Dose-Incidence Relations

Although the data are not sufficient to define the shapes of the dose incidence curves in most instances, a markedly increased risk of cancer has been noted in a number of more heavily exposed populations (Ikble 6.5). In 2-naphthylamine distillers, for example, the latency and incidence of bladder cancer have been observed to vary systematically in relation to the duration of exposure (Figure 6.2). In those with exposures lasting more than five years, the cumulative incidence approached 100 percent (Figures 6.2 6.3). 

Fig. 8.6 Estimated risk of liver cancer, P(d), in relation to dose of aflatoxin, d, as determined with different dose-incidence models. The models for the different curves. are as follows OH. one-hit model MS, multi-stage model W, Weibull model MH, multihit model MB, Mantel-Bryan (log-probit model) (from Krewski and Van Ryzin, 1981).

If the exposure had been much smaller, the risk calculation would have been less direct and less certain. For purposes of risk reduction in public health, we may choose to err on the pessimistic side in risk estimations. For purposes of attribution, however, we want to make best estimates. Most of the numbers in Ikble 8.4 are overestimates of the risks. For radiation-induced leukemia, as described in Section 6.1.2, the best dose-incidence model might be lineai>quadratic and not linear. Thus, someone exposed to 50 mSv (5 rem) might be considered, on a linear extrapolation basis, to have a radiation related lifetime risk of cancer mortality of 10 (2 x 10 Sv 2 x 10 rem ), or a lifetime risk of mortality from leukemia of approximately 1.5 x 10 (0.3 x 10" Sv 0.3 X 10 rem ). The natural lifetime risk of mortality from leukemia other than chronic lymphocytic leukemia is approximately 56 x 10 . Therefore, the percent attribution to radiation according to the linear model would be ... 

The total dose is determined from the length of time the sample is irradiated, expressed in watthours m-2. A fundamental difference between irradiance and dose is that the former describes a beam of photons, whereas the latter relates to the irradiated sample. In other words, the irradiance of a photon beam may be constant, but the dose will vary according to how an irregularly shaped sample is orientated with respect to the beam. In most experimental work, the irradiance is measured, although, strictly, the dose incident on the sample is more important. The radiation may be absorbed, transmitted, scattered, or reflected, but in terms of photochemical reaction, that which is absorbed is the critical quantity. Measuring the quantity of photons absorbed can only be achieved for liquid samples that transmit the unabsorbed photons to be measured by a detector behind the sample. 

In 40 selected patients, age range 18-64 years, who were randomized in an open study for migraine prophylaxis to topiramate 25, 50, 75 or 100 mg as an evening dose paresthesia was by far the most common adverse reaction (55% of patients) and the incidence was dose related [280. Fatigue, giddiness, diarrhea, nausea, and drowsiness were reported in a few patients, but there was no apparent dose-effect relation. 

Sheldon PW et al. (1974) The incidence of lung metastases in C3H mice after treatment of implanted solid tumors with X-rays or surgery. Br J Cancer 30(4) 342 348 SRC Trial Group (1997) Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 336(14) 980-987 Stausbol-Gron B, Overgaard J (1999) Relationship between tumor cell in vitro radiosensitivity and clinical outcome after curative radiotherapy for sqiuimous cell carcinoma of the head and neck. Radiother Oncol 50(l) 47-55 Stuschke M, Thames HD (1999) Fractionation sensitivities and dose-control relations of head and neck carcinomas analysis of the randomized hyperfractionation trials. Radiother Oncol 51(2) 113-121... 

Antithyroid drags have several side effects. The most frequent side effects are maculopapular rashes, pruritus, urticaria, fever, arthralgia and swelling of the joints. They occur in 1-5% of patients [1, 2]. Loss of scalp hair, gastrointestinal problems, elevations of bone isoenzyme of alkaline phosphatase and abnormalities of taste and smell are less common. The incidence of all these untoward reactions is similar with MMI and PTU. Side effects of MMI are dose-related, whereas those of PTU are less clearly related to dose [1]. PTU may cause slight transient increases of serum aminotransferase and y-glutamyl transpeptidase concentrations but also severe hq atotoxicity whereas methimazole or carbimazole can be associated with cholestasis. The side... 

Corticosteroids a chronic painless myopathy associated with the long-term use of corticosteroids is a particularly common example of drug-induced muscle disorder. It is almost certain that mild cases are overlooked because steroids are so frequently used to treat inflammatory myopathies such as polymyositis. Fluorinated steroids are particularly frequently implicated, and the incidence of drug-induced muscle disease is dose and time-related. The presence of muscle weakness can even complicate topical steroid therapy. Corticosteroid-induced myopathy is mediated via intramuscular cytosolic steroid receptors. The steroid-receptor complexes inhibit protein synthesis and interfere with oxidative phosphorylation. The myopathy is associated with vacuolar changes in muscle, and the accumulation of cytoplasmic glycogen and mitochondrial aggregations. 

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