Abstract This paper will provide a comprehensive


paper will provide a comprehensive introduction to the chemical Chloroform,
comprising a description of its toxic characteristics as well as their
manipulation throughout human history. Through studying the toxicodynamics of
Chloroform as determined by various studies, its effects on the health of
humans, other organisms, and the environment will be assessed. Considering both
its deleterious health effects and potential benefit to human industries, the extant
regulation which has been established to address Chloroform usage will be examined.
 Following analysis of the nature of this
compound and current standards for its management, more appropriate regulation measures
and further avenues which might be pursued for Chloroform research will be

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                        Keywords: Chloroform, Toxicodynamics,
Human Health, Toxicant Regulation












Toxicant Assessment: Chloroform (Trichloromethane,

by its chemical name trichloromethane, chloroform bears the molecular formula
CHCl13. The molecule’s tetrahedral structure renders it both polar
and highly reactive, often necessitating its stabilization for industrial use
with amylene or ethanol (“Prudent Practices,” 2016). While the compound occurs
naturally in the environment from the oxidation of chlorine-containing detritus
in soil and the autotrophic action of marine plants, biogenic chloroform levels
are negligible to the amount produced by humans (Laturnus, Haselmann, Borch,
; Grøn, 2002). Such synthesis is largely intentional, namely the preparation
of chloroform as a solvent in the pharmaceutical industry via the reduction of tetrachloromethane
or the hydrolysis of chloral hydrate (Sethuraman, Jones, and Dyer, 2016). However,
chloroform also enters the atmosphere as an inadvertent by-product of the
chlorination of water sources, such as recreational pools and drinking
reserves, for the purpose of disinfection. Accordingly, the Environmental
Protection Agency (2017) recognizes chloroform among “disinfection byproducts,”
trihalomethanes produced by chlorinated water.

at room temperature, chloroform is a substance of high volatility which vaporizes
into a colorless gas with a saccharine odor. Denser than air, gaseous
chloroform concentrates at low elevations. The EPA has identified a detection
threshold of 85 PPM for chloroform’s odor, at which concentration it becomes sufficient
for human perception (National Center for Biotechnology Information, n.d.). Its
imperceptibility below this threshold raises concerns about chloroform levels
among unsuspecting populations, as studies have recorded adverse effects of
chloroform vapor in male rats at a mere 25 PPM (Torkelson, Oyen, & Rowe, 1976).
Contextualizing this value, an LC50 of 692 PPM was recorded among
male mice exposed to chloroform via acute inhalation within a maximum period of
three hours (Deringer, Dunn, and Heston, 1953).

As previously mentioned, chloroform’s dipole
molecular alignment has made it a popular solvent in the pharmaceutical
industry, facilitating the dissolution of various substances and the extraction
of plant materials (Shephard, Soper, Callear,
Imberti, Evans, and Salzmann, 2015). Relatively inexpensive to synthesize and thermally
stable, chloroform is purified specifically for its application in nuclear
magnetic resonance spectroscopy, a technology which aids in the determination
of compounds’ structures (Burfield, 1979).

            Currently restricted to industrial
and commercial production in the United States, chloroform was previously
administered as anesthesia after the discovery of its medicinal applications by
Edinburgh obstetrician James Simpson; although initial synthesis of chloroform in
1837 is attributed to American physician Samuel Guthrie, who stumbled upon the
chemical in his search for a more effective pesticide (Pawling, 1948), Simpson is credited with having performed
the first  chloroform narcosis (Wawersik, 1997). Distorted to folkloric
proportions throughout history, this first instance of narcosis was performed on
November 4, 1847, when Simpson administered chloroform to himself and several
dinner guests (Henry, 2010). Chloroform was popular for uses beyond surgical anesthesia:
sedation of the institutionalized, insomnia relief, pain maintenance in
obstetrics (Rossen, 2016). Patients were treated via the application of a
chloroform saturated compress or mask covering the mouth and nasal regions.
Although regulation passed by the Food and Drug Administration in the 1970s has
nearly eliminated chloroform’s presence consumer goods, the compound remains
accessible to patients in low-income countries with limited health care
resources. (12th Report on
Carcinogens, 2014).    This permissible
use of chloroform globally threatens the well-being of financially vulnerable
populations, as the compound has been regulated in the United States due to the
revelation of its potentially detrimental effects on human health through
toxicity testing.

such study performed by the National Cancer Institute Frederick Research Center
administered chloroform orally in a minimum dose of 90mg/kg to a population of
100 mice, comprising equal representations of males and females. Repeating
exposure for 78 weeks, findings suggested a correlation between chloroform and
carcinogenicity in the mice, females being more susceptible to the development
of specific indicators: tumors in the liver and thyroid, liver necrosis,
lesions in major organs (Reuber, 1979).  Further
positive results of carcinogenicity were obtained from a study which exposed
mice to the toxicant via inhalation over a two-year period, suggesting a
directly proportional relationship between increased chloroform concentration
and hepatocellular or renal carcinomas (Matsushima, 1994). Although studies have consistently demonstrated
carcinogenicity in animals, the data obtained from such models cannot be
satisfactorily extrapolated for human assessment. Thus, the EPA has merely
identified chloroform as a possible human carcinogen (American Cancer Society,

