Dose-response relationship hazard identification

Stages in hazard characterization according to the European Commission s Scientific Steering Committee are (1) establishment of the dose-response relationship for each critical effect (2) identification of the most sensitive species and strain (3) characterization of the mode of action and mechanisms of critical effects (including the possible roles of active metabolites) (4) high to low dose (exposure) extrapolation and interspecies extrapolation and (5) evaluation of factors that can influence severity and duration of adverse health effects. 

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. 

Identification of Chemicals That Cause Deterministic Responses. Hazardous chemicals having a threshold in the dose-response relationship are identified using the following process ... 

Although dose-response assessments for deterministic and stochastic effects are discussed separately in this Report, it should be appreciated that many of the concepts discussed in Section 3.2.1.2 for substances that cause deterministic effects apply to substances that cause stochastic effects as well. The processes of hazard identification, including identification of the critical response, and development of data on dose-response based on studies in humans or animals are common to both types of substances. Based on the dose-response data, a NOAEL or a LOAEL can be established based on the limited ability of any study to detect statistically significant increases in responses in exposed populations compared with controls, even though the dose-response relationship is assumed not to have a threshold. Because of the assumed form of the dose-response relationship, however, NOAEL or LOAEL is not normally used as a point of departure to establish safe levels of exposure to substances causing stochastic effects. This is in contrast to the common practice for substances causing deterministic effects of establishing safe levels of exposure, such as RfDs, based on NOAEL or LOAEL (or the benchmark dose) and the use of safety and uncertainty factors. 

Dose-response data based largely on animal studies. It is noteworthy that rodent studies now used to predict the dose-response relationship in humans were never intended for that purpose (Barr, 1988). These studies were designed for purposes of hazard identification (see Section 3.1.4.1.2) and were not intended to be the basis for estimating human responses at low doses (Paustenbach, 1995). For example, there usually are significant differences between animals and humans with respect to the rate at which chemicals are metabolized, distributed, and excreted, and these are not taken into account when animal tests are designed. Also, animal tissues will frequently respond differently to toxicants than human tissue. 

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. 

See also American Conference of Governmental Industrial Hygienists Biomarkers, Human Health Biotransformation Dose-Response Relationship Exposure Hazard Identification Medical Surveillance Occupational Safety and Health Administration Psychological Indices of Toxicity Risk Assessment, Ecological Risk Assessment, Human Health. 

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. 

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. 

Identifying the potential harm of an agent may involve all or any of observation, experimental work, information retrieval and deductive work based on physicochemical parameters and structure activity relationships. Hazard identification and dose-response... 

The effect of a chemical on the environment (open ocean, coastal waters, estuary, aquatic fauna, aquatic flora, etc.) depends on the toxicity of the chemical and on the amount of the chemical the environment is exposed to (for example, the amount of chemical discharged, the administered dose, the concentration of chemical, and the length of exposure). Accordingly, to determine the effects, two factors have to be investigated toxicity and exposure. Identification of hazards requires studies of toxicity, whereas exposure data are needed for the estimation of risk. Risk is the probability that the exposure conditions are such that the hazards may materialize and result in an effect. Toxicity data consist of dose-response relationships and, in the aquatic environment, dose is usually given by the concentration and the length of exposure. 

After hazard identification, hazard characterisation is undertaken, and this is normally based on dose-response relationships in the range of toxicological studies summarized in Section 2.5.1. It is assumed that a threshold dose for response can be identified, where the NOEL is the highest dose that causes no (adverse) detectable effect in the most sensitive animal species or strain. Other approaches have been used, however, such as determination of a benchmark... 

The second element of health risk assessment for lead is the identification of dose—response relationships for the various adverse health effects noted in the previous chapter. Dose—response relationships, like health hazard characterizations, are general in nature and independent of site-specific lead exposure scenarios. 

Hazard identification is the process of collecting and evaluating information on the effects of an agent on animal or human health and well-being. In most cases, this involves a careful assessment of the adverse effects and what is the most sensitive population. The dose-response assessment involves evaluation of the relationship between dose and adverse effect. Typically, an effort is made to determine the lowest dose or exposure at which an effect is observed. A comparison is often made between animal data and any human data that might be available. Next is exposure assessment, in which an evaluation of the likely exposure to any given population is assessed. Important parameters include the dose, duration, frequency, and route of exposure. The final step is risk characterization, in which all the above information is synthesized and a judgment made on what is an acceptable level of human exposure. In the simplest terms, risk is the product of two factors hazard and exposure (i.e. hazard x exposure = risk). In real risk assessments, all hazards may not be known and exposure is often difficult to quantify precisely. As a result, the calculated risk may not accurately reflect the real risk. The accuracy of a risk assessment is no better than the data and assumptions upon which it is based. 

---