Abstract            Thispaper will provide a comprehensive introduction to the chemical Chloroform,comprising a description of its toxic characteristics as well as theirmanipulation throughout human history. Through studying the toxicodynamics ofChloroform as determined by various studies, its effects on the health ofhumans, other organisms, and the environment will be assessed. Considering bothits deleterious health effects and potential benefit to human industries, the extantregulation which has been established to address Chloroform usage will be examined. Following analysis of the nature of thiscompound and current standards for its management, more appropriate regulation measuresand further avenues which might be pursued for Chloroform research will besuggested.                          Keywords: Chloroform, Toxicodynamics,Human Health, Toxicant Regulation           Toxicant Assessment: Chloroform (Trichloromethane,CHCl13)            Indicatedby its chemical name trichloromethane, chloroform bears the molecular formulaCHCl13. The molecule’s tetrahedral structure renders it both polarand highly reactive, often necessitating its stabilization for industrial usewith amylene or ethanol (“Prudent Practices,” 2016). While the compound occursnaturally in the environment from the oxidation of chlorine-containing detritusin soil and the autotrophic action of marine plants, biogenic chloroform levelsare negligible to the amount produced by humans (Laturnus, Haselmann, Borch,; Grøn, 2002).

Such synthesis is largely intentional, namely the preparationof chloroform as a solvent in the pharmaceutical industry via the reduction of tetrachloromethaneor the hydrolysis of chloral hydrate (Sethuraman, Jones, and Dyer, 2016). However,chloroform also enters the atmosphere as an inadvertent by-product of thechlorination of water sources, such as recreational pools and drinkingreserves, for the purpose of disinfection. Accordingly, the EnvironmentalProtection Agency (2017) recognizes chloroform among “disinfection byproducts,”trihalomethanes produced by chlorinated water.             Liquidat room temperature, chloroform is a substance of high volatility which vaporizesinto a colorless gas with a saccharine odor. Denser than air, gaseouschloroform concentrates at low elevations.

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The EPA has identified a detectionthreshold of 85 PPM for chloroform’s odor, at which concentration it becomes sufficientfor human perception (National Center for Biotechnology Information, n.d.). Itsimperceptibility below this threshold raises concerns about chloroform levelsamong unsuspecting populations, as studies have recorded adverse effects ofchloroform vapor in male rats at a mere 25 PPM (Torkelson, Oyen, & Rowe, 1976).Contextualizing this value, an LC50 of 692 PPM was recorded amongmale mice exposed to chloroform via acute inhalation within a maximum period ofthree hours (Deringer, Dunn, and Heston, 1953).As previously mentioned, chloroform’s dipolemolecular alignment has made it a popular solvent in the pharmaceuticalindustry, facilitating the dissolution of various substances and the extractionof plant materials (Shephard, Soper, Callear,Imberti, Evans, and Salzmann, 2015). Relatively inexpensive to synthesize and thermallystable, chloroform is purified specifically for its application in nuclearmagnetic resonance spectroscopy, a technology which aids in the determinationof compounds’ structures (Burfield, 1979).             Currently restricted to industrialand commercial production in the United States, chloroform was previouslyadministered as anesthesia after the discovery of its medicinal applications byEdinburgh obstetrician James Simpson; although initial synthesis of chloroform in1837 is attributed to American physician Samuel Guthrie, who stumbled upon thechemical in his search for a more effective pesticide (Pawling, 1948), Simpson is credited with having performedthe first  chloroform narcosis (Wawersik, 1997).

Distorted to folkloricproportions throughout history, this first instance of narcosis was performed onNovember 4, 1847, when Simpson administered chloroform to himself and severaldinner guests (Henry, 2010). Chloroform was popular for uses beyond surgical anesthesia:sedation of the institutionalized, insomnia relief, pain maintenance inobstetrics (Rossen, 2016). Patients were treated via the application of achloroform saturated compress or mask covering the mouth and nasal regions.Although regulation passed by the Food and Drug Administration in the 1970s hasnearly eliminated chloroform’s presence consumer goods, the compound remainsaccessible to patients in low-income countries with limited health careresources.

(12th Report onCarcinogens, 2014).    This permissibleuse of chloroform globally threatens the well-being of financially vulnerablepopulations, as the compound has been regulated in the United States due to therevelation of its potentially detrimental effects on human health throughtoxicity testing.             Onesuch study performed by the National Cancer Institute Frederick Research Centeradministered chloroform orally in a minimum dose of 90mg/kg to a population of100 mice, comprising equal representations of males and females. Repeatingexposure for 78 weeks, findings suggested a correlation between chloroform andcarcinogenicity in the mice, females being more susceptible to the developmentof specific indicators: tumors in the liver and thyroid, liver necrosis,lesions in major organs (Reuber, 1979).  Furtherpositive results of carcinogenicity were obtained from a study which exposedmice to the toxicant via inhalation over a two-year period, suggesting adirectly proportional relationship between increased chloroform concentrationand hepatocellular or renal carcinomas (Matsushima, 1994). Although studies have consistently demonstratedcarcinogenicity in animals, the data obtained from such models cannot besatisfactorily extrapolated for human assessment. Thus, the EPA has merelyidentified chloroform as a possible human carcinogen (American Cancer Society,2016).

