©2001 CRC Press LLC chapter seven Organic solvents and related chemicals “ ’Tis a sordid profit that’s accompanied by the destruc- tion of health.” Treatise on the Diseases of Tradesmen B. Ramazzini, 1705 Introduction Organic solvents are common in the workplace where they may constitute an occupational hazard. They also occur in the home in the form of cleaning solutions, paint strippers, and brush cleaners and they can thus be a source of household poisoning as well as being an environmental hazard. Because they are all fat solvents, they may cause local defatting of tissue and irrita- tion on contact. Many also are systemic toxicants, affecting the CNS like volatile anesthetics or, in some cases, the hematopoietic (blood-forming) system. Commercial solvents are frequently complex mixtures having nitro- gen- and sulfur-containing elements (e.g., gasoline and other petroleum- based products). Industrially, the uses of solvents are many and varied. They are used in extraction processes in the food and pharmaceutical industries (e.g., ethyl alcohol and acetone), for the removal of impurities, for degreasing and vapor cleaning (e.g., trichloroethylene and 1,1,1,-trichloroethane), as vehicles for paints, as carriers for pesticides, for printing inks (e.g., toluene and ethyl acetate), and in adhesives (e.g., hexane, toluene, and methylethyl ketone). In short, volatile solvents are used whenever a fast-drying property is desired in order to leave a coating on a surface. They are also used in the chemical industry for a variety of manufacturing processes. ©2001 CRC Press LLC Classes of solvents Aliphatic hydrocarbons Aliphatic hydrocarbons are straight-chain or branched carbon-hydrogen compounds. They are often present in complex mixtures in common com- mercial products such as gasoline, mineral turpentine, and kerosene. These mixtures can also contain smaller amounts of unsaturated and cyclic carbon- hydrogen substances. While the vapors of these agents are generally less toxic than those of most organic solvents, inhaling the fumes can not only cause disorientation and stupor through effects on the CNS, but also can sensitize the heart to adrenaline. The result may be ventricular fibrillation that can be fatal if not corrected quickly. Fatalities have occurred in workmen cleaning storage tanks and rail tank cars. Chemical pneumonia often occurs from aspiration of the low-viscosity liquid (an occupational hazard for those who siphon gasoline from others’ cars!). One member of this solvent group of special note is n -hexane, the main ingredient of petroleum ether. With a boiling point of 60 to 80°C, it evaporates readily and produces an insidious form of poisoning. An outbreak of industrial poisoning occurred in Japan in 1973 when workers exposed to fumes from a glue used in making sandals lost sensation and function in fingers and toes from impaired nerve conduc- tion. When the exposure was terminated, they all recovered slowly over several months. Hexane neuropathy has both a central and a peripheral component resulting from demyelination of nerve fibers. The actual toxicant is a metabolite of n -hexane, hexane-2,5-dione. An intermediate, 2-hexanone, is also more toxic than the parent substance. If the neurotoxicity of n -hexane is rated as 1, then 2-hexanone would be 10 and hexane-2,5-dione would be 40. Metabolites are produced in the liver by cytochrome P450 oxidases. They appear to condense with lysine in the myeline, causing disorganization of the membrane. Halogenated aliphatic hydrocarbons This group of substances containing chlorine substituents includes methyl- ene dichloride, chloroform, carbon tetrachloride, and chlorinated ethylenes (e.g., trichloroethylene), as well as a number of chemicals that contain other halogens such as bromine and fluorine. They are used as anesthetics and refrigerants. Hepatotoxicity and nephrotoxicity characterize this group. The liver converts carbon tetrachloride (CCl 4 ) to the free radical · CCl 3 that attacks the endoplasmic reticulum, causing protein synthesis to cease. Recovery will O O O CH 3 (CH 2 ) 4 CH 3 — oxidation CH 3 -C-(CH 2 ) 3 CH 3 — oxidation CH 3 -C-(CH 2 ) 3 -C-CH 3 n-HEXANE 2-HEXANONE HEXANE-2,5-DIONE ©2001 CRC Press LLC usually occur from a single toxic exposure, but repeated exposures lead to cirrhosis. Chloroform is converted to phosgene (COCl 2 ), which has similar toxicity to