5 Characterization of Dose-Response Relationships
The quantitative relationships between dose and the incidence of adverse response (see Appendix 1) provide the basis for evaluating chemical hazard and the derivation of exposure limits. The approach used to assess the dose-response relationship depends on whether the chemical produces threshold or nonthreshold end points (19, 20). 5.1 Threshold and Nonthreshold Effects
A threshold dose-response relationship is used to evaluate chemicals that produce no adverse effects below a certain dose. The underlying mechanism for a threshold is that multiple cells must be injured for an adverse effect to occur (52). A nonthreshold ("zero" threshold) dose-response relationship is used to evaluate chemicals that convey some risk of adverse response at any dose above zero. The mechanism of carcinogenesis is considered nonthreshold, whereby a genotoxic insult in a single cell is theoretically sufficient to produce a malignant tumor eventually.
Traditionally, the threshold dose-response relationship has been used for assessing noncancer end points and the nonthreshold approach for cancer end points. The use of a nonthreshold dose-response relationship to evaluate nongenotoxic carcinogens has been a subject of much debate because it has been suggested that these substances are likely to produce cancer via a threshold phenomenon (53). Both threshold and nonthreshold approaches have also been applied to evaluate reproductive and developmental toxins (54, 55).
To facilitate interspecies comparisons of the dose-response relationship for adverse effects, it is necessary to obtain an estimate of the human equivalent dose. The two methods that are most commonly used to convert animal dose or exposure to an equipotent dose for humans are based on body characteristics.
The first method calculates the equivalent human dose from an animal study by scaling (adjusting) the animal dose rate for animal body weight, often expressed as mg/kg body weight/day. Similarly, the second method is based on body surface area scaling by adjusting for differences in metabolic rate, using the factor of body weight to the power of 2/3 or 3/4. Body weight scaling, however, is simpler and has been used by the USEPA for risk assessment and derivation of numerical criteria.
Ideally, the concentration at the target site would provide the best dosimetry. A method has been developed to estimate target tissue exposure (concentration x time) using a physiologically based pharmacokinetic model that incorporates biological data and processes. Because input data on the biokinetics and mechanisms of toxicity are rarely available for animals or humans, it is difficult to verify the validity of using this model for dose scaling.
The dose-response relationship is characterized for each of the adverse responses that a chemical produces by using data from the most relevant and scientifically sound studies. For threshold responses the NOAEL, TD50, or LD50 are determined (see Appendix 1). Depending on the response that is modeled, each response to a chemical can have a different threshold. For nonthreshold end point, models for extrapolation from high doses to low doses below the observed range are applied (see section 6.2).
A chemical can produce various effects ranging from not toxic to very toxic or "frank effect level" (FEL) (25, 56). The critical adverse effect is defined as "the first adverse effect, or its known precursor that occurs as the dose rate increases" (14). Operationally, for threshold end points, the critical effect is the most conservative LOAEL. This end point is used to derive the exposure limit (see section 6).
Figure 10.2 shows a hypothetical example of a chemical that produces two adverse threshold effects at different dose ranges. Liver pathology occurs at higher doses than respiratory function impairment. In this case, respiratory impairment is considered the critical end point with a corresponding experimentally measured LOAEL. The highest dose level that does not produce a statistically or biologically significant impaired respiratory function is the NOAEL. The NOAEL or LOAEL can be used to derive the exposure limit (see section 6).
If a chemical produces both threshold and nonthreshold (cancer) adverse effects, exposure limits can be calculated on the basis of the threshold effect that is observed at the lowest dose and also on the nonthreshold end point (see section 6). For a nonthreshold effect, various curves of excess risk versus dose may be used to extrapolate downward from an experimental dose, depending on the quantitative risk model applied (see Fig. 10.3). Then the lowest concentration or the most conservative estimate for exposure limit is recommended.
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