Evaluation of a three‐exposure mouse bone marrow micronucleus protocol: Results with 49 chemicals

Abstract

Forty-nine chemicals were tested in a mouse bone marrow micronucleus test that employed three daily exposures by intraperitoneal injection. Bone marrow samples were obtained 24 hr following the final exposure. Twenty-five rodent carcinogens and 24 noncarcinogens were selected randomly from the 44 carcinogens and 29 noncarcinogens used by Tennant et al. (Science 236:933-941, 1987) to evaluate the performance of four in vitro genetic toxicity tests. As in that study of in vitro tests, the micronucleus tests were conducted with coded chemicals and test results (positive or negative) were determined prior to decoding. This study was conducted as part of an effort to assess the ability of the micronucleus test to discriminate between rodent carcinogens and noncarcinogens and to determine its potential role, in combination with other short-term tests, in identifying genotoxic chemicals that present a carcinogenic hazard. Nine chemicals were judged to be positive in the micronucleus test. This relatively low number of positive results, along with published and unpublished results from rodent micronucleus and chromosome aberration assays on several of these 49 chemicals, contributed to the conclusion that a single micronucleus test protocol is not adequate to detect all chemicals capable of inducing chromosomal damage in the bone marrow. However, a combination of two relatively simple assays such as the Salmonella and micronucleus tests can provide important information on the genetic toxicity of test chemicals and may provide guidance on the need for and the nature and extent of future toxicity studies.

Comparative Activity of Human Carcinogens and NTP Rodent Carcinogens in the Mouse Bone Marrow Micronucleus Assay: An Integrative Approach to Genetic Toxicity Data Assessment

“…Ic). If Shelby et al (1) noted that several of the NTP carcinogens that were negative in the MN assay may eventually be shown to produce tumors in rodents by a nongenotoxic mechanism of action. If that were to be established, the negative MN assay responses would help define such chemicals as nongenotoxic carcinogens, rather than challenging the sensitivity of the MN assay itself.…”

“…Such a synthesis of all available data enables, for example, the potential human hazard posed by exposure to fotemustine or vitamin C to be objectively distinguished (Table 5), despite the fact that each chemical can be described as "active in the mouse bone marrow micronucleus assay." A similarly integrated approach to rodent carcinogenicity data assessment would probably also reveal a gulf between the potential carcinogenic hazard presented to humans by classical rodent carcinogens such as ethylnitrosourea and dimethylbenzanthracene ( Table 2) and most of the NTP rodent carcinogens studied by Shelby et al (1).…”

“…Thus, we have become accustomed to conducting exploratory MN assays on agents suspected of having carcinogenic activity in humans at the low starting dose of 1 mg/kg. Within that context, we became concerned when Shelby et al (1) reported the micronucleus results for 49 chemicals tested earlier for rodent carcinogenicity by the U.S. National Toxicology Program (NTP). Only 5 (data from Table 3); (c) 4 of the 24 Tables 1 and 2 could have been tested at higher dose levels, therefore the maximum fold-increases shown sometimes represent a conservative estimate (eg., fotemustine, chlorambucil, and procarbazine).…”

Titanium dioxide (respirable fraction) [MAK Value Documentation, 2009]

“…The value in the high dose group, in which low cytotoxicity was determined (47.6% PCE compared with 49.8% in the controls), was not significantly increased. The authors regard the result as positive (Shelby et al 1993) As the particle size of the titanium dioxide used is not specified, it is not possible to clarify whether ultrafine or fine particles were used.…”

Comparison of the Effects of Cinnamyl Anthranilate on Hepatic Peroxisome Proliferation and Cell Replication in the Rat and Mouse

“…The compound has been reported to ' be generally negative in a number of short-term tests for mutagenic and genotoxic potential (LARC, 1983;Wild et al, 1983;Ashby, 1988Ashby, , 1994Mirsalis et al, 1989;Shelby et al, 1993).…”