CCl 4 . Phosgene was used as a poison gas in World War I. The chemical reactions involved in this process are illustrated in Chapter 4 (see Figure 24). Trichloroethylene was used as a light anesthetic in childbirth. It and similar agents are used as industrial solvents. Fatalities have occurred when workers in enclosed tanks were overcome. Death usually results from aspi- ration of vomit. It is also hepatotoxic. Dichloromethane (methylene chloride) was used for many years as a paint stripper. It has a boiling point of 40°C and thus readily forms vapor. It is converted to carbon monoxide (CO), which forms carboxyhemoglobin in the red blood cells (see Chapter 5). Bis(chloromethyl)ether is discussed below under “Solvent-related cancer in the workplace.” Other halogenated hydrocarbons are discussed in Chapter 4, and the chlorofluorcarbons (CFCs) and their impact on the environment in Chapter 5. Some anesthetics are halogenated hydrocarbons. One such is halothane, chemically a haloalkane, a volatile liquid. Although most hal- othane is eliminated in the expired air, some undergoes hepatic biotransfor- mation to a reactive metabolite, an alkylating radical, which causes lipid peroxidation and is hepatotoxic. It does not deplete glutathione as do some hepatotoxic agents. The reaction is mediated by cytochrome P450 and tox- icity is increased by hypoxia. The incidence of this toxic reaction is low, perhaps 1 in 38,000 patients, and it appears to be genetically determined. Other halogen-containing general anesthetics are methoxyflurane, enflu- rane, and isoflurane. Methoxyflurane is rarely used in North America now because it releases free fluoride during biotransformation. Free fluoride is toxic to the kidney. Aliphatic alcohols Ethanol (ethyl alcohol) is present in alcoholic beverages and also in some lotions, perfumes, mouth washes, cough syrups, etc. Although there is a tendency to trivialize ethanol’s toxicity, 3 to 6 mL/kg of pure ethanol can be fatal. Because 70 proof liquor contains 40% ethanol, this fatal adult dose equates with as little as 525 mL of liquor. In severe poisoning, the classical signs of inebriation (difficulty with balance, locomotion, and talking) progress to coma, metabolic acidosis, hypothermia, hypotension, and severe respiratory depression. Hypoglycemia may be present, especially in young children. Treatment is largely supportive, with correction of acidosis and hypoglycemia (5% glucose i.v.) and hemodialysis to remove ethanol and its metabolites. Other simple alcohols and glycols produce early effects resem- bling ethanol intoxication, which is why they are often abused by alcoholics who are at the bottom of the socioeconomic scale. Methanol is by far the most toxic of the alcohols. In humans and other primates, it is oxidized to formaldehyde, a very reactive substance which ©2001 CRC Press LLC the eye cannot convert to the harmless formate anion. As little as 4 mL has caused blindness through retinal damage. The transformation is illustrated below. CH 3 OH– alcohol dehydrogenase → HCHO Methanol is present in paint thinners and removers, windshield washer fluids, and fuels for small engines. It is also present in pineapple, where the levels may exceed the recommended limit of 2 ppm. Outbreaks of poisoning have occurred as a result of deliberate adulteration of wine. Home-distilled liquor has also caused poisonings, and “skid road” alcoholics may consume substances containing methanol as a substitute for ethanol. Initial symptoms are those of ethanol intoxication. A fairly long latency period may occur (6 to 30 hr), followed by acidosis; delirium; coma; visual disturbances, which may or may not progress to permanent blindness; cardiac disturbances; and death. Treatment consists of administering activated charcoal by mouth, ethanol (orally or i.v.) as a competitive substrate for alcohol dehydrogenase, and hemodialysis to remove methanol, formaldehyde, and formic acid (which causes acidosis). A fatal dose is 60 to 250 mL. An experimental approach to treatment involves the administration of inhibitors of alcohol dehydrogenase, such as 4-methylpyrazole. Isopropyl alcohol is found in rubbing alcohols, after-shave lotions, and window-cleaning fluids and is a widely used industrial solvent. It is oxidized to acetone and causes acetonemia but not acidosis. Its toxicity lies between that of ethanol and methanol, being about twice