            While human carcinogenicity yet to
be concretely substantiated, acute exposure to chloroform bears immediate
consequences, as demonstrated in case
studies of individual harm. In addition to the kidney and liver, chloroform
targets the central nervous system and hearts of exposed individuals and
threatens to depress neurological or cardiac function to the point of fatality,
which has occurred with the ingestion of less than 10 mL of the toxicant (Kolman,
2007). This risk was magnified by the imprecise nature in which chloroform was
historically administered to patients, which complicated accurate dosing and
allowed for incidental ingestion in addition to inhalation. While its narcotic
effect was desired, non-lethal adverse effects of chloroform include
disorientation or vertigo, gastrointestinal distress, hepatitis, nausea, cardiac
tremors, jaundice, and respiratory trauma (ASTDR, 1997). Once used in obstetrics,
chloroform’s role in reproductive health also merits investigation, as was
attempted in a Swedish study of pregnant women with a history of industrial
exposure; while researchers neglected to consider confounding lifestyle variables,
they found an apparent correlation between chloroform exposure and teratogenic
effects among 869 observed pregnancies: miscarriages, birth defects, and
improper birth weights (Committee on Acute Exposure, 2012). In vitro studies by
the University of Sydney have measured such teratogenic effects of chloroform
on rat embryos, finding that the compound triggers cell death within the neural
tube of the developing conceptus within 16 hours (Brown-Woodman et al., 1998).
When extrapolated for humans, this data suggests that embryotoxic levels of
chloroform may exist at both fatal and tolerable levels for pregnant
individuals, able to penetrate the blood-placental barrier regardless of harm
sustained by the parent (Kolman, 2007).

In order to comprehend the severity of chloroform’s
health threats, one must consider available pharmacokinetic data and the mechanisms
by which it induces toxicity.  While
inhalation in clinical practice was the predominant route of exposure for
Americans before the 1970s and persists in nations which have not regulated the
toxicant, chloroform is now largely encountered by the general public through oral
ingestion or dermal absorption of contaminated water (Weisel and Jo, 1996).  With an elimination half-life of approximately
1.5 hours (Kolman, 2007), chloroform moves rapidly through an individual once
absorbed. In terms of the biologically effective dose, inhalation allows a
greater amount of active chloroform metabolites to reach the liver but
ingestion and dermal routes allow the toxicant to circulate to a greater number
of organs: brain, kidney, heart, and bladder (Blancato and Chiu, 1993). Once
introduced to the circulatory system, chloroform pervades the body quickly and
concentrates in lipids; the risk of bioaccumulation in fatty tissues, however,
is unlikely due to the toxicant’s high volatility and rate of metabolism (ATSDR
2015). Metabolism is mediated in the liver and kidney by oxidative reactions of
cytochrome P450, specifically the CYP2EI enzyme (Gemma, Vittozzi, & Testai,
2003). These reactions produce the metabolite Phosgene, previously implemented
in chemical warfare, which attacks hepatocyte and renal tissues by reducing levels
of the protective antioxidant glutathione (Branchflower, Nunn, Highet, Smith,
Hook, and Pohl, 1984). Increased mutations in may result in attempts to recover
from cellular damage, raising further concerns for the carcinogenic effects of
chloroform toxicity (Tilley and Fry, 2015). While excretion pathways vary,
chloroform is typically eliminated via exhalation and urine or feces; animal
studies have revealed detectable traces of radioactivity in waste products of
rats nearly 48 hours after exposure (ASTDR, 1997).  

Although its adverse effects propelled the
regulation of chloroform in the United States health care system, the toxicant persists
in American manufacturing. The Occupation Safety and Health Administration
(1976) has established a tolerable level of industrial exposure to chloroform
at 2 PPM. Despite arguing the exposure below this threshold poses no
significant threat, OSHA recommends annual urinalysis and liver examinations,
cautioning laborers to consult with a physician regarding symptoms similar to
chronic alcoholism. Additionally, the administration mandates the provision of
constant protective outwear and respirators in emergencies. While such
recommendations are prudent, employees’ adherence to regular medical consultations
cannot be enforced. Given the responsibility to determine emergency conditions,
employers might sacrifice the well-being of workers to minimize costs of
equipment and testing, as occurred in the decision to establish the permissible
exposure level of chloroform over an eight-hour period rather than institute a preferable
hourly evaluation of levels (NIOSH, 1978).

In addition to the FDA legislation barring
chloroform in greater amounts than .05mg/in2 in food, cosmetics, and
drugs (ATSDR 1997), the EPA has identified 0.07mg/L as the maximum contaminant
level for chloroform in water sources (EPA, n.d.). Annual evaluations to
determine contaminant levels are ensured by the 1976 Congressional Safe
Drinking Water Act, but Stages 1 and 2 of the Disinfection By-product Rules
were developed specifically to address chlorinated contaminants in community
water sources. Similar to its inclusion of chloroform under the Clean Air Act (Keith,
1995), these rules lack strict enforcement and represent an inadequate response
to rising environmental contamination levels. Only greater vigilance and
enforcement of compliance will prevent disturbances in aquatic ecosystems caused
by the toxic effects of chloroform, such as its lethality to Bullhead and
Sucker fish (Clayberg, 1917). An effective model is the Montreal Protocol of
1987, an international treaty signed by the United Nations to reduce the
production of chloromethanes and other compounds which threaten the ozone layer
(Tsai, 2017).

confronted with studies of chloroform’s adverse human health effects, the
United States decision to federally regulate its presence in consumer goods and
medicine appears sound. Yet, the most alarming threat of chloroform is not the evidence
of its immediate harm but the lack of research into its potential to inflict
lasting damage on humans and their environment. Until further research into its
carcinogenicity is pursued, alternative solvents and disinfectants must be
substituted for chloroform; thorough studies into its chronic health effects
should be performed, to redress harm sustained in the workplace. Finally,
government leaders must strive to develop global movements against chloroform
dependence, protecting vulnerable populations around the world. Whether such
movements involve international compromise like the Montreal Protocol or simply
require the United States to set a precedent for nations of lower income, it is
imperative that world leaders advocate for Chloroform alternatives in areas of industry,
medicine, and water treatment