Risk characterization

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With information about the dose-response and exposure features of the substance, the risk can be characterized. Risk characterization is the process of estimating the probable incidence of an adverse health effect to humans who are under the circumstances of exposure. When every data is available, risk characterization should be based on human data. However, frequently human data is fragmented, incomplete, or even lacking. Thus, extrapolations are made from dose-response relationships established by controlled chronic animal studies. Whether the dose-response relationships are zero or nonzero thresholds, i.e., whether they are threshold or non-threshold, respectively, should be determined. Figure 6.3 provides graphical examples of such hypothetical options for extrapolated dose-response curves. The

FIGURE 6.3 Graphical examples of hypothetical options for an extrapolated dose-response curve.

threshold represents a dose below which no response is observed in the low-dose region; alternatively, in the nonthreshold approach, numerous dose-response curves can be proposed in the low-dose region of the dose-response curve if a threshold assumption is not made.

Threshold Relationships

For threshold responses, there will be a level below which adverse health effects are not likely to occur. Some examples include organ or tissue effects such as neuro-toxicity, hepatotoxicity, nephrotoxicity, developmental effects, and germ-cell mutations or noncancer endpoints. Human exposure data are usually limited and animal bioassay data must be extrapolated. However, risk assessments usually require looking for dose-response at low human exposures, way below the experimentally observable range of response in animal bioassays. Extrapolation from animal data to the human risk situation represents a major aspect of dose-response assessment. Often, one has little idea of the exact shape of the lower end of the dose-response relationship, which is linear or curvilinear. This is because of difficulties in preselecting a range of doses in a chronic or subchronic toxicity testing that appropriately will result in a range of toxicological effects from overt toxicity through some intermediate toxicity expression to no toxicity, representing the highest, moderate, and lowest doses, respectively.

Figure 6.4 shows a theoretical dose-response relationship showing dose-related toxicity. A number of effect-related endpoints can be assigned at the lower end of the dose-response curve. The no observed effect level (NOEL) is that dose of the test agent at which exposed animals appear to be identical in all respects to control

Log Dose

FIGURE 6.4 Dose-response relationships for adverse effects and endpoints for the lower end of the dose-response curves.

Log Dose

FIGURE 6.4 Dose-response relationships for adverse effects and endpoints for the lower end of the dose-response curves.

animals. The lowest observed effect level (LOEL) is that dose of a test agent at which the exposed animals may show some changes associated with the substance but the changes are not considered adverse effects. The no observed adverse effect level (NOAEL) is that dose at which there are no statistically or biologically significant increases in frequency or severity of effects between the exposed and the control groups. For each toxic substance, an adverse effect may be manifested by a separate threshold dose. Figure 6.4 illustrates progressively adverse responses: hair loss, reduced fertility, and liver pathology. The risk assessor would judge that hair loss is not an adverse effect and assign a NOEL. The lowest observed adverse effect level (LOAEL) is the dose of the substance at which there are statistically no biologically significant differences in the frequency or severity of adverse health effects between the exposed and the control groups. The lowest observed effect (LOEL) is shown with regards to the increased body weight and reduced fertility. At increased doses, fertility is reduced and NOAEL and LOAEL are assigned.

One or more of these values may be obtained and there might be some debate on which is best able to assess the toxic situation of the substance. In a practical sense, regulatory agencies will apply a series of safety factors to these endpoints in arriving at an acceptable concentration such as a reference dose (RfD), acceptable daily intakes (ADIs) promoted by the World Health Organization (WHO), or tolerable upper limit (UL), which has recently been identified for various dietary nutrients by the National Research Council. Typically, these are found by dividing the calculated NOAEL values by safety factors, i.e., uncertainty factors (UFs) or modifying factors (MFs), or both:

The purpose of the safety factors is to allow for human (intraspecies) or animal to human (interspecies) variation. UFs are often used to account for extrapolation of results of short-term animal studies to the real-world situation that involves chronic exposure. UFs can also account for the limited numbers of animals used or other limitations found in the experiments. The usual default value assigned to each uncertainty factor is 10. Modifying factors are used to further adjust the UFs in situations where data may be lacking regarding mechanisms of action or toxicoki-netics, or if there are concerns about the relevance of the test animal's response to human risk. Anything not considered within the UFs can be adjusted for by modifying factors, either up or down. For example, to determine the UL in the dietary reference intakes (DRIs) for vitamin E, the UF was adjusted to 3 rather than 10 because the scientific thinking was that the research derived from the test animal, the rat, mimicked the human situation very well.

In practice, regulatory agencies prefer using NOEL over NOAEL and so on. For NOEL, the most suitable number derived from various study results may be divided by a factor of 100, accounting for 10-fold uncertainty for intraspecies variability and another 10-fold for interspecies differences:

NOEL/100

Applying such UFs considers the possibility that the human may be up to 10-fold more sensitive than the animal species used and allows for a 10-fold variability in sensitivity within the human population.

In a situation where only the NOAEL may be derived from the literature, the risk assessor may take a N0AEL/100 and include an additional safety factor of 5-to 10-fold to address the problem of lack of data:

N0AEL/500 or N0AEL/1000 If there is only a LOAEL to work with, 1000 or 500 can be used as the safety factor:

L0AEL/1000 or L0AEL/5000

Although the process of applying safety factors may appear to be subjective and even arbitrary, the system has been demonstrated to function reasonably well. Because of the paucity of definitive data, deriving an acceptable daily intake for humans cannot be taken directly from the results of animal studies without adjustment by an appropriate safety factor. 0ne needs to account for many factors, such as multienvironmental exposures or the effects over an acute or chronic exposure or a lifetime. The number derived should be as conservative an estimate as possible.

Sometimes N0AEL values have been used in risk assessment to evaluate a margin of safety (M0S), which is the ratio of N0AEL determined in test animals (mg/kg/day) to the level to which a human might be exposed. For example, if a population is exposed through food ingestion of a toxicant at 0.5 mg/kg/day for a 60-kg man and the N0AEL found for neurotoxicity is 50 mg/kg/day, the M0S is 1000 for ingestion of the neurotoxicity. This large number, above 100, reassures the public that the risk is low. M0S values below 100 usually result in appropriate actions by regulatory agencies.

Nonthreshold Relationships

There are some types of toxic effect in which the perceived mechanism supports the notion that there may be no threshold for the biological effect. Theoretically, for a chemical carcinogen, a single molecule can be sufficient to interact with DNA and cause a permanent alteration of the genome of a single cell, which could become a cancer. The model is referred to as the one-hit type of exposure and gives a linear dose-response relationship with no dose threshold when extrapolated through zero, as shown in Figure 6.3. Much of the information and subsequent cancer modeling regarding this linear dose-response relationship is based on radiation research. Such models assume that for the toxicant, there are infinite number of target DNA, that the toxic response occurs only after a minimum number of the target DNA have been

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