Dose-response relationship risk characterization

As described in a highly referenced document (NRC, 1983), important components of this process include hazard identification, assessment of exposure and dose-response relationships, and characterization of the risk. Uncertainty factors are built into the risk assessment process to account for variations in individual susceptibility, extrapolation of data from studies in laboratory animals to humans (i.e. interspecies variation in toxicokinetics), and extrapolation from high-dose to low-dose exposures. In the case of the association between exposure to chemicals and drugs and autoimmunity or autoimmune diseases, much of the information needed to evaluate risk in the context of the traditional United States National Research Council paradigm is not available. The following represents a discussion of issues in chemical-induced autoimmunity relevant to the use of existing data and data needs in risk assessment. 

Hazard characterization and delineation of dose-effect or dose-response relationships. 3. Assessment of exposure 4. Risk characterization... 

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 using the inhalation route might be useful to determine the potential human health risk in populations that may be occupationally exposed to hexachloroethane vapors for long periods. Additional chronic oral studies may be useful to help further clarify the dose-response relationships and better characterize thresholds. Studies by the dermal route would not be useful until the rate and extent of absorption have been better characterized. 

Decision Analysis. An alternative to making assumptions that select single estimates and suppress uncertainties is to use decision analysis methods, which make the uncertainties explicit in risk assessment and risk evaluation. Judgmental probabilities can be used to characterize uncertainties in the dose response relationship, the extent of human exposure, and the economic costs associated with control policies. Decision analysis provides a conceptual framework to separate the questions of information, what will happen as a consequence of control policy choice, from value judgments on how much conservatism is appropriate in decisions involving human health. 

Our assignment for EPA was to apply quantitative risk analysis methods to the determination of risk for a particular chemical. The health risks for perchloroethylene turned out to be highly uncertain, but by using decision analysis concepts we were able to display this uncertainty in terms of alternative assumptions about the dose response relationship. Similar methods might be used to characterize uncertainties about human exposure to a chemical agent or about the costs to producers and consumers of a restriction on chemical use. 

Since risk analysis plays an important role in public policy decision making, efforts have been made to devise a means by which to identify, control, and communicate the risks imposed by agricultural biotechnology. A paradigm of environmental risk assessment was first introduced in the United States by Peterson and Arntzen in 2004. In this risk assessment, a number of assumptions and uncertainties were considered and presented. These include (1) problem formulation, (2) hazard identihcation, (3) dose-response relationships, (4) exposure assessment, and (5) risk characterization. Risk assessment of plant-made pharmaceuticals must be reviewed on a case-by-case basis because the plants used to produce proteins each have different risks associated with them. Many plant-derived biopharmaceuticals will challenge our ability to define an environmental hazard (Howard and Donnelly, 2004). For example, the expression of a bovine-specihc antigen produced in a potato plant and used orally in veterinary medicine would have a dramatically different set of criteria for assessment of risk than, as another example, the expression of a neutralizing nonspecihc oral antibody developed in maize to suppress Campylobacter jejuni in chickens (Peterson and Arntzen, 2004 Kirk et al., 2005). 

Risk assessment An empirically based paradigm that estimates the risk of adverse effects) from exposure of an individual or population to a chemical, physical or biological agent. It includes the components of hazard identification, assessment of dose-response relationships, exposure assessment and risk characterization. 

Risk assessment The evaluation of scientific information on the hazardous properties of environmental agents (hazard characterization), the dose-response relationship (dose-response assessment), and the extent of human exposure to those agents (exposure assessment). 

In characterizing the database, a number of assumptions are applied when data are not available or are incomplete (USEPA, 1991 IPCS, 2005 Kimmel et al., 2006). These include uncertainties about toxicokinetics, mechanism of action, low-dose-response relationships, and human exposure patterns. Each of these assumptions is supported to some extent by the scientific literature. The following assumptions are generally accepted in risk assessment strategies ... 

Identifying dose-response relationships is an important component of any risk assessment. This process establishes the exposure levels that produce effects, as well as those that produce no effects. As noted in Box 2, it is important to characterize what data were used, what model was employed to develop the dose-response curve(s), and whether chemical-specific information is available to support the observed dose-response relationship. While the risk assessment paradigm shown in Figure 21 separates hazard... 

The use of Monte Carlo and other stochastic analytical methods to characterize the distribution of exposure and dose-response relationships is increasing (IPCS, 2001a). The Monte Carlo method uses random numbers and probability in a computer simulation to predict the outcome of exposure. These methods can be important tools in risk characterization to assess the relative contribution of uncertainty and variability to a risk estimate. 

CHARACTERIZING DOSE AND RISK IN A CUMULATIVE ASSESSMENT 277 CASE STUDY 280 Case Study Defining Risk 280 Case Study The Dose-Response Relationship 280 Case Study Using the Margin of Exposure to Characterize the Risk 281 Case Study Benchmark Doses 282 Case Study Margins of Exposure 284... 

Dose-Response Evaluation The process of quantitatively evaluating toxicity information and cliaracterizing 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-response 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. 

In the evaluation of carcinogenicity of chemicals, data obtained from human and animal studies are analyzed for hazard identification and dose-response relationships. The results are used in combination with exposure assessment and risk characterization for the assessment of cancer risks of the chemicals to humans. 

Potency estimates derived from such animal studies help to characterize the dose-response relationship at the low-exposure levels to which humans are likely to be exposed and to predict the quantitative estimate of the risks that humans are likely to encounter at ambient exposures. Experimental evidence for various shapes of the dose-response curve for carcinogens showed that reliable high-dose data from human studies contain examples of superlinearity, linearity, and sublinearity. These are also seen in animal studies. But there are no data to indicate the shape of the dose-response relationship corresponding to lifetime risk of one in a million, the insignificant risk level generally used by the regulatory agencies. 

Toxicity assessment includes characterization of the toxicity of a chemical, development of a dose-response relationship, and ultimately the development of exposure criteria. Toxicity values express a dose that is associated with either a given risk of cancer occurring over a lifetime of exposure (e.g., slope factors and unit risks) or a dose that is not expected to cause harm (e.g., RfDs). Some toxicity values are used as the basis for developing exposure criteria (RfDs) and some can be used as exposure criteria (e.g., RfCs). US EPA has developed toxicity values for many chemicals commonly associated with environmental contamination. Verified US EPA criteria are available in the Integrated Risk Information System (IRIS). 

See also Carcinogen Classification Schemes Dose-Response Relationship Exposure Assessment Exposure Criteria Hazard Identification Risk Assessment, Ecological Risk Based Corrective Action (RBCA) Risk Characterization Risk Communication Risk Management Uncertainty Analysis. 

See also Dose-Response Relationship Margin of Exposure (MOE) Risk Assessment, Ecological Risk Assessment, Human Health Risk Characterization. 

While the dose-response relationship observed in cancer bioassays is commonly nsed as the basis for risk characterization for substances that are considered as carcinogens, the extent to which it meaningfully informs risk is limited by the small number of dose groups and the magnitude of the variation between exposure of humans and administered doses. The limited munbers of doses examined is necessarily a function of the costs associated with close-to-lifetime observation of gronps of (commonly) 50 animals each. 

The process of combining the risk characterization, dose-response relationships, and exposure estimates to quantify the risks in a specific population. 

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