Dose-response assessment chemicals

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 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... 

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. 

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). 

Chemical hazard identification. In contrast to radiation, most chemicals are thought not to be hazardous to human health at a sufficiently low dose. In the United States, the process of determining whether a chemical is hazardous relies upon principles established by EPA. These principles are used extensively, but not universally, in other countries. This Section describes the general principles used by EPA to identify hazardous chemicals. Hazard identification is related to the process of dose-response assessment for hazardous chemicals discussed in Section 3.2.1. 

Principal studies are those that are the most significant for determining whether a chemical is potentially toxic in humans. These studies are of two types studies of human populations and studies using laboratory animals. EPA also uses the principal studies in the dose-response assessment (see Section 3.2.1). 

Dose-Response Assessment for Chemicals That Cause Deterministic Effects. For hazardous chemicals that cause deterministic effects and exhibit a threshold in the dose-response relationship, the purpose of the dose-response assessment is to identify the dose of a substance below which it is not likely that there will be an adverse response in humans. Establishing dose-response relationships for chemicals that cause deterministic effects has proved to be complex because (1) multiple responses are possible, (2) the dose-response assessment is usually based on data from animal studies, (3) thousands of such chemicals exist, and (4) the availability and quality of data are highly variable. As a consequence, the scientific community has needed to devise and adhere to a number of methods to quantify the most important (low or safe dose) part of the dose-response relationship. 

There are two possible approaches to estimating the human safe dose for chemicals that cause deterministic effects the use of safety and uncertainty factors and mathematical modeling. The former constitutes the traditional approach to dose-response assessment for chemicals that induce deterministic effects. Biologically-based mathematical modeling approaches that more realistically predict the responses to such chemicals, while newer and not used as widely, hold promise to provide better extrapolations of the dose-response relationship below the lowest dose tested. 

Dose-response concepts. Dose-response assessment for hazardous chemicals that can cause deterministic effects begins with the toxicology data developed during the hazard identification step described in Section 3.1.4.1.2. In many cases, hazard identification and dose-response assessment occur simultaneously. For each chemical, the critical response (a specific response in a specific organ) is identified in the hazard identification process. Using the available data for the critical response, one of the following is established ... 

Dose-Response Assessment for Chemicals That Cause Stochastic Effects. For hazardous chemicals that do not have a threshold in the dose-response relationship, which is currently believed to... 

UCL takes into account measurement uncertainty in the study used to estimate the dose-response relationship, such as the statistical uncertainty in the number of tumors at each administered dose, but it does not take into account other uncertainties, such as the relevance of animal data to humans. It is important to emphasize that UCL gives an indication of how well the model fits the data at the high doses where data are available, but it does not indicate how well the model reflects the true response at low doses. The reason for this is that the bounding procedure used is highly conservative. Use of UCL has become a routine practice in dose-response assessments for chemicals that cause stochastic effects even though a best estimate (MLE) also is available (Crump, 1996 Crump et al., 1976). Occasionally, EPA will use MLE of the dose-response relationship obtained from the model if human epidemiologic data, rather than animal data, are used to estimate risks at low doses. MLEs have been used nearly universally in estimating stochastic responses due to radiation exposure. 

Uncertainties and Deficiencies in Dose-Response Assessment. Any approach to determining the dose-response relationship for hazardous chemicals involves many attendant uncertainties that limit its accuracy. In addition, many dose-response assessments suffer from deficiencies in the way they are conducted, which further decreases accuracy. These two aspects of dose-response assessment, which in some ways have led to adoption of such conservative approaches as large safety factors and UCLs in applying the results to health protection of the public, are discussed in the following two sections. 

Low-dose extrapolation models are the backbone of dose-response assessments. Because they can play such a dominant role in the regulatory process, it is important to understand some of their characteristics. As shown in Figure 3.10, different extrapolation models usually fit the data in the observable dose region in animal tests about equally well (Krewski et al., 1989), but they often give quite different results in the unobserved low-dose region of interest in assessments of risk to human health. The results obtained by extrapolation of the most commonly used low-dose models usually vary in a predictable manner, because the models use different mathematical equations to describe the chemical s likely behavior in the low-dose region. 

