Carcinogens dose-response relationships

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. 

Carcinogenic solvents, 23 113 Carcinogenic substances, dose-response relationship for, 25 236. See afso Carcinogens... 

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). 

The critical question of dose-response relationships is given only cursory mention in this chapter. Keep in mind that all of the toxic phenomena described in this chapter and those on carcinogens exhibit such relationships we return to the dose-response issue in the chapters on risk assessment. 

Before we plunge into the world of carcinogens, we should note that all of the toxic phenomena we have described exhibit dose-response relationships and that LOAELs and NOAELs can be identified for all. As we shall see in later chapters these quantitative features of toxic phenomena are at center stage when we begin to examine risk to exposed populations. 

Dose-response relationships for two animal carcinogens, strikingly different in potency, are presented in Tables 6.2 and 6.3. The type of information presented in the tables is the usual starting point for risk assessments as we shall see, human exposures to these carcinogens are very much less than the NOAELs and LOAELs from the animal data. 

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. 

For non-threshold mechanisms of genotoxic carcinogenicity, the dose-response relationship is considered to be linear. The observed dose-response curve in some cases represents a single ratedetermining step however, in many cases it may be more complex and represent a superposition of a number of dose-response curves for the various steps involved in the tumor formation (EC 2003). Because of the small number of doses tested experimentally, i.e., usually only two or three, almost all data sets fit equally well various mathematical functions, and it is generally not possible to determine valid dose-response curves on the basis of mathematical modeling. This issue is addressed in further detail in Chapter 6. 

An additional assessment factor, of up to 10, has been apphed in some cases where the NOAEL has been derived for a critical effect, which is considered as a severe and irreversible effect, such as teratogenicity or non-genotoxic carcinogenicity, especially if associated with a shallow dose-response relationship. The principal rationale for an additional factor for nature of toxicity has been to provide a greater margin between the exposure of any particularly susceptible humans and the dose-response curve for such toxicity in experimental animals. 

The 95% confidence limits of the estimate of the linear component of the LMS model, /, can also be calculated. The 95% upper confidence limit is termed qi and is central to the US-EPA s use of the LMS model in quantitative risk assessment, as qi represents an upper bound or worst-case estimate of the dose-response relationship at low doses. It is considered a plausible upper bound, because it is unlikely that the tme dose-response relationship will have a slope higher than qi, and it is probably considerably lower and may even be zero (as would be the case if there was a threshold). Lfse of the qj as the default, therefore, may have considerable conservatism incorporated into it. The values of qi have been considered as estimates of carcinogenic potency and have been called the unit carcinogenic risk or the Carcinogen Potency Factor (CPF). 

Hemminki, K., Paasivirta, J., Kurkirinne, T. Virkki, L. (1980) Alkylation products of DNA bases by simple epoxides. Chem.-biol. Interact., 30, 259-270 Hine, C.H., Kodama, J.K., Wellington, J.S., Dunlap, M.K. Anderson H.H. (1956) The toxicology of glycidol and some glycidyl ethers. Arch. ind. Health, 14, 250-264 Hooper, K., LaDou, J., Rosenbaum, J.S. Book, S.A. (1992) Regulation of priority carcinogens and reproductive or developmental toxicants. Am. J. ind. Med., 22, 793-808 Hussain, S. (1984) Dose-response relationships for mutations induced in E. coli by some model compounds. Hereditas, 101, 57-68... 

Zeise, Lauren, Richard Wilson, and Edmund A. C. Crouch. 1987. Dose-Response Relationships for Carcinogens A Review. Environmental Health Perspectives 73 259-308. 

Zeise, L., Wilson, R., and Crouch, E.A.C. (1987). The dose response relationships for carcinogens a review, Environ. Health Perspective 73,259. 

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