Dose-response relationship risk assessment

See also Aggregate Exposures Dose-Response Relationship Risk Assessment, Ecoiogicai Risk Assessment, Human Heaith. 

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

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. 

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. 

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 Exposure Assessment Risk Assessment, Human Health Risk Management. 

See also Behavioral Toxicology Dose-Response Relationship Exposure Assessment Mixtures, Toxicology and Risk Assessment Multiple Chemical Sensitivities Neurotoxicity Pollution, Air Indoor Psychological Indices of Toxicity Respiratory Tract Sensory Organs. 

Dose—response relationships are useful for many purposes in particular, the following if a positive dose—response relationship exists, then this is good evidence that exposure to the material under test is causally related to the response the quantitative information obtained gives an indication of the spread of sensitivity of the population at risk, and hence influences ha2ard evaluation the data may allow assessments of no effects and minimum effects doses, and hence may be valuable in assessing ha2ard and by appropriate considerations of the dose—response data, it is possible to make quantitative comparisons and contrasts between materials or between species. 

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. 

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. 

Most immunotoxic responses express a clear dose-response relationship that can be used for human risk assessment. However, it is more difficult to extrapolate in vitro concentrations than in vivo animal doses (plasma concentrations) to the clinical dose. 

Therapeutic confirmatory (Phase III) Demonstrate/confirm efficacy Establish safety profile Provide an adequate basis for assessing the benefit/risk relationship to support licensing Establish dose-response relationship Adequate and well controlled studies to establish efficacy Randomized parallel dose-response studies Clinical safety studies Studies of mortality/morbidity outcomes Large simple trials Comparative studies... 

Dose-response relationships figure prominently in the development of risk assessments, and we shall have much to say about them. 

The critical question of dose-response relationships is given only cursory mention in this chapter. Keep in mind that all of the toxic phenomena described in this chapter and those on carcinogens exhibit such relationships we return to the dose-response issue in the chapters on risk assessment. 

Dose-response relationships for two animal carcinogens, strikingly different in potency, are presented in Tables 6.2 and 6.3. The type of information presented in the tables is the usual starting point for risk assessments as we shall see, human exposures to these carcinogens are very much less than the NOAELs and LOAELs from the animal data. 

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)). 

And there are significant questions (as yet unanswered) regarding methods for assessing risks. Perhaps, for example, traditional notions of dose-response relationships are inapplicable when the particle size, or perhaps the surface area (huge relative to mass) is the real risk determinant. There is much to be done, and those promoting these exciting new products should no doubt be equally determined to promote the development of the information needed for reliably assessing their health and environmental risks. 

Other terms often used indiscriminately for the dose-response relationship include concentration-effect relationship and dose-effect relationship. According to the joint OECD/IPCS project (OECD 2003 a), which has developed internationally harmonized generic and technical terms used in chemical hazard and risk assessment, the following definitions have been provided although consensus was not achieved ... 

The TGD (EC 2003), Chapter 3.8, on sensitization gives definitions of skin and respiratory sensitization, and provides advice on the data to be used in the effects assessment, evaluation on the available data, and assessment of the dose-response relationship to be used in the EU-specific risk assessments. 

WHO/IPCS (1994, 1996, 1999) have adopted the approach that in simations where a NOAEL has not been achieved but the data on effects are of sufficient quality to be the basis of the risk assessment, a NAEL should be developed by the application of an appropriate UF to the LOAEL. According to WHO/IPCS (1994), UFs of 3, 5, or 10 have been used previously to extrapolate from a LOAEL to a NOAEL depending on the nature of the effect(s) and the dose-response relationship. A BMD may be developed as an alternative to the UF in extrapolating to the NOAEL. 

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