Animal studies dose-response assessment

In general, data from studies in humans are preferred to animal data for purposes of hazard identification and dose-response assessment. 

FIGURE S.6 Schematic illustration of the traditional setting of an acceptable level of exposure (ADI) by dividing the NOAEL from an animal study by an assessment factor (AF). The two dose-response relationships have identical NOAEL. If a uniform assessment factor is applied, there will be an adequate MOS at the ADI for effect b but not for effect a. (Modified from KEMI, Human health risk assessment. Proposals for the use of assessment (uncertainty) factors. Application to risk assessment for plant protection products, industrial chemicals and biocidal products within the European Union. Report No. 1/03, Solna, Sweden, 2003. 

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. 

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. 

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. 

Although rarely presented in a dose-response assessment, in nearly all cases the lower bound on the incremental probability of a response will be zero or less (see Figure 3.7). That is, the statistical model that accounts for the uncertainty in the results of an animal study also accommodates the possibility that no response may occur at low doses and that, in fact, there may be fewer responses (e.g., cancers) than observed in the control population at some low doses. The possibility of reduced responses at low doses also is shown by the lower confidence limit of data on radiation-induced cancers in some organs of humans including, for example, the pancreas, prostate, and kidney (Thompson et al., 1994). 

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.,... 

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. 

For food allergens, validated animal models for dose-response assessment are not available and human studies (double-blind placebo-controlled food challenges [DBPCFCs]) are the standard way to establish thresholds. It is practically impossible to establish the real population thresholds this way. Such population threshold can be estimated, but this is associated with major statistical and other uncertainties of low dose-extrapolation and patient recruitment and selection. As a matter of fact, uncertainties are of such order of magnitude that a reliable estimate of population thresholds is currently not possible. The result of the dose-response assessment can also be described as a threshold distribution rather than a single population threshold. Such distribution can effectively be used in probabilistic modeling as a tool in quantitative risk assessment (see Section 15.2.5)... 

In the absence of human data (the most preferred data for risk assessment), the dose-response assessment for either cancer or noncancer toxicity is determined from animal toxicity studies using an animal model that is relevant to humans or using a critical study and species that show an adverse effect at the lowest administered dose. The default assumption is that humans may be as sensitive as the most sensitive experimental species. 

Qf fundamental importance in conducting a risk assessment for a substance such as a nanomaterial is an understanding of the dose-response for adverse effects associated with exposure. A dose-response assessment is an evaluation of the relationship between dose and incidence (or severity) of an adverse effect. In many cases, a dose-response assessment must be conducted to extrapolate the doses associated with adverse effects observed in toxicological studies (typically in an animal model that has been treated with... 

Some animal studies indicate that dietary exposure to methyl parathion causes decreased humoral and cellular responses (Shtenberg and Dzhunusova 1968 Street and Sharma 1975). A more recent, well-designed animal study that included a battery of immuno/lymphoreticular end points showed few effects at the nonneurotoxic doses tested (Crittenden et al. 1998). No adequate studies are available in humans to assess the immunotoxic potential of methyl parathion. Therefore, studies measuring specific immunologic parameters in occupationally exposed populations are needed to provide useful information. Further studies are also needed to investigate the mechanism for methyl parathion-induced immunotoxicity since this information would help to identify special populations at risk for such effects. 

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