PRINCIPLES OF TOXICOLOGY - Biology East Borneo

18.4 DOSE–RESPONSE ASSESSMENT 455Nonthreshold Models for Assessing Cancer RisksConceptual Issues The nonthreshold dose–response model is typically reserved for cancer riskassessment. The assumption by regulatory agencies that chemical carcinogenesis has no dose thresholdbegan several decades ago. This assumption was initially based largely on empirical evidence thatradiation-induced cancer had no threshold and on the theory that some finite amount of DNA damagewas induced by all doses of radiation. Smaller doses simply carried smaller risks, but all doses wereassumed to carry some mathematical chance of inducing cancer. Following this lead, theories ofchemical-induced carcinogenesis began to evolve along the same lines, centering around effects ofhighly reactive, DNA damaging carcinogens. It was presumed that, like radiation, chemical carcinogensinduced cancer via mutations or genetic damage and therefore had no thresholds. So, like radiationbefore it, chemical-induced carcinogenesis was assumed to carry some quantifiable risk of cancer atany dose.If viewed somewhat simplistically, a biologic basis for the absence of a practical threshold forcarcinogens can be hypothesized. If one ignores the DNA repair processes of cells, or assumes thatthese protective processes become saturated or overwhelmed by “background” mutational events, itcan be postulated that some unrepaired genetic damage occurs with each and every exposure to acarcinogenic substance. As this genetic damage is presumed to be permanent and carry the potentialto alter the phenotypic expression of the cell, any amount of damage, no matter how small, might carrywith it some chance that the affected cell will ultimately evolve to become cancerous.With this viewpoint, scientists and regulatory agencies initially proposed that the extrapolation ofa cancer hazard must be fundamentally different from that used to extrapolate noncancer hazards, andcancer risk assessment models became probability-based. In contrast to assessing the risk of noncancerhealth effects, where the dose at which no toxic effect will occur is determined, cancer risk assessmentis a matter of assigning probabilities of cancer to different doses. The determination of safety or a safedose is then a matter of deciding what cancer risks are so small that they can be regarded as de minimisor inconsequential.Determining the relationship between carcinogen dose and cancer risk is very difficult for a numberof reasons. One reason is that the concept of latency complicates the interpretation of dose–responserelationships for carcinogens. Latency is the interval of time between the critical exposure and theultimate development of disease. While noncancer effects tend to develop almost immediately or verysoon after a toxic dose is received, cancer may not develop until an interval of 20 years or more haselapsed. For some carcinogens, increasing the dose shortens the latency period, causing tumors todevelop more quickly. A positive carcinogenic response can then be thought of in two ways: asincreased numbers of tumors or subjects with tumors, or as a decrease in the time to appearance oftumors. The latter is important, because a dose capable of producing tumors has no consequence if thetime required for the tumors to develop exceeds the remaining lifespan of the human or animal.Another problem is that the critical portion of the dose–response curve for most risk assessments,the low-dose region applicable to most environmental and occupational exposures, is one for whichempirical data are not available. Chronic cancer bioassays in animals are expensive, and seldom testmore than two or three doses. Also, cost limits the number of animals tested to about 50 or less perdose group. With this group size, only tumor responses of about 10% or more can be detected withstatistical significance. Detection of the kinds of cancer responses that might be of interest to the riskassessor, e.g. a response of 0.1%, 0.001%, or 0.00001% (10 –3 , 10 –5 , or 10 –6 , respectively) aretherefore beyond the capabilities of these experiments. Consequently, the doses needed to producethese cancer responses are not determined. Expanding the number of animals routinely tested is noteconomically feasible, and even very large studies may not eliminate this problem. One attempt to testthe utility of using larger dose groups, the so-called “megamouse” experiment, was still unable toincrease the sensitivity of measurement beyond about 1%, even though almost 25,000 animals wereused in this experiment. In short, animal cancer bioassays will typically provide only one or twodose–response points, and these points are always several orders of magnitude above the range of smallrisks/doses in which we are ultimately interested.