as toxic as ethanol, with coma and respiratory arrest resulting from CNS depression. Higher alcohols are generally less toxic. N -butanol vapors can produce eye irritation (conjunctivitis, keratitis) and inhalation may cause pulmo- nary edema. Acetone (C 3 H 6 O), although a ketone rather than an alcohol, produces similar toxic symptoms to those of ethanol and the treatment is the same. Acetone, like the aliphatic hydrocarbons, dissolves lipids from the skin and can be extremely damaging to the cornea by virtue of defatting the epithe- lial cells. Note: The hepatotoxicity of the halogenated hydrocarbons can be potentiated by numerous alcohols, including ethanol, methanol, and isopropyl alcohol, and acetone. The mechanism is unclear. Glycols and glycol ethers Ethylene glycol is present in antifreeze. An oral dose of 100 mL can be fatal for an adult. Early signs and symptoms resemble ethanol poisoning. After 24 hr, there may be pulmonary edema and myocardial depression; and after 48 hr, renal tubular necrosis and renal failure. Hypoglycemia and hypocal- cemia may occur. Treatment is as for methanol. ©2001 CRC Press LLC The toxicity of ethylene glycol is due to its metabolites. It is metabolized by alcohol dehydrogenase, which is why ethanol is given orally or i.v., as it is for methanol poisoning. When hemodialysis is used in conjunction with i.v. ethanol, ethanol is often added to the dialyzer fluid to maintain blood ethanol levels. Otherwise, the ethanol would be dialyzed because of the concentration gradient. One metabolite of ethylene glycol is oxalate, which chelates calcium (hence the hypocalcemia; see also Chapter 11) and which precipitates as calcium oxalate crystals in the kidney, causing tubular necro- sis. Other metabolites are aldehyde, glycolate, and lactate, which cause aci- dosis. A simplified scheme for the metabolism of ethylene glycol is shown in Figure 27. Propylene glycol is fairly nontoxic and it is used in lotions and as a vehicle for injectable drugs. Too rapid injection may cause cardiac depression. A subgroup of this class of compounds is the glycol ethers. Monomethyl and monoethyl ethylene glycol are used extensively in industry, being present in latex paints and as solvents in the manufacture of lacquers, var- nishes, and dyes. There is some evidence that they are reproductive toxins, causing teratogenesis in experimental animals. They are not well-absorbed orally, but transdermal absorption and inhalation are the important portals of entry. Human toxicity has not been well established, but there have been reports of kidney damage and bone marrow depression. Precautions are taken to limit industrial exposure of women. Aromatic hydrocarbons Benzene is one of the simplest and most toxic of these cyclic, special hydro- carbons. It is highly volatile and exposure in the workplace is primarily by inhalation. Benzene is unique in this group because of its bone marrow toxicity. Chronic exposure causes a progressive reduction in all formed ele- ments of the blood, including red cells, white cells, and platelets. Aplastic anemia, resulting from almost complete destruction of the marrow, may occur and the mortality rate is high, the only treatment being bone marrow transplantation. Bone marrow depression is dose-time dependent. Leukemia can also develop. Several reports have noted a higher than normal incidence of acute myelogenous leukemia in workers exposed to benzene. Although Figure 27 The conversion of ethylene glycol to calcium oxalate. ©2001 CRC Press LLC leukemia has not been demonstrated in animals exposed to benzene, solid tumors have been observed. Chromosomal abnormalities have been seen in animals exposed to ben- zene. The toxic agent may be a metabolite of benzene because animal studies have shown that toluene, which competes with benzene in its metabolic pathway, reduces its toxicity. A number of metabolites have been identified, including phenol. Alkylbenzenes are a group of related compounds consisting of the aro- matic ring with one or more aliphatic side chains. As a group, they lack the serious toxic effects of benzene because they are detoxified to metabolites with low toxicity, including hippuric acids, which are readily excreted by the kidney. They are, however, potent CNS depressants, acting like general anesthetics. No mutagenic properties have been demonstrated. The group includes toluene (1-methylbenzene) and the xylenes (1,2-, 1,3-, and 1,4-dimethylbenzene), as well as ethylbenzene and cumene (isopropylbenzene). Dinitrobenzene is a related substance that is used extensively in the manufacture of plastics, dyes, pigments, explosives, and insecticides, and in many other processes. The opportunity for an industrial exposure to toxic levels is thus fairly high. Meta, para, and ortho forms exist, all are crystals in the pure form, and all volatilize with steam and are soluble in boiling water and organic solvents. They are absorbed across the skin and promote the formation of methemoglobin (MetHb), in which the normal ferrous (Fe 2+ ) iron is converted (oxidized) to ferric (Fe 3+ ) iron. Methemoglobin binds irre- versibly to O 2 and reduces the oxygen-carrying capacity of the red blood cells. If MetHb exceeds 1% of total hemoglobin, mild hypoxia results. If it exceeds 15%, a severe condition known as cyanosis-anemia syndrome results. Dinitrobenzene is the second most common industrial cause of meth- emoglobinemia. The chemical structures of some of the aromatic hydrocar- bons are shown in Figure 28. Solvent-related cancer in the workplace Benzene As noted above, benzene is capable of causing leukemia. The first case of “benzene leukemia” was observed in 1928 in a worker who was so heavily exposed that others could not work in the same environment without becom- ing acutely ill, which probably saved them from a similar fate. By 1980, about 200 cases of benzene-related leukemia were reported. In Italy, which banned it in 1963, workers in the shoemaking and rotogravure industries were esti- mated to have a risk of leukemia 20 times that of the general population. The latency period may be 15 years or more. In Japan, studies of the survivors of Hiroshima and Nagasaki revealed that the risk of leukemia was increased 2.5 times in those who had worked in jobs involving benzene exposure. In the U.S., benzene was used extensively in the rubber industry until it was ©2001 CRC Press LLC banned. Overall, workers in this industry had a three-fold increase, and those with high exposures a five-fold increase, in their risk of leukemia. Bis(chloromethyl) ether (BCME) BCME is a potent alkylating agent and carcinogen used in a variety of industrial syntheses. An American study conducted by NIOSH (U.S. National Institute of Occupational Safety and Health) of 136 men exposed to high levels of BCME indicated a 10 times risk of lung cancer. Exposures averaged 5 years or more, and cancer rates were highest in those exposed for 10 years or more. Sputum cytology tests indicated a 34% incidence of abnormal lung cells in exposed worker vs. 11% in those not exposed. A much larger study involving 1800 workers in New York found a 2.5 times increase in risk, and in a Philadelphia chemical plant, heavily exposed workers had an 8 times increased risk. The discovery that fumes of HCl and formaldehyde could react spontaneously to form BCME led to regulations prohibiting the use of these agents in the same area without special ventilation. Dimethylformamide (DMF) and glycol ethers These agents are widely used in the tanning industry for finishing hides. There have been three clusters of testicular cancer identified in this popula- tion of workers. Three cases were identified in a tannery in Fulton County, Figure 28 Chemical structures of some aromatic hydrocarbon solvents. CH 3 CH 2 CH 3 CH ( CH 3 ) 2 CUMENE BENZENE TOLUENE XYLENE (ortho form) CH 3 CH 3 ETHYLBENZENE ©2001 CRC Press LLC New York between 1982 and 1984. Collection and analysis of air samples by NIOSH identified significant levels of the glycol ethers 2-ethoxyethanol, 2-ethoxyethyl acetate, and 2-butoxyethanol. The workers had previously been exposed to high levels of dimethylformamide (DMF) on the job, although none was detected at time of sampling. Two other clusters of testicular cancer in workers in the tanning industry have been identified. DMF has been shown to be a testicular toxin in animal studies, but not a mutagen, and glycol ethers are known to be reproductive toxins in animals. At the present time, the precise cause of these tumors has not been identified. Ethylene oxide (CH 2 CH 2 O) Although it is not strictly speaking a solvent, it is appropriate to consider this chemical here. It exists as a sweetish, ether-like gas at room temperature and becomes a liquid at 12°C. It is used as an