            While human carcinogenicity yet tobe concretely substantiated, acute exposure to chloroform bears immediateconsequences, as demonstrated in casestudies of individual harm. In addition to the kidney and liver, chloroformtargets the central nervous system and hearts of exposed individuals andthreatens 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 washistorically administered to patients, which complicated accurate dosing andallowed for incidental ingestion in addition to inhalation. While its narcoticeffect was desired, non-lethal adverse effects of chloroform includedisorientation or vertigo, gastrointestinal distress, hepatitis, nausea, cardiactremors, jaundice, and respiratory trauma (ASTDR, 1997). Once used in obstetrics,chloroform’s role in reproductive health also merits investigation, as wasattempted in a Swedish study of pregnant women with a history of industrialexposure; while researchers neglected to consider confounding lifestyle variables,they found an apparent correlation between chloroform exposure and teratogeniceffects among 869 observed pregnancies: miscarriages, birth defects, andimproper birth weights (Committee on Acute Exposure, 2012). In vitro studies bythe University of Sydney have measured such teratogenic effects of chloroformon rat embryos, finding that the compound triggers cell death within the neuraltube of the developing conceptus within 16 hours (Brown-Woodman et al., 1998).When extrapolated for humans, this data suggests that embryotoxic levels ofchloroform may exist at both fatal and tolerable levels for pregnantindividuals, able to penetrate the blood-placental barrier regardless of harmsustained by the parent (Kolman, 2007).

In order to comprehend the severity of chloroform’shealth threats, one must consider available pharmacokinetic data and the mechanismsby which it induces toxicity.  Whileinhalation in clinical practice was the predominant route of exposure forAmericans before the 1970s and persists in nations which have not regulated thetoxicant, chloroform is now largely encountered by the general public through oralingestion or dermal absorption of contaminated water (Weisel and Jo, 1996).  With an elimination half-life of approximately1.

5 hours (Kolman, 2007), chloroform moves rapidly through an individual onceabsorbed. In terms of the biologically effective dose, inhalation allows agreater amount of active chloroform metabolites to reach the liver butingestion and dermal routes allow the toxicant to circulate to a greater numberof organs: brain, kidney, heart, and bladder (Blancato and Chiu, 1993). Onceintroduced to the circulatory system, chloroform pervades the body quickly andconcentrates in lipids; the risk of bioaccumulation in fatty tissues, however,is unlikely due to the toxicant’s high volatility and rate of metabolism (ATSDR2015). Metabolism is mediated in the liver and kidney by oxidative reactions ofcytochrome P450, specifically the CYP2EI enzyme (Gemma, Vittozzi, & Testai,2003). These reactions produce the metabolite Phosgene, previously implementedin chemical warfare, which attacks hepatocyte and renal tissues by reducing levelsof the protective antioxidant glutathione (Branchflower, Nunn, Highet, Smith,Hook, and Pohl, 1984). Increased mutations in may result in attempts to recoverfrom cellular damage, raising further concerns for the carcinogenic effects ofchloroform toxicity (Tilley and Fry, 2015). While excretion pathways vary,chloroform is typically eliminated via exhalation and urine or feces; animalstudies have revealed detectable traces of radioactivity in waste products ofrats nearly 48 hours after exposure (ASTDR, 1997).  Although its adverse effects propelled theregulation of chloroform in the United States health care system, the toxicant persistsin American manufacturing.

The Occupation Safety and Health Administration(1976) has established a tolerable level of industrial exposure to chloroformat 2 PPM. Despite arguing the exposure below this threshold poses nosignificant threat, OSHA recommends annual urinalysis and liver examinations,cautioning laborers to consult with a physician regarding symptoms similar tochronic alcoholism. Additionally, the administration mandates the provision ofconstant protective outwear and respirators in emergencies. While suchrecommendations are prudent, employees’ adherence to regular medical consultationscannot be enforced. Given the responsibility to determine emergency conditions,employers might sacrifice the well-being of workers to minimize costs ofequipment and testing, as occurred in the decision to establish the permissibleexposure level of chloroform over an eight-hour period rather than institute a preferablehourly evaluation of levels (NIOSH, 1978).In addition to the FDA legislation barringchloroform in greater amounts than .05mg/in2 in food, cosmetics, anddrugs (ATSDR 1997), the EPA has identified 0.

07mg/L as the maximum contaminantlevel for chloroform in water sources (EPA, n.d.). Annual evaluations todetermine contaminant levels are ensured by the 1976 Congressional SafeDrinking Water Act, but Stages 1 and 2 of the Disinfection By-product Ruleswere developed specifically to address chlorinated contaminants in communitywater sources. Similar to its inclusion of chloroform under the Clean Air Act (Keith,1995), these rules lack strict enforcement and represent an inadequate responseto rising environmental contamination levels. Only greater vigilance andenforcement of compliance will prevent disturbances in aquatic ecosystems causedby the toxic effects of chloroform, such as its lethality to Bullhead andSucker fish (Clayberg, 1917).

An effective model is the Montreal Protocol of1987, an international treaty signed by the United Nations to reduce theproduction of chloromethanes and other compounds which threaten the ozone layer(Tsai, 2017). Whenconfronted with studies of chloroform’s adverse human health effects, theUnited States decision to federally regulate its presence in consumer goods andmedicine appears sound. Yet, the most alarming threat of chloroform is not the evidenceof its immediate harm but the lack of research into its potential to inflictlasting damage on humans and their environment. Until further research into itscarcinogenicity is pursued, alternative solvents and disinfectants must besubstituted for chloroform; thorough studies into its chronic health effectsshould be performed, to redress harm sustained in the workplace. Finally,government leaders must strive to develop global movements against chloroformdependence, protecting vulnerable populations around the world.

Whether suchmovements involve international compromise like the Montreal Protocol or simplyrequire the United States to set a precedent for nations of lower income, it isimperative that world leaders advocate for Chloroform alternatives in areas of industry,medicine, and water treatment