Exalnination of lacZ Mutant Induction in the Liver and Testis of Muta Mouse following Injection of Halogenated Aliphatic Hydrocarbons Classified as Human Carcinogens.

Abstract

Possible induction of lacZ mutation was examined in the liver and testis of Muta™Mouse following the administration of carcinogenic halogenated compounds, namely 1,2-dichloroethane (DCE), 1,2-dibromoethane (DBE), carbon tetrachloride, or 1,2-dibromo-3-chloropropane (DBCP). Slight increases were observed on the mutant frequency in the testis DNA isolated from the mice 14 days after treatment with DBCP at 40 mg/kg or with DBE at 60 mg/kg but not in the liver. Further investigation was necessary to confirm the mutation induction by these chemicals in the testis including experiments with longer sampling intervals. No increase was detected in the frequency following DCE administration of single doses of up to 150 mg/kg or of consecutive injections of up to 280 mg/ kg. Marginal but biologically insignificant responses were observed in the liver from the carbon tetrachloride exposed mice. The present results suggest that these carcinogenic chemicals are less efficient for induction of gene mutation in the liver of Muta™Mouse.

Investigation of potential early key events and mode of action for 1,2‐dichloroethane‐induced mammary tumors in female rats

“…However, in tissues where the cells are not actively dividing (e.g., liver), a key component for the fixation of DNA damage into mutations is lacking. Negative results for mutation induction in the livers of a transgenic MutaMouse study are consistent with the above conclusion (Hachiya & Motohashi, 2000). Unfortunately, Hachiya and Motohashi (2000) did not follow the current OECD guideline exposure protocol and a rapidly proliferating tissue such as the bone marrow was not examined; however, several peripheral blood erythrocyte micronucleus tests in mice reported negative results for DNA mutation following DCE exposure by inhalation (Armstrong & Galloway, 1993) or oral gavage (NTP, 1993; OECD, 2002).…”

“…Negative results for mutation induction in the livers of a transgenic MutaMouse study are consistent with the above conclusion (Hachiya & Motohashi, 2000). Unfortunately, Hachiya and Motohashi (2000) did not follow the current OECD guideline exposure protocol and a rapidly proliferating tissue such as the bone marrow was not examined; however, several peripheral blood erythrocyte micronucleus tests in mice reported negative results for DNA mutation following DCE exposure by inhalation (Armstrong & Galloway, 1993) or oral gavage (NTP, 1993; OECD, 2002). As the target tissue for the endpoint scored in the above assays was the bone marrow, the negative results would seem to indicate that the extent of DCE‐induced DNA damage in vivo is not adequate to lead to a detectable increase in chromosomal damage.…”

“…(i.e., adduct formation and DNA strand breakage) are not sufficient to induce apical mutagenicity(Pottenger et al, 2019 and references therein). Specifically for DCE, more work is needed to evaluate specific target organ mutagenicity (both mutation and chromosomal aberration), extending the work ofHachiya and Motohashi (2000) using an OECD 488-compliant protocol and including a rapidly dividing tissue (e.g., bone marrow). Contrary to the conclusion of Gwinn et al(2011), we believe that the results of the current study along with the previously reported in vivo mutagenicity data are not consistent with a mutagenic MoA for DCE.Assessment of the in vivo Comet assay in MEC enabled the direct assessment of cancer target cells for primary DNA damage, albeit via the use of an indicator assay as opposed to an assay directly measuring a mutagenic response.…”

Evaluating genotoxicity data to identify a mode of action and its application in estimating cancer risk at low doses: A case study involving carbon tetrachloride

“…An induction of micronuclei was reported in two studies in which the frequency of micronuclei was measured during the wave of cell proliferation that followed extensive liver toxicity [Van Goethem et al, 1993. Of particular note, CT was concluded to be nonmutagenic when assayed in three separate lacI or lacZ transgenic mouse assays [Mirsalis et al, 1994;Tombolan et al, 1999;Hachiya and Motohashi, 2000;Lambert et al, 2005].…”

Factors influencing mutagenic mode of action determinations of regulatory and advisory agencies

“…Negative results were seen in all properly conducted studies of unscheduled DNA synthesis in the hepatocytes of treated mice or rats. Of particular note, CCl 4 was considered to be nonmutagenic when assayed in three separate lacI or lacZ transgenic mouse assays [80][81][82][83].…”