Dense Nonaqueous Phase Liquids (DNAPLs)

Halogenated Alkanes

Chloroform

Human Health Toxicity

The general population is exposed to chloroform via inhalation of ambient air, and through consumption of chlorine-disinfected drinking water. Chloroform in drinking water is also inhaled and/or absorbed through the skin when showering. Nursing infants can be exposed to chloroform in breast milk, or in formula prepared with treated drinking water. Some foods, dairy products for example, have been determined to contain chloroform. Although chloroform is no longer intentionally added to cosmetics, the chemical may be present as a byproduct or contaminant present in another ingredient. Workplace exposure to chloroform has been reported in industries that employ the chemical as a solvent or feedstock (pharmaceutical, photographic and pesticide industries, and laboratories).

Mammals, including humans, readily absorb chloroform by inhalation, ingestion, and skin absorption. Although a reductive pathway for chloroform metabolism exists in mammals, the major metabolic pathway is oxidative and generates carbon dioxide; however, the toxic gas phosgene is produced as an intermediary metabolite in the generation of carbon dioxide, with the formation of another toxic metabolite, hydrochloric acid. Rat studies indicate that the liver is probably the major site of chloroform metabolism.

There is evidence to suggest that chloroform's toxicity results from the cytotoxicity of its metabolites. The strongly electrophilic phosgene binds covalently to cellular proteins and phospholipids, disrupting cell function and ultimately causing cell death. Sustained tissue exposure to sufficiently high concentrations of chloroform results in a continuing cycle of cytotoxicity followed by regenerative cell proliferation. The evidence suggests these cyclical events are key to the induction of kidney and liver tumors in laboratory rodents (Watts et al 2004).

Many attempts have been made to determine whether a relationship exists between the use of chlorinated drinking water and the incidence of cancer in the human population, but chlorine-treated water contains many halogenated disinfection byproducts (e.g., trihalomethanes, or THMs) in addition to chloroform that might also exert toxic effects. A meta-analysis of epidemiological evidence suggests that THMs in drinking water can pose an increased risk of bladder cancer after long-term ingestion; however, the increased risk cannot be attributed solely to chloroform.

Many animal studies have been performed to determine the effects of chloroform on reproductive health and development. Most investigations reported no effects on development or reproduction.

Chloroform has been extensively investigated to establish whether it is genotoxic. The great majority of the studies report no evidence of genotoxicity.

The eleventh Report on Carcinogens classifies chloroform as "reasonably anticipated to be a human carcinogen" (NTP 2005). EPA's Integrated Risk Information System (IRIS) summary for chloroform states: "Chloroform is likely to be carcinogenic to humans by all routes of exposure under high-exposure conditions that lead to cytotoxicity and regenerative hyperplasia in susceptible tissues. Chloroform is not likely to be carcinogenic to humans by any route of exposure under exposure conditions that do not cause cytotoxicity and cell regeneration." This descriptor is consistent with EPA's current cancer guidelines (EPA 2005).

IRIS presents an RfD (an estimated daily oral exposure to chloroform that is likely to be without deleterious effects on the general population, including sensitive sub-groups) for chloroform of 0.01 mg/kg/day. IRIS also provides an Inhalation Unit Risk (IUR), the carcinogenic risk associated with continuous (lifetime) exposure to 1 µg/m3 chloroform in air. The IUR value is 2.3E-5 per µg/m3.

As of 2010, EPA has not developed a maximum contaminant level (MCL) for chloroform alone, but the total annual average trihalomethane amount for bromoform, chloroform, bromodichloromethane, and dibromochloromethane together should not exceed 80 mg/L for safe drinking water (EPA 2001).

The Regional Screening Levels (formerly Preliminary Remediation Goals) posted by EPA Region 9 identify risk-based concentrations for chloroform for the following common exposure pathways:

Residential soil	2.9 E-01 mg/kg
Industrial soil	1.5 E-00 mg/kg
Residential air	1.1 E-01 ug/m3
Industrial air	5.3 E-01 ug/m3
Tapwater	1.9 E-01 ug/l

References

Chloroform
Watts, P., G. Long, and M. Meek.
World Health Organization, Geneva, Concise International Chemical Assessment Document 58, 64 pp, 2004

Chloroform, CAS No. 67-66-3
Report on Carcinogens, Fourteenth Edition. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program (NTP), 2016