industrial chemical in the manufacture of plastics, as a fumigant in agriculture, and as a sterilizing agent for heat-sensitive materials in health care facilities. All of these uses relate to the fact that this chemical is highly reactive with other organic substances, including proteins, because it contains an epoxide. The structural formula is: It exhibits the same toxicity as other organic solvents including CNS depres- sion, local irritation including respiratory irritation, frostbite due to the rapid evaporation of the liquid, and multi-organ toxicity following chronic expo- sure. It is completely miscible with both organic solvents and water. When exposures are minimal, as they should be when safe handling practices are observed, ethylene oxide poses little risk. Poor safety procedures or acciden- tal exposure carry the risk of a toxic reaction. Populations at risk include workers in health care institutions, exterminators, fumigators, and chemical plant workers. The question of carcinogenicity of this agent remains unan- swered. It is highly suspect because of its structure (see Chapter 1 and Figure 4), and animal studies have shown clear evidence of increased incidences of cancers of the adrenal gland, spleen, kidney, skin, lung, stomach, and brain as well as mononuclear cell leukemias. However, a study of workers exposed to 5 to 10 ppm for an average of 10.7 years did not reveal any increased frequency of cancer. H | H–C | H–C | H O ©2001 CRC Press LLC Factors influencing the risk of a toxic reaction Virtually all of the factors (discussed in Chapter 1) that can influence the response of experimental animals to a toxic agent can also affect toxicity to humans. The risk of a toxic reaction is a function of the toxicity of the chemical and the duration of the exposure, hence the need to establish exposure limits such as the Short Term Exposure Limit (STEL). As noted above, toxicity may also be affected by the presence of other agents such as ethanol. N-hexane and benzene will enhance the nephrotoxicity of chlori- nated hydrocarbons. This may be especially important when exposure to mixed solvents occurs, as it often does. The uptake and distribution of a toxic agent will be influenced by its air/water (blood) partition coefficient and by its water (blood)/oil (fat) partition coefficient. Body depot fat may thus serve as a reservoir for highly lipid-soluble solvents, just as it does for some anesthetics (including sodium thiopental; see Chapter 1), and prolong their CNS-depressing effects. Age, the presence of hepatic disease, and the general state of health all influence individual risk. Non-occupational exposures to solvents Solvents are present in many household products, including cleaning agents, waxes and polishes, glues, paints, automotive products (cleaners, polishes, etc.), paint removers, thinners, and brush cleaners, even hair sprays and, of course, gasoline. Exposures may be accidental, usually involving skin contact or inhalation in an enclosed space or ingestion by small children, deliberate, as in the ingestion or inhalation of a substance in a suicide attempt, or as a consequence of substance abuse as in gasoline sniffing. A great tragedy of our time is the high incidence of gasoline sniffing, which has resulted in several deaths among native Canadian and American youths living on Indian reserves. Glue sniffing also is a form of substance abuse which can be practiced by adolescents in large cities and where access to other drugs of abuse is restricted. A somewhat unexpected source of exposure is products used in arts and crafts. These include adhesives, paints, lacquers, and cleaning solvents. Cig- arette smoke also contains volatile solvents, including benzene. Further reading Glenn, W., Ethylene oxide: another question mark, Occup. Health and Safety Can ., 5, 28–33, 1989. Klassen, C.D., Amdur, M.O., and Doull, J., Eds., Casarett and Doull’s Toxicology: The Basic Science of Poisons , 5th ed., McGraw-Hill, New York, 1996. Marquardt, H., Schafer, S.G., McClellan, R., and Welsch, F., Toxicology , Academic Press, New York, 1999. ©2001 CRC Press LLC Methemoglobinemia due to occupational exposure to dinitrobenzene, Morbid. Mortal. Wk. Rep ., 37, 353–355, 1988. Niesink, R.J.M., Hollinger, M.A., and de Vries, J., Eds., Toxicology: Principles and Applications , CRC Press, 1996. Testicular cancer in leather workers — Fulton County, New York, Morbid. Mortal. Wk. Rep ., 38, 105–114, 1989. Review questions For Questions 1 to 8, answer True of False. 