PRINCIPLES OF TOXICOLOGY - Biology East Borneo

456 RISK ASSESSMENTBecause low-dose responses cannot be measured, they must be modeled. There are three types ofmodels:1. The first category of models consists of the “mechanistic” models. These are dose–responsemodels that attempt to base risk on a general theory of the biological steps that might be involved inthe development of carcinogenesis. Examples of mechanistic models include the early “one-hit” andthe subsequent “multihit” models for carcinogenesis. These models were based on assumptionsconcerning the number of “hits” or events of significant genetic damage that were necessary to inducecancer. A related model, the “linearized multistage” (LMS) model of carcinogenesis, is based on thetheory that cancer cells develop through a series of different stages, evolving from normal cells tocancer cells that then multiply.2. The second category of cancer extrapolation models includes the “threshold distribution”models. Rather than attempting to mimic a particular theory of carcinogenesis, these models are basedupon the assumption that different individuals within a population of exposed persons will havedifferent risk tolerances. This variation in tolerance in the exposed population is described withdifferent probability distributions of the risk per unit of dose. Models that fall within this categoryinclude the probit, the logit, and the Weibull.3. The third category of model is the “time-to-tumor” model. This type of model bases the risk orprobability of getting cancer on the relationship between dose and latency. With this model, the riskof cancer is expressed temporally (in units of time), and a safe dose is selected as one where the intervalbetween exposure and cancer is so long that the risk of other diseases becomes of greater concern.Each of these models can accommodate the assumption that any finite dose poses a risk of cancer, theessential tenet of a nonthreshold model. However, the shape of the dose–response curve in the low-doseregion can vary substantially among models (see Figure 18.6). Because the shape of the dose–responsecurve in the low-dose region cannot be verified by measurement, there is no means to determine whichshape is correct. A simple example of the impact of choosing one cancer extrapolation model overanother is given in Table 18.1, which compares the results of dose–response modeling using threedifferent models where it was assumed in each model that a relative dose of 1.0 produced a 50% cancerincidence. The results generated by all three models are essentially indistinguishable at high doseswhere the animal cancer incidence might be observable, and so one would conclude they all “fit” theexperimental data equally well. However, when modeling the risks associated with lower doses, thedose/risk range in which regulatory agencies and risk assessors are most frequently interested, thereis a wide divergence in the risk projected by each model for a given low dose. In fact, at 1 / 10,000thof the dose causing a 50% cancer incidence in animals, the risks predicted by these three modelsproduce a 70,000-fold variation in the predicted response.Regulatory agencies utilize cancer risk estimates in regulating carcinogens, but they are faced withmany models that yield a wide range of risk estimates. In the absence of any scientific basis to determinewhich is most correct, they must make a science policy decision in selecting the model to use. Generally,in the face of this uncertainty, they have selected models that tend to provide higher estimates of risk,particularly when combined with conservative exposure assumptions (see Table 18.2). This is consistentwith their mission to protect public health, and consequently the need to avoid underestimatingrisks. For example, the USEPA has historically used conservative models such as the one-hit or LMSmodel in calculating cancer risks from exposure to all carcinogens. These models assume linearity inthe low-dose range, and as shown in Table 18.1, tend to require a larger reduction in dose to attain acertain low level of risk relative to other models.Extensive research in the area of chemical carcinogenesis indicates that many chemical carcinogensact via epigenetic or promotional mechanisms that, like noncancer toxicities, do not involve or requiregenetic damage. It has been proposed that these mechanisms and carcinogenic responses should havethresholds. Similarly, numerous enzyme systems have been identified as responsible for maintainingthe integrity of the genetic code. These repair enzymes and pathways could provide an effective dose