Chloroform, toxicity

Smith, J.H., Maita, K., Sleight, S.D. and Hook, J.B. (1983). Mechanism of chloroform nephrotoxicity. I. Time course of chloroform toxicity in male and female mice. Toxicol. Appl. Pharmacol. 70 467-479. 

Most of the data regarding inhalation exposure to chloroform in humans were obtained from clinical reports describing health effects in patients under anesthesia. In some instances, the results may have been confounded by the concurrent administration of other drugs with chloroform or by artificial respiration of patients under chloroform anesthesia. Furthermore, most of the studies did not provide any information regarding actual exposure levels for observed effects. Nonetheless, chloroform-induced effects in humans are supported by those observed in animals under experimental conditions. The human studies cited in the profile provide qualitative information on chloroform toxicity in humans. 

The central nervous system is a major target for chloroform toxicity in humans and in animals. 

Differences in chloroform toxicity based on the vehicle have also been recently reported elsewhere (Larson etal. 1994b, 1995a)... 

Risk Assessment. This model successfully described the disposition of chloroform in rats, mice and humans following various exposure scenarios and developed dose surrogates more closely related to toxicity response. With regard to target tissue dosimetry, the Corley model predicts the relative order of susceptibility to chloroform toxicity consequent to binding to macromolecules (MMB) to be mouse > rat > human. Linking the pharmacokinetic parameters of this model to the pharmacodynamic cancer model of Reitz et al. (1990) provides a biologically based risk assessment model for chloroform. 

Most of the presented information regarding chloroform toxicity following inhalation exposure in humans was obtained from clinical case reports of patients undergoing anesthesia. In some instances, the results in these studies may have been confounded by unreported data, such as the intake of other drugs or the use of artificial respiration during anesthesia. 

The target organs of chloroform toxicity in humans and animals are the central nervous system, liver, and kidneys. There is a great deal of similarity between chloroform-induced effects following inhalation and oral exposure. No studies were located regarding reproductive effects in humans after exposure to chloroform alone however, Bove et al. (1995) studied the effects of drinking-water consumption on birth outcomes and found that exposure to TTHM at levels >0.1 ppm resulted in reduced birth weight and size as well as an increased risk of oral cleft, central nervous system, and neural tube defects. Since the authors... 

The reader is advised to exercise caution in the extrapolation of toxicity data from animals to humans. Species-related differences in sensitivity must be accounted for. Some studies utilized to derive MRLs or otherwise extrapolate data, is dated however, they do represent the body of knowledge regarding chloroform toxicity. In addition, many of the human studies quoted involved clinical case reports in which chloroform was utilized either as an anesthetic or as an agent of suicide. Such doses are clearly excessive and would not be encountered by the general population. These and other issues are addressed in Section 2.10. 

Musculoskeletal Effects. Little data is available that examines the effects of chloroform toxicity on the musculoskeletal system however, it appears that chloroform has few significant toxic effects on this system. 

Hepatic Effects. The liver is a primary target organ of chloroform toxicity in humans and animals after inhalation and oral exposure, with some evidence that suggests that the damage may be reversible (Wallace 1950). Impaired liver function was indicated by increased sulfobromophthalein retention in some patients exposed to chloroform via anesthesia (Smith et al. 1973). Acute toxic hepatitis developed after childbirth in several women exposed to chloroform via anesthesia (Lunt 1953 Royston 1924 Townsend 1939). 

Endocrine Effects. No reports of chloroform toxicity to endocrine organs have been reported. 

The clinical effects of chloroform toxicity on the central nervous system are well documented. However, the molecular mechanism of action is not well understood. It has been postulated that anesthetics induce their action at a cell-membrane level due to lipid solubility. The lipid-disordering effect of chloroform and other anesthetics on membrane lipids was increased by gangliosides (Harris and Groh 1985), which may explain why the outer leaflet of the lipid bilayer of neuronal membranes, which has a large ganglioside content, is unusually sensitive to anesthetic agents. Anesthetics may affect calcium-dependent potassium conductance in the central nervous system (Caldwell and Harris 1985). The blockage of potassium conductance by chloroform and other anesthetics resulted in depolarization of squid axon (Haydon et al. 1988). 

A mixture of cadmium and chloroform potentiated the cytotoxicity of each in in vitro experiments in rat hepatocytes (Stacey 1987a, 1987b). In contrast, mirex did not increase chloroform toxicity in mice (Hewitt... 

Target organs of chloroform toxicity are the central nervous system, liver, and kidneys (see Section 2.2). Respiratory, cardiovascular, and gastrointestinal toxic effects have also been reported. Studies in animals also indicated that chloroform exposure may induce reproductive and developmental effects and cause cancer. Several studies investigated the possible mechanism for chloroform-induced toxicity (see Section 2.5). Proposed mechanisms of chloroform toxicity and potential mitigations based on these mechanisms are discussed below. The potential mitigation techniques mentioned are all experimental. 

Acute-Duration Exposure. Clinical reports indicate that the central nervous system, cardiovascular system, stomach, liver, and kidneys in humans are target organs of chloroform toxicity after inhalation and oral exposure to chloroform (Schroeder 1965 Smith et al. 1973 Whitaker and Jones 1965). These findings are supported by results obtained from acute inhalation and oral-exposure studies in animals in which target organs identical to those observed in human studies (central nervous... 

Aniya Y, Ojiri Y, Sunagawa R, et al. 1989. Glutathione s-transferases and chloroform toxicity in streptozotocin-induced diabetic rats. Jpn J Pharmacol 50 263-269. 

Clemens TL, Hill RN, Bullock LP, et al. 1979. Chloroform toxicity in the mouse Role of genetic factors and steroids. Toxicol Appl Pharmacol 48 117-130. 

Davis ME, Bemdt WO. 1992. Sex differenees in monoehloroaeetate pretreatment effects on chloroform toxicity in rats. Fundam Appl Toxicol 18(1) 66-71. 

El-shenawy NS, Abdel-Rahman MS. 1993a. The mechanism of chloroform toxicity in isolated rat hepatocytes. Toxicol Lett 69(l) 77-85. 

Hill RN, Clemens TL, Liu DK, et al. 1975. Genetic control of chloroform toxicity in mice. Science 190 159-161. 

Ilett KF, Reid WD, Sipes IG, et al. 1973. Chloroform toxicity in mice Correlation of renal and hepatic necrosis with covalent binding of metabolites to tissue macromolecules. Exp Mol Pathol 19 215-229. 

Kluwe WM, Hook JB. 1978. Polybrominated biphenyl-induced potentiation of chloroform toxicity. Toxicol Appl Phannacol 45 861-869. 

Davis ME. Dichloroacetic acid and trichloroacetic acid increase chloroform toxicity. J Toxicol Environ Health 1992 37(1) 139-48. 

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