1. Aliphatic solvents are straight or branched-chain carbon-hydrogen compounds. 2. Inhaling gasoline fumes can sensitize the heart to adrenaline. 3. Hexane is oxidized to a hepatotoxic metabolite. 4. Monomethyl ethylene glycol is less toxic acutely than ethylene glycol. 5. Propylene glycol is highly toxic. 6. Chloroform is hepatotoxic without being metabolized. 7. Ethylene oxide is liquid at room temperature. 8. Workers in the tanning industry may show an increased frequency of testicular cancer. For Questions 9 to 12, use the following code: Answer A if statements a, b, and c are correct. Answer B if statements a and c are correct. Answer C if statements b and d are correct. Answer D if statement d only is correct. Answer E if all statements (a, b, c, d) are correct. 9. Halogenated aliphatic solvents: a. Cause CNS depression. b. Are hepatotoxic. c. Are nephrotoxic. d. Never require biotransformation to exert their toxicity. 10. Methanol: a. Is converted to formaldehyde in the body. b. Can cause blindness. c. Poisoning is treated with ethanol. d. May be present in fairly high concentrations in pineapple. 11. Ethylene glycol: a. Is metabolized to a toxic substance or substances. b. Is toxic in the parent state. c. Is metabolized to oxalate, which may precipitate as calcium ox- alate in the renal tubules. d. Poisoning is not treated with alcohol. [...]... National Institute for Occupational Safety and Health (NIOSH) was solicited Q What analysis might next be called for? Q What steps might you recommend in the interim? Case studies 15 and 16 Cast study 15 A 52-year-old woman was hospitalized for routine hemodialysis for chronic kidney failure She became somnolent after dialysis and developed metabolic acidosis and shock within 12 hr She died 24 hr after... 16 Two children, 4 and 7 years of age, were admitted around 7: 00 p.m to a small rural hospital with an acute onset of marked somnolence, vomiting, and weakness They developed hematuria (blood in the urine) and were transferred to a nearby city hospital with a pediatric intensive care unit Urinalysis showed calcium oxalate crystals They were treated with intravenous fluid therapy and recovered uneventfully...12 Benzene: a Depresses the CNS b May cause anemia and reduced platelet count c Is carcinogenic in animals d May cause fatal aplastic anemia 13 Ethylene oxide: a Contains an epoxide bond b Is a suspected human carcinogen c Depresses the CNS d May cause multi-organ toxicity following long-term exposure Answers 1 2 3 4 5 6 7 8 9 10 11 12 13 True True True True False False False True A E... 12 13 True True True True False False False True A E B E E Case study 14 Five steam press operators in a rubber plant became ill with signs and symptoms including blue discoloration of the lips and nail beds, headache, nausea, chest pain, dizziness, confusion, and difficulty in concentrating One worker suffered a seizure Blood methemoglobin (MetHb) levels ranged from 3.8 to 41.2% (normal < 1%) The product... including the two who required hospitalization, were children under 10 years of age The most common symptoms were sleepiness, fatigue, dizziness, and unsteadiness when walking A common denominator in those who became ill appeared to be consumption of a non-carbonated beverage made from crystals with tap water taken from the firehouse A few individuals who had not consumed the beverage, but had drunk... calcium oxalate crystals mentioned in Case 16 provide a clue? Q What organ system was most affected in both cases? In both of these cases, there was a direct connection between the general water supply and chilled-water air conditioning systems Could this have been a factor in these illnesses? ©2001 CRC Press LLC . O O O CH 3 (CH 2 ) 4 CH 3 — oxidation CH 3 -C-(CH 2 ) 3 CH 3 — oxidation CH 3 -C-(CH 2 ) 3 -C-CH 3 n-HEXANE 2-HEXANONE HEXANE-2,5-DIONE ©2001 CRC Press LLC usually occur from a. complex mixtures having nitro- gen- and sulfur-containing elements (e.g., gasoline and other petroleum- based products). Industrially, the uses of solvents are many and varied. They are used in extraction. been demonstrated. The group includes toluene (1-methylbenzene) and the xylenes (1, 2-, 1, 3-, and 1,4-dimethylbenzene), as well as ethylbenzene and cumene (isopropylbenzene). Dinitrobenzene is