R 299.38 Determination of cancer slope factors for use in calculation of criteria based on carcinogenic endpoints.

Rule 38. (1) A non-threshold mechanism of carcinogenesis shall be assumed unless biological data adequately demonstrate the existence of a threshold on a hazardous substance-specific basis. (2) All appropriate human epidemiologic data, animal cancer bioassay data, and all other pertinent data shall be considered and a cancer slope factor developed if the weight of evidence for carcinogenicity is sufficient. Preferred data are those from studies which use the same route of exposure addressed by the criteria. However, in the absence of such data, route-to-route extrapolations may be conducted where appropriate, considering whether the critical effect is systemic and thus possible for each different route of exposure. The risk-associated dose shall be set at a level corresponding to an increased cancer risk of 1 in 100,000. If acceptable human epidemiologic data are available for a hazardous substance, then those data shall be used to derive the risk-associated dose. If acceptable human epidemiologic data are not available, then the risk-associated dose shall be derived from available animal bioassay data. Data from a species that is considered most biologically relevant to humans, that is, responds most like humans, is preferred where all other considerations regarding quality of data are equal. In the absence of data to distinguish the most relevant species, data from the most sensitive species tested, that is the species showing a carcinogenic effect at the lowest administered dose, shall generally be used. (3) If animal bioassay data are used and a non-threshold mechanism of carcinogenicity is assumed, then the data shall be fitted to a linearized multistage model, for example, a Global ‘86 or equivalent computer model. Global ‘86 is the linearized multistage model that was derived by Howe, Crump, and Van Landingham (1986), which was prepared for the United States environmental protection agency under subcontract 2-251u-2745 to Research Triangle Institute, contract 68-01-6826, and which the United States environmental protection agency uses to determine cancer potencies. The upper-bound 95% confidence limit on risk, or the lower 95% confidence limit on dose, at the 1 in 100,000 risk level shall be used to calculate a risk-associated dose for individual hazardous substances. Other models, including modifications or variations of the linearized multistage model that are more appropriate to the available data, may be used where scientifically justified. (4) If the duration of the study is significantly less than the natural lifespan of the test animal, then the slope factor may be adjusted on a case-by-case basis to compensate for latent tumors that were not expressed. The lifespan of a rat is assumed to be 104 weeks and the lifespan of a mouse is assumed to be 90 weeks. If the test animal is a rat and the study duration is less than 90 weeks, or if the test animal is a mouse and the study duration is less than 78 weeks, then the slope factor shall be multiplied by the following factor: the expected lifespan (L) divided by the study duration (Le ) raised to the third power, [(L/Le)3]. (5) A species scaling factor shall be used to account for differences between test species and humans. It shall be assumed that scaling daily administered doses by body mass raised to the 3/4 power achieves equivalence in lifetime carcinogenic risk in different mammalian species. To derive a human slope factor from animal data, the default procedure shall be to multiply the animal slope factor by the ratio of human to animal body weights raised to the 1/4 power. However, if adequate pharmacokinetic and metabolism studies are available, then these data may be factored into the adjustment for species differences on a case-by- case basis. (6) Additional adjustments shall be made to the data as appropriate. For some cancer data sets, it may be appropriate to combine incidences of multiple tumor types or combine benign and malignant tumors of the same histogenic origin. All doses shall be adjusted to give an average daily dose over the study duration. Adjustments shall be made to the tumor incidence for early mortality. Animals dying before the appearance of the first tumor within their dose group shall be removed from the data set. Before quantification of the dose response, a goodness-of-fit evaluation of the data shall be conducted. (7) If human epidemiologic data, animal bioassay data, or other biological data indicate that a chemical causes cancer via a threshold mechanism, then the risk-associated dose may, on a case-by-case basis, be calculated using a method that assumes a threshold mechanism is operative. (8) Inhalation unit risk factors shall be calculated in the same manner as cancer risk screening levels for inhalation risk under part 55 of the act.