Assessment dose-response

Categorization of the health-related database3 Sufficient evidence 

The sufficient evidence category includes data that collectively provide enough information to judge whether or not a human developmental hazard could exist within the context of dose, duration, timing, and route of exposure. This category may include both human and experimental animal evidence. 

This category includes data from epidemiological studies (e.g. case-control and cohort) to provide convincing evidence for the scientific community to judge that a causal relationship is or is not supported. A case-series in conjunction with strong supporting evidence may also be used. Supporting animal data may or may not be available. 

Sufficient experimental animal evidence — Limited human data 

This category includes agents for which there is less than the minimum sufficient evidence necessary for assessing the potential for developmental toxicity, such as when no data are available on developmental toxicity, as well as for databases from studies in animals or humans that have a limited study design (e.g. small numbers, inappropriate dose selection/exposure information, other uncontrolled factors), or data from a single species reported to have no adverse developmental effects, or databases limited to information on structure/activity relationships, shortterm tests, pharmacokinetics, or metabolic precursors. 

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TToxidty assessment hazard identification and dose-response assessment... 

Most human or environmental healtli hazards can be evaluated by dissecting tlie analysis into four parts liazard identification, dose-response assessment or hazard assessment, exposure assessment, and risk characterization. For some perceived healtli liazards, tlie risk assessment might stop with tlie first step, liazard identification, if no adverse effect is identified or if an agency elects to take regulatory action witliout furtlier analysis. Regarding liazard identification, a hazard is defined as a toxic agent or a set of conditions that luis the potential to cause adverse effects to hmnan health or tlie environment. Healtli hazard identification involves an evaluation of various forms of information in order to identify the different liaz.ards. Dose-response or toxicity assessment is required in an overall assessment responses/cffects can vary widely since all chemicals and contaminants vary in their capacity to cause adverse effects. This step frequently requires that assumptions be made to relate... 

The health risk evaluation process consists of four steps hazard identification, dose-response assessment or hazard assessment, exposure assessment, mid risk cliaracterization. 

In dose-response assessment, effects are evaluated and these effects vary widely because tlieir capacities to cause adverse effects differ. 

Dose-response assessment is the process of characterizing the relationship between the dose of an agent administered or received and the incidence of an adverse health effect in e.xposed populations, and estimating the incidence of the effect as a function of e.xposure to the agent. This process considers such important factors as intensity of exposure, age pattern of exposure, and possibly other variables that might affect response, such as sex, lifestyle, and other modifying factors. 

Altliough the technical conununity has come a long way in understanding how to do a better job in luizard identification, dose-response assessment, and exposure assessment portions of risk assessment, it lias only begun to understand how to best cluiractcrize hcaltli risks and how to present tliese risks most appropriately to both the public and decision makers. Tlie next tliree sections specifically address tlicse issues. Tliis section deals witli qualitative risk assessment while tlie next two sections deal witli quantitative risk assessment. 

Dose-response assessment is the process of obtaining quantitative information about the probability of human illness following exposure to a hazard it is the translation of exposure into harm. Dose-response curves have been determined for some hazards. The curves show the relationship of dose exposure and the probabihty of a response. Since vahdated dose-response relationships are scarce, various other inputs are used to underpin the hazard characterization phase of risk assessment. 

Studies in rodents, dogs, and non-human primates have demonstrated all of the major types of health effects of lead that have been observed in humans, including cardiovascular, hematological, neurodevelopmental, and renal effects (EPA 1986a). These studies also provide support for the concept of blood lead concentration as a metric of internal dose for use in dose-response assessments in humans. 

The analysis of chemical risk is a process comprising the following elements hazard identification, exposure assessment, dose-response assessment, and risk characterization [6]. Figure 1 shows the main elements that constitute the risk characterization process together the methodologies used for their determination. The essence of risk characterization is to relate the exposure (the concentration of a... 

Hazard characterization (or dose-response assessment) is the qualitative and, as far as possible, quantitative description of the inherent properties of an agent or situation having the potential to cause adverse effects. This step should include a dose-response assessment that describes the severity of adverse effects (the responses) related to the amount and condition of exposure to an agent (the dose). 

EUSES. As in the case of USEtox model, the present model provides outputs such as human intake fraction of a certain substance for different exposure pathways. In the present case study, estimation of the human intake doses for Guiyu was calculated. These results were compared with the incidence and severity of the effects (dose-response assessment). 

Risk Assessment The scientific process of evaluating the toxic properties of a chemical and the conditions of human exposure to it, in order to ascertain the likelihood that exposed humans will be adversely affected, and to characterize the nature of the effects they may experience. It may contain some or all of the following four steps hazard identification, dose-response assessment, exposure assessment, and risk characterization. 

Acknowledging the possible existence of deviations, this simplified approach of using C and t for dose determination provides that basis for dose-response assessments in practically all inhalation toxicological studies. 

Within the framework depicted in Figure 7.1, the content of risk assessment proposed by the committee is shown as comprising four analytic steps hazard identification, dose-response assessment, human exposure assessment, and a final, integrating step called risk characterization. These four terms and the activities they describe have come to be widely accepted within the risk assessment community, on... 

