial. The components of a risk assessment are universal in their application for assessing the hazards and risks of chemicals or products for a variety of industries or environmental exposures, regardless of the types of chemicals of interest (such as solvents, fibers, particulates and nanomaterials). 

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