Chloroform (CASRN 67-66-3)
U.S. EPA, Integrated Risk Information System (IRIS)

Guidelines for Carcinogen Risk Assessment
U.S. Environmental Protection Agency, Washington, DC
EPA 630-P-03-001F, 166 pp, 2005

Stage 1 Disinfectants and Disinfection Byproducts Rule
U.S. EPA, Office of Water. EPA 816-F-01-014, 4 pp, 2001

Ecological Toxicity

Chloroform has been observed to inhibit the anaerobic digestion of sewage sludge at a concentration of 0.1 mg/L. Some investigations indicate an inhibitory effect at 0.5 mg/L, although the microorganisms responsible for anaerobic digestion will acclimate to the presence of higher concentrations of chloroform, up to 15 mg/L. A concentration of 20 mg/L inhibited digestion, and the microbial community did not recover (Watts et al. 2004). Other microorganisms, such as freshwater and marine algae, have been found to be sensitive to chloroform. A species of marine phytoplankton, Skeltonema costatum, showed no effects from a 5-day exposure to a chloroform concentration of 216 mg/L. An EC₅₀ (5-day) for a cell count of 477 mg/L was determined. An EC₅₀ is the median concentration of a toxicant that produces an effect on 50% of the population under consideration in a stated time. A 13.3 mg/L EC₅₀ (72 hours) for growth inhibition has been reported for the freshwater alga Chlamydomonas reinhardtii.

LC₅₀ studies indicate that chloroform is "slightly toxic" to the northern pink shrimp and "not acutely toxic" to the fairy shrimp. Chloroform is "slightly toxic" to the midge Chironimus riparus but "not acutely toxic" to Tallaperia maria, a species of stonefly (Kegley et al. 2010).

A 96-hour LC₅₀ study using immature ramshorn snails (Heliosoma trivolvis), an aquatic mollusk, as the test subject reported that chloroform was not acutely toxic at a concentration of 232.4 mg/L.

Most of the large number of LC₅₀ studies performed on fish indicate either slight chloroform toxicity, or that the compound is not acutely toxic; however, moderate toxicity to 4-day post-hatch rainbow trout (Oncorhynchus mykiss) and bluegill (Lepomis macrochirus) has been reported, with 28-day LC₅₀s from 1 to 2 mg/L and a 7-day LC₅₀ of 2 mg/L, respectively. Although chloroform is not acutely toxic to the Japanese medaka, chronic exposure (9 months) to 1.463 mg/L was associated with gall bladder and bile duct abnormalities that included cell proliferation and hyperplasia (Kegley et al. 2010).

The 4-day post-hatch rainbow trout and bluegill were found to be most sensitive to chloroform, and the tadpole stage of some amphibians appeared to be similarly sensitive. LC₅₀ values (7 to 9 day exposure) of 0.27 mg/L and 4.16 mg/L have been determined for 4-day post-hatch spring peepers (Hyalis crucifer) and leopard frogs (Rana pipiens), respectively. The African clawed toad (Xenopus laevis) is less sensitive, with an LC₅₀ >68 mg/L for the 4-day post-hatch stage (Kegley et al. 2010).

Very few studies are available that have investigated the toxicity of chloroform to terrestrial wildlife; however, there is concern for the potential toxicity of VOCs toward burrowing animals, such as snakes, tortoises, gophers, ground squirrels, rats, moles, voles, coyotes, badgers, and foxes, as well as birds such as the burrowing owl. Subsurface soil contaminated with VOCs presents a risk from inhalation exposure, as there may be little dispersion of the contaminant from air in a burrow to the external atmosphere. Some species spend most of their lives within their burrows, and many burrowing species rear their young in nurseries constructed within them. An Ecological Screening level (ESL) of 20 mg/m³ for chloroform has been developed and is described in Roy et al. (2009).

References

Chloroform
Watts, P., G. Long, and M. Meek.
World Health Organization, Geneva, Concise International Chemical Assessment Document 58, 64 pp, 2004

Chloroform: Identification, Toxicity, Use, Water Pollution Potential, Ecological Toxicity and Regulatory Information
Kegley, S.E., B.R. Hill, S. Orme, and A.H. Choi.
PAN Pesticide Database. Pesticide Action Network, San Francisco, CA, 2010