THMs induce cytotoxicity in the liver and kidneys of rodents exposed to doses of about 0.5 mmol/kg of body weight. The vehicle of administration significantly affects the toxicity of the THMs. The THMs have little reproductive and developmental toxicity, but BDCM has been shown to reduce sperm motility in rats consuming 39 mg/kg of body weight per day in drinking-water. Like chloroform, BDCM, when administered in corn oil, induces cancer in the liver and kidneys after lifetime exposures to high doses. Unlike chloroform and DBCM, BDCM and bromoform induce tumours of the large intestine in rats exposed by corn oil gavage. BDCM induces tumours at all three target sites and at lower doses than the other THMs. Since the publication of the 1994 WHO Environmental Health Criteria monograph on chloroform, additional studies have added to the weight of evidence indicating that chloroform is not a direct DNA-reactive mutagenic carcinogen. In contrast, the brominated THMs appear to be weak mutagens, probably as a result of GSH conjugation.
The HAAs have diverse toxicological effects in laboratory animals. Those HAAs of most concern have carcinogenic, reproductive and developmental effects. Neurotoxic effects are significant at the high doses of DCA that are used therapeutically. Carcinogenic effects appear to be limited to the liver and to high doses. The bulk of the evidence indicates that the tumorigenic effects of DCA and TCA depend on modifying processes of cell division and cell death rather than their very weak mutagenic activities. Oxidative stress is also a feature of the toxicity of the brominated analogues within this class. Both DCA and TCA cause cardiac malformations in rats at high doses.
Haloaldehydes and haloketones
Chloral hydrate induces hepatic necrosis in rats at doses equal to or greater than 120 mg/kg of body weight per day. Its depressant effect on the central nervous system in humans is probably related to its metabolite trichloroethanol. Limited toxicity data are available for the other halogenated aldehydes and ketones. Chloroacetaldehyde exposure causes haematological effects in rats. Exposure of mice to 1,1-dichloropropanone (1,1-DCPN), but not 1,3-dichloropropanone (1,3-DCPN), results in liver toxicity.
Chloral hydrate was negative in most but not all bacterial tests for point mutations and in in vivo studies on chromosomal damage. However, it has been shown that chloral hydrate may induce structural chromosomal aberrations in vitro and in vivo. Chloral hydrate has been reported to cause hepatic tumours in mice. It is not clear if it is the parent compound or its metabolites that are involved in the carcinogenic effect. The two chloral hydrate metabolites, TCA and DCA, have induced hepatic tumours in mice.
Some halogenated aldehydes and ketones are potent inducers of mutations in bacteria. Clastogenic effects have been reported for chlorinated propanones. Liver tumours were noted in a lifetime drinking-water study with chloroacetaldehyde. Other halogenated aldehydes, e.g., 2-chloropropenal, have been identified as tumour initiators in the skin of mice. The haloketones have not been tested for carcinogenicity in drinking-water. However, 1,3-DCPN acted as a tumour initiator in a skin carcinogenicity study in mice.
Testing of these compounds for toxicological effects has been limited to date. Some of the groups are mutagenic, but these effects do not relate well to the activity of the chemicals as tumour initiators in the skin. There are only very limited studies on the carcinogenicity of this class of substances. Early indications of developmental toxicity of members of this class appear to be largely attributable to the vehicle used in treatment.
Halogenated hydroxyfuranone derivatives
Based on experimental studies, the critical effects of MX appear to be its mutagenicity and carcinogenicity. Several in vitro studies have revealed that MX is mutagenic in bacterial and mammalian test systems. MX caused chromosomal aberrations and induced DNA damage in isolated liver and testicular cells and sister chromatid exchanges in peripheral lymphocytes from rats exposed in vivo. An overall evaluation of the mutagenicity data shows that MX is mutagenic in vitro and in vivo. A carcinogenicity study in rats showed increased tumour frequencies in several organs.