Arguments on the following issues will be considered by the Secretary in identifying or classifying any substance pursuant to this part, if evidence for the specific substance subject to the rulemaking conforms to the following criteria. Such arguments and evidence will be evaluated based upon scientific and policy judgments.
(a) Non-positive results obtained in human epidemiologic studies. Non-positive results obtained in human epidemiologic studies regarding the substance subject to the rulemaking or to a similar or closely related substance will be considered by the Secretary only if they meet the following criteria:
Criteria. (i) The epidemiologic study involved at least 20 years' exposure of a group of subjects to the substance and at least 30 years' observation of the subjects after initial exposure;
(ii) Documented reasons are provided for predicting the site(s) at which the substance would induce cancer if it were carcinogenic in humans; and
(iii) The group of exposed subjects was large enough for an increase in cancer incidence of 50% above that in unexposed controls to have been detected at any of the predicted sites.
Arguments that non-positive results obtained in human epidemiologic studies should be used to establish numerical upper limits on potential risks to humans exposed to specific levels of a substance will be considered only if criteria (i) and (ii) are met and, in addition:
(iv) Specific data on the level of exposure of the group of workers are provided, based either on direct measurements made periodically throughout the period of exposure, or upon other data which provide reliable evidence of the magnitude of exposure.
(b) Tumors induced at site of administration. Arguments that tumors at the site of administration should not be considered will be considered only if:
(i) The route of administration is not oral, respiratory or dermal; and
(ii) Evidence is provided which establishes that induction of local tumors is related to the physical configuration or formulation of the material administered (e.g., crystalline form or dimensions of a solid material, or matrix of an impregnated implant) and that tumors are not induced when the same material is administered in a different configuration or formula.
(c) Metabolic differences. Arguments that differences in metabolic profiles can be used to demonstrate that a chemical found positive in an experimental study in a mammalian species would pose no potential carcinogenic risk to exposed workers will be considered by the Secretary only if the evidence presented for the specific substance subject to the rulemaking meets the following criteria:
Criteria. (i) A complete metabolic profile, including identities of trace metabolites, is presented for the experimental animal species;
(ii) A complete metabolic profile, including identities of trace metabolites, is available for a human population group representative of those who are occupationally exposed;
(iii) Documented evidence is provided for ascribing the carcinogenic activity of the substance in the test animal species to metabolite(s) produced only in that species and not in humans; and
(iv) Documented evidence is provided to show that other metabolites produced also in humans have been adequately tested and have not been shown to be carcinogenic.
(d) Use of high doses in animal testing. Arguments that positive results obtained in carcinogenesis bioassays with experimental animals subjected to high doses of a substance are not relevant to potential carcinogenic risks to exposed workers will be considered by the Secretary only if the evidence for the specific substance subject to the rulemaking meets the following criteria:
Criteria. (i) Documented evidence is presented to show that the substance in question is metabolized by the experimental animal species exposed at the dose levels used in the bioassay(s) to metabolic products which include one or more that are not produced in the same species at lower doses.
(ii) Documented evidence is presented to show that the metabolite(s) produced only at high doses in the experimental animal species are the ultimate carcinogen(s) and that the metabolites produced at low doses are not also carcinogenic; and
(iii) Documented evidence is presented to show that the metabolite(s) produced only at high doses in the experimental animal species are not produced in humans exposed to low doses.
(e) Benign tumors. The Secretary will consider evidence that the substance subject to the rulemaking proceeding is capable only of inducing benign tumors in humans or experimental animals provided that the evidence for the specific substance meets the following criteria:
Criteria. (i) Data are available from at least two well-conducted bioassays in each of two species of mammals (or from equivalent evidence in more than two species);
(ii) Each of the bioassays to be considered has been conducted for the full lifetime of the experimental animals;
(iii) The relevant tissue slides are made available to OSHA or its designee and the diagnoses of the tumors as benign are made by at least one qualified pathologist who has personally examined each of the slides and who provides specific diagnostic criteria and descriptions; and
(iv) All of the induced tumors must be shown to belong to a type which is known not to progress to malignancy or to be at a benign stage when observed. In the latter case, data must be presented to show that multiple sections of the affected organ(s) were adequately examined to search for invasion of the tumor cells into adjacent tissue, and that multiple sections of other organs were adequately examined to search for tumor metastases.
(f) Indirect mechanisms. The Secretary will consider evidence that positive results obtained in a carcinogenesis bioassay with experimental animals are not relevant to a determination of a carcinogenic risk to exposed workers, if the evidence demonstrates that the mechanism by which the observed tumor incidence is effected is indirect and would not occur if humans were exposed. As examples, evidence will be considered that a substance causes a carcinogenic effect by augmenting caloric intake or that the carcinogenic effect from exposure to a substance is demonstrated to be the result of the presence of a carcinogenic virus and it is demonstrated that, in either case, the effect would not take place in the absence of the particular carcinogenic virus or the augmented caloric intake.
[45 FR 5282, Jan. 22, 1980, as amended at 46 FR 5881, Jan. 21, 1981]