Failure to adjust dose-response estimates by considering biological information. In many dose-response assessments, potentially important biological information is not taken into account in selecting an extrapolation model. Examples of information often not included when a model is selected are the types of tumors, time to onset, and whether the chemical is genotoxic. Some... 

Comparison of Dose-Response Assessments for Radionuclides and Chemicals... 

The discussions in Sections 3.2.1 and 3.2.2 have indicated that there are important differences in the approaches to dose-response assessment for radionuclides and hazardous chemicals. An understanding of these differences is important in developing a risk-based waste classification system that applies to both types of substances. 

A fundamental difference between radionuclides and hazardous chemicals in regard to dose-response assessment is the following. Estimates of responses from exposure to radionuclides can be based on estimates of absorbed dose and equivalent dose in all organs and tissues, and the dose-response relationships for different organs or tissues obtained from human or animal studies can be applied to any radionuclide and any exposure situation. Separate studies of responses from exposure to each radionuclide of concern are not needed. For hazardous chemicals, however, quantities analogous to absorbed dose and equivalent dose have not been developed i.e.,... 

Given the different approaches to dose-response assessment and the different measures of response normally used for radionuclides and chemicals that cause stochastic effects, estimates of responses from exposure to the two types of substances clearly are not equivalent, and the correspondence of the estimated frequency of responses to the frequency that might actually be experienced differs substantially. Specifically, if the results of experiments indicating chemical-induced stochastic responses in animals are assumed to be indicative of stochastic responses in humans, estimates of responses for chemicals could be considerably more conservative (pessimistic) than estimates for radionuclides. This difference is primarily the result of... 

Stochastic responses from exposure to radionuclides and hazardous chemicals generally are of concern in health protection of the public and in classifying waste. Of the three differences in approaches to dose-response assessment identified above, the most important is the use of a best estimate (MLE) of the dose-response relationship for radionuclides but upper-bound estimates (UCLs) for hazardous chemicals that cause stochastic effects. UCL in the dose-response relationship for chemicals that cause stochastic effects normally exceeds MLE by a factor of 5 to 100 or more. If this difference... 

In spite of the differences among carcinogens, the principles of dose-response assessment that have proven to be useful for ionizing radiation appear to be applicable, within limits, to chemicals, particularly those chemicals that resemble radiation in genotoxicity, cytotoxicity, and in the stages of carcinogenesis that are affected. 

Dose-response assessments for chemical carcinogens generally are more uncertain than dose-response assessments for ionizing radiation. 

However, given the current state of knowledge and methods of dose-response assessment for substances that cause stochastic responses, there appear to be important technical and institutional impediments to the use of either incidence or fatalities exclusively. Data on radiation-induced cancer incidence and chemical-induced cancer fatalities for use at the low doses and dose rates relevant to health protection are not readily available, and current regulatory guidance calls for calculation of cancer incidence for hazardous chemicals. Since use of a common measure of response for all substances that cause stochastic responses may not be practical in the near term, both measures (fatalities for radionuclides and incidence for hazardous chemicals) could be used in the interest of expediency. The primary advantage of this approach is that the measures of stochastic response for radionuclides and hazardous chemicals would be based on the best available information from studies in humans and animals, and it would involve the fewest subjective modifying factors. This approach also would be the easiest to implement. 

NCRP s recommendations on specifying an allowable risk or dose in the denominator of the risk index for the purpose of classifying waste are discussed in the following two sections. A general discussion of dose-response assessment for hazardous chemicals and radionuclides is presented in Section 3.2. 

Hertzberg RC, Teuschler LK. 2002. Evaluating quantitative formulas for dose-response assessment of chemical mixtures. Environ Hlth Perspect 110 965-970. 

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