Michigan Administrative Code › Department - Environmental Quality › Remediation and Redevelopment Division › Environmental Contamination Response Activity › CLEANUP CRITERIA REQUIREMENTS FOR RESPONSE ACTIVITY › Section R. 299.38 - Determination of cancer slope factors for use in calculation of criteria based on carcinogenic endpoints

Current through Vol. 24-12, July 15, 2024
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.