Cancer dose-response relationship

Three additional points need to be mentioned. First, if the observed cancer dose-response relationship derives from epidemiology data, the observed risks are relative, not absolute (the latter are usually reserved for data from animal experiments). Thus, for human carcinogens with reliable dose-response information (e.g., as exists for benzene, arsenic, chromium (+6), asbestos, and several other carcinogens), it is necessary to convert relative risks to absolute risks before extrapolating to low dose. 

Raabe OG, Book SA, Parks NJ. 1983. Lifetime bone cancer dose-response relationships in beagles and people from skeletal burdens of Ra and Sr. Health Physics 44(Suppl. 1) 33-48. 

Similar to cancer dose-response relationships (figure 10.1), the best-fit curve steepness and location are uncertain. Therefore, a 95UCL curve is identified based on the variability of the laboratory data. An EDjg is also identified from this 95UCL curve. This lower (e.g., more health-protective) EDjo is then selected as the BMD. This is shown in figure 10.3. 

In 1981, Lawson et al.,87 for example, compared a group of 210 women hospitalized for fibrocystic disease with 241 women who had breast cancer and were drawn from two ongoing studies in different countries. They matched each case to three female control patients on age, current smoking habits, country, and study. Recent coffee and tea consumption in cases and controls were compared and were shown to have a modest positive association with hot beverage consumption for both fibrocystic disease and breast cancer, but there was no dose-response relationship. The risk of fibrocystic disease associated with heavy consumption of hot beverages (7+ cups per day) vs. none was elevated but not statistically significant. 

Nishi, M., Ohba, S., Hirata, K., Miyake, H., Dose-response relationship between coffee and the risk of pancreas cancer, Jpn J Clin Oncol, 26, 42, 1996. 

According to EPA (IRIS 1999), the available human epidemiological studies lack quantitative exposure data for lead and for possible confounding exposures (e.g., arsenic, smoking). Cancer excesses in the lung and stomach of lead-exposed workers that are reported are relatively small, dose-response relationships are not demonstrated neither is there consistency in the site of cancers reported. EPA (IRIS 1999) concluded that the human data are inadequate to refute or demonstrate the potential carcinogenicity of lead exposure. 

The carcinogenicity of orally administered phenol was examined in rats and mice in a study reported by the National Cancer Institute (NCI 1980). Rats and mice received 0, 2,500, or 5,000 ppm in drinking water for 103 weeks. Calculated intakes for rats were 322 and 645 mg/kg/day for males and 360 and 721 mg/kg/day for females. Calculated intakes for mice were 590 and 1,180 mg/kg/day for males and 602 and 1,204 mg/kg/day for females. Statistically significant increased incidences of pheochromocytomas of the adrenal gland and leukemia or lymphomas were observed in male rats exposed to 322 mg/kg/day (2,500 ppm), but not in male rats exposed to 645 mg/kg/day (5,000 ppm). No significant effects were seen in female rats or mice of either sex exposed to either exposure level. Since cancer occurred only in males of one of the two species tested and a positive dose-response relationship could not be established, these results are inconclusive regarding the carcinogenic potential of orally administered phenol. 

Phenol has been tested in animals for carcinogenicity by the oral and dermal routes, but results are equivocal. In a chronic NCI cancer bioassay (NCI 1980), a significant incidence of tumors (pheochro-mocytomas of the adrenal gland, leukemia, or lymphomas) occurred only in male rats exposed to the lowest dose level (2,500 ppm, 277 mg/kg/day) of phenol but not in male or female mice or male rats exposed to a higher dose level (5,000 ppm, 624 mg/kg/day). Since tumors occurred only in males in one of the two species tested, and since a positive dose-response relationship was not established, this study does not provide sufficient evidence to conclude that phenol is carcinogenic when administered by the oral route. Dermal application of phenol has been shown to result in tumors in mice phenol is a tumor promoter when it is applied after the application of the tumor initiator DMBA (Boutwell and Bosch 1959 Salaman and Glendenning 1957 Wynder and Hoffmann 1961). However, this effect occurs at dose levels of phenol that produce severe skin... 

Models for determining the dose-response relationship vary based upon the type of toxicological hazard. In the dose-response for chemical carcinogens, it is frequently assumed that no threshold level of exposure (an exposure below which no effects would occur) exists, and, therefore, any level of exposure leads to some finite level of risk. As a practical matter, cancer risks of below one excess cancer per million members of the population exposed (1 x 10 ), when calculated using conservative (risk exaggerating) methods, are considered to represent a reasonable certainty of no harm (Winter and Francis, 1997). 

It seems that large numbers of chemicals, in equally large numbers of test systems, from mammals to insects, vertebrates to invertebrates, microorganisms to plants, exhibit hormetic dose-response relationships. The relationship is not the same as that described earlier for nutrients, in two ways. First, in the case of hormesis the biological response - the toxicity endpoint - is the same in the protective region and in the region of toxicity (i.e., liver cancer incidence is reduced relative to control incidence over a range of low doses, and then as the NOAEL is exceeded, liver cancer incidence increases above that of controls). This is true hormesis. 

Differences of opinion are common among epidemiologists based on what appears to be similar, if not comparable, data. In spite of the numerous large-scale and long-term investigations, the debate eontinues over whether there is a safe (threshold) level for asbestos or other fibrous materials, or if there is a linear dose-response relationship in the induction of cancer. Conclusions and interpretations of this body of data usually reflect personal philosophy and tolerance of risk. 

An important qualification must be made. While a biomarker may be of proven value in establishing whether a drug has the desired effect in patients or healthy volunteers (see Section 4.6.3) and for evaluation of the dose-response relationship, a biomarker may not be a surrogate for the clinical endpoint. Thus, suppression of testosterone after an initial rise will give an almost immediate endpoint for the effect of GnRH analogues in prostate cancer but the relationship breaks down later in the disease. Measures of blood glucose control are vital... 

The most recent report of a cohort of CMME chemical workers followed for 30 years found 67 deaths with 25 attributable to lung cancer and a dose-response relationship. Standardized mortality ratios were elevated among the moderately and heavily exposed workers, peaking at 23.1 in the first decade and then declining to 7.4 and 7.9 in later decades. Small cell carcinoma accounted for 80% of the moderately and heavily exposed cases, and 3 of 12 heavily exposed cases occurred in nonsmokers. 

Conzelman GM Jr, Moulton JE Dose-response relationships of the bladder tumori-gen 2-naphthylamine A study in beagle dogs. J Natl Cancer Inst 49 193-205, 1972... 

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