Risk assessment dose-response analyses

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... 

In the concept proposed in 1983 in the US, risk assessment comprised of four steps, namely, hazard identification, dose-response analysis, exposure analysis, and risk characterisation. In a simplified procedure of risk assessment, only three types of information is needed, namely, physico-chemical characteristics, toxicology, the behavior of the chemical at the use situation. The physicochemical data is supposed to show some sense of toxicity and behaviour of the chemical. The toxicology data shows the kind of symptoms to be elucidated, the target organism, and the amount of chemicals needed for showing the symptoms. Behaviour data would show the extent the receptor - here, humans or other natural organisms - is contacted by the chemical at the use situation. The risk assessment is simply to compare the extent the receptor is contacted and the amount of the chemicals needed to show the symptom. 

By facilitating the simulation of the dose metrics for use in cancer dose-response analysis, the PBPK models address the uncertainty associated with interspecies, route-to-route, and high-dose to low-dose extrapolations (Andersen et al. 1993 Andersen and Krishnan 1994 Clewell et al. 2002a Clewell and Andersen 1987 Melnick and Kohn 2000). Since the first demonstration of the application of PBPK models in cancer risk assessment by Andersen and co-workers in 1987, there have been substantial efforts to evaluate the appropriate dose metrics and cancer risk associated with a number of other volatile organic chemicals using the PBPK modeling approach (Table 21.3). These risk assessments have been based on the PBPK model simulations of a variety of dose metrics that reflect the current state... 

Stacey NH, Cantilena LR Jr, Klaassen CD (1980) Cadmium toxicity and lipid peroxidation in isolated rat hepatocytes. Toxicol Appl Pharmacol 53 470-480 Stayner L, Smith R, Thun M, Schorr T, Lemen R (1992) A dose-response analysis and quantitative assessment of lung cancer risk and occupational cadmium exposure. Ann Epidemiol 2 177-194... 

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... 

An important input to the Risk Estimation step, as shown in Figure 1, is the analysis of health effects associated with the pollutant in question. Since environmental toxicology is itself a complex and difficult field, we have confined this paper to a discussion of how dose-response estimates can be utilized within a risk assessment, with emphasis on human carcinogenesis. Thus, the scope of this paper corresponds to the four steps surrounded by a dashed line in Figure 1. 

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. 

Risk assessment Some participants suggested that further development and validation of appropriate methods to assess the ecological risks of chemical agents are required. Dose-response curves should be established at the community and ecosystem levels. Several participants suggested that when applying for an exemption of chemicals according to the Stockholm Convention, China might need to support its application with risk-based analysis. 

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. 

Dose-response assessment evaluates potential risks to humans at particular exposure levels. The approach to dose-response assessment for a particular agent is based on the conclusion reached as to its potential mode(s) of action for each tumor type. If the mode of action for known carcinogens is anticipated to be a DNA-reactive and direct mutagenic activity, such substances are assessed with a linear approach. Other modes of action may be modeled with either linear or nonhnear approaches after a rigorous analysis of available data. 

Because an agent may induce multiple mmor types, the dose-response assessment includes an analysis of aU tumor types, followed by an overall evaluation that includes a characterization of the risk estimates across tumor types, the strength of the mode of action information of each mmor type, and the anticipated relevance of each mmor type to humans, including susceptible populations and fife stages (e.g., childhood). 

Immunotoxicity. There are currently no data on the effects of 2-hexanone on the human immune system via any route of exposure. Animal data included an inhalation study in which there was a 40% decrease in peripheral white blood cells in rats exposed to 2-hexanone (Katz et al. 1980). In addition, 2,5-hexanedione, a metabolite of 2-hexanone, was shown to adversely affect lymphoid organs of the immune system in rats and to cause impairment of immunity in mice (Upreti and Shanker 1987). Immunological assessments, including analysis of peripheral blood components and effects on lymphoid tissue, conducted as part of intermediate-or chronic-duration studies and skin sensitization tests would be useful in developing a dose-response relationship and assessing the potential risk to chronically exposed persons in the vicinity of hazardous waste sites or to exposed workers. 

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). 

G. L., Gargas, M. L, Strother, D. E. Improving cancer dose-response characterization by using physiologically based pharmacokinetic modeling An analysis of pooled data for acrylonitrile-induced brain tumors to assess cancer potency in the rat. Risk Anal 2000, 20 135-151. 

In this context it is important to improve the analysis of the extent to which sensitive organisms and ecosystems in such areas may need specific test methods and specific concern in environmental risk assessment of chemicals (Breitholtz et al. 2006a). In the future, it is therefore important to increase research efforts to elucidate potential consequences of varying physical and chemical environmental factors for toxicity of a wide range of chemical substances, in order to develop tools for hazard identification and dose-response assessment that include scientifically well-based combinations of species, endpoints and environmental factors. The battery of endpoints to select from should, as far as possible, comprise population level data (Forbes and Calow 1999, Forbes et al. 2001, Breitholtz et al. 2006a), possibly obtained by using population models. 

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