As has been emphasized so many times in the preceding chapters, these various manifestations of toxicity all display dose-response characteristics, where by response we refer to the incidence or severity of specific adverse health effects. As we demonstrated in earlier chapters, toxic responses increase in incidence, in severity, and sometimes in both, as dose increases. Moreover, just below the range of doses over which adverse effects can be observed, there is usually evidence for a threshold dose, what we have called the no-observed adverse effect level (NOAEL). The threshold dose must be exceeded before adverse effects become observable (Chapter 3). Deriving from the literature on toxic hazards, descriptions of the dose-response relationships for those hazards comprise the dose-response assessment step of the four-step process. 

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

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 identification and dose-response assessment. 

Assessment of environmental and health risks is based on the dose-response assessment and also on the systematic estimation of the exposure levels along the various exposure pathways. 

Dose-response assessment is the second of four steps in risk assessment. 

The Risk Assessment process includes four steps hazard identification, hazard characterization (related term dose-response assessment), exposure assessment, and risk characterization. It is the first component in a risk analysis process. 

Hazard characterization, also known as dose-response assessment, is the second stage in hazard assessment, and the second step in the process of risk assessment. At this step, the No-Observed-Adverse-Effect Level (NOAEL) and the Lowest-Observed-Adverse-Effect Level (LOAEL) are derived for the observed effects, where possible and appropriate. 

One important aspect in the dose-response assessment is the shape of the dose-response curve. For certain effects, the dose should be increased considerably for a response to occur and the dose-response curve will in such cases be rather shallow as illustrated by curve C in Figure 4.5. For other types of effects, even a small increase in the dose results in a marked response and the dose-response curve will in such cases be rather steep as illustrated by curves A and B in Figure 4.5. It should be noted, however, that in general, there is no direct correlation between the shape of the dose-response curve and the severity of the effect, i.e., a steep dose-response curve does not necessarily implicate a severe effect and vice versa. 

However, in addition to the dose levels at which the various effects are observed as well as to the steepness of the dose-response curve, the type of the various effects observed is also a very important aspect in the dose-response assessment. If effect A is an alteration in an unspecihc liver enzyme blood level, effect B is an increase in the relative liver weight, and effect C is the incidence of liver tumors, then both effects B and C obviously are evaluated as being more severe effects than effect A i.e., an example of an exception from situation 1 and 3 above. Similarly, effect C is evaluated as being more severe than effect B i.e., an example of an exception from situation 2 above. 

It is recognized that the NOAEL derived by using this traditional approach for dose-response assessment is not very accurate with respect to the degree to which it corresponds with the (unknown) tme NAEL. Furthermore, in this traditional approach, only the data obtained at one dose (NOAEL) are used in the hazard assessment rather than the complete dose-response data set. In case sufficient data are available, the shape of the dose-response curve should be taken into account in the hazard assessment. In the case of a steep dose-response curve, the derived NOAEL can be considered as more reliable because the greater the slope, the greater the reduction in response to reduced doses. In the case of a shallow dose-response curve, the uncertainty in the derived NOAEL may be higher and this has to be taken into account in the hazard assessment (see Section 5.7). If a LOAEL has to be used in the hazard assessment, then this value can only be considered reliable in the case of a very steep dose-response curve. 

The concept of the Benchmark Dose (BMD), a benchmark is a point of reference for a measurement, in health risk assessment of chemicals was first mentioned by Crump (1984) as an alternative to the NOAEL and LOAEL for noncancer health effects in the derivation of the ADI/TDI these terms are addressed in detail in Chapter 5. The BMD approach provides a more quantitative alternative to the dose-response assessment than the NOAEL/LOAEL approach. The goal of the BMD approach is to define a starting point of depariure (POD) for the establishment of a tolerable exposure level (e.g., ADI/TDI) that is more independent of the study design. In this respect, the BMD approach is not... 

A recently pubhshed WHO/IPCS document regarding chemical-specific adjustment factors for interspecies differences and human variability (WHO/IPCS 2005) provides guidance for use of toxicokinetic data in dose-response assessment to develop the so-called Compound-Specific Assessment Factors (CSAFs) (Section 5.2.1.12). 

The TGD (EC 2003), Chapter 3.6, addresses acute toxicity, provides guidance on data requirements, evaluation of data, and dose-response assessment for acute toxicity. 

Any test of skin sensitizing capabUity that includes dose-response assessment can be used to assess potency. Even though potency cannot be directly derived from human elicitation data, a low ehcitation threshold is suggestive of a high potency. Where possible, attempts should be made to use clinical data for quantitative risk assessment. ... 

In addition, human data adequate to serve as the sole basis for the dose-response assessment are rare. In many human studies, the circumstances of exposure and the exposure levels themselves are not well known, mixed exposure may have occurred, the incidence of effects is low, the number of exposed individuals is small, and the latency period between exposure and disease may be long. 

For threshold carcinogens, it is possible to identify a NOAEL for the underlying toxicity responsible for tumor formation. The following general guidance is provided for the dose-response assessment for non-genotoxic (threshold) carcinogens (EC 2003). The dose-response assessment for the relevant tumor types is performed in a two-step process. 

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