Chapter 24: Toxic Effects of Solvents

Organic Solvents

Organic solvents are frequently used to dissolve, dilute, or disperse materials that are insoluble in water.

Most organic solvents are refined from petroleum.

For organic solvents, the lipophilicity increases with increasing numbers of carbon and/or halogen atoms, while volatility decreases.

Classification of Solvents

Solvents are classified largely according to molecular structure or functional group. The main determinants of a solvent’s toxicity are:

• the number of carbon atoms

• the degree of saturation

• straight chain, branched chain, cyclic, aromatic

• the presence of functional groups

The toxicity of solvents within the same class can vary dramatically.

Most solvent exposures involve a mixture of chemicals, rather than a single compound.

The toxic effects of mixed solvents may be additive, solvents may also interact synergistically or antagonistically.

Adverse Health Effects of Solvents

The possibility of the adverse health effects from solvent exposure depends on several factors:

• toxicity of the solvent or its metabolites

• exposure rate (inhalation, ingestion, dermal)

• amount or rate of exposure

• duration of exposure

• individual susceptibility

• interaction with other chemicals

Exposure to Solvents

Household use of solvents and solvent-contaminated water may result in solvent intake from inhalation and dermal absorption as well as ingestion.

Occupational exposures occur during production, processing, storage, and transport activities. In many applications the evaporation of the solvent is intended (e.g., aerosol propellants, paint thinners, cleaners, and soil fumigants).

Environmental exposures to solvents in air and groundwater are frequent; however, concentrations are typically in the low parts per billion (ppb) range.

Exposure Through Lungs

The majority of systemic absorption of inhaled VOCs occurs in the alveoli, where gases equilibrate with blood.

In blood, more hydrophilic solvents dissolve better, while levels of lipophilic solvents in the blood and tissues (other than fat) increase only modestly.

Solvents can be removed by exhalation by the lungs during their first pass through the pulmonary circulation.

Pulmonary first-pass elimination is a process in which a fixed percentage of the chemical exits the pulmonary blood at each pass through the pulmonary circulation.

Exposure via GI Tract

Solvents are well absorbed from the GI tract.

Peak blood levels are observed within a few minutes of dosing fasted subjects, although the presence of fatty food in the GI tract can significantly delay absorption.

It is now usually assumed that % of an oral dose of most solvents is absorbed systemically.

Absorbed chemicals can be removed by first-pass elimination as blood passes through the liver.

Exposure Through Skin

Absorption of solvents through the skin can result in both local and systemic effects.

Skin contact with vapors and concentrated solutions of solvents is a common occurrence in the workplace.

Lipophilic solvents penetrate the stratum corneum by passive diffusion.

Trichloroethylene

Widely used solvent identified at over one-half of the nearly 1300 hazardous waste sites on the EPA’s National Priorities List.

• released into the atmosphere during degreasing operations.

• rapidly absorbed into the systemic circulation via oral and inhalation routes. There are many published studies of cancer incidence and mortality among TCE-exposed populations (the kidney, liver, lung, non-Hodgkin’s lymphoma)

The toxicities associated with TCE are thought to be mediated by metabolites rather than parent compound.

The majority of TCE undergoes oxidation in the liver by P450s, with a small proportion being conjugated with GSH by glutathione transferases

Methylene Chloride

Methylene chloride (dichloromethane, MC) - a widespread solvent in industrial processes, food preparation, degreasing agents, aerosol propellants, and agriculture.

Large numbers of people are exposed occupationally and at home.

MC escapes into the environment by evaporation.

Low boiling point (40C), high solubility in water (150 mM). The primary route of exposure to this solvent is inhalation.

Inhaled MC is extensively absorbed and reaches a near steady concentration in the blood of humans within 1-2 hours of continuous exposure.

Less than 5% of the absorbed dose is exhaled unchanged. Metabolism of MC in humans and rodents is believed to occur via three pathways:

• Cytochrome P450-catalyzed oxidation to carbon monoxide via formyl chloride, a reactive intermediate

• a glutathione transferase-mediated pathway

• carbon dioxide is formed via the oxidative pathway by reaction of formyl chloride with a nucleophile such as GSH

Methylene Chloride Metabolism

The GST pathway is a low affinity, high capacity pathway operative at the high exposure levels used in cancer bioassays.

The P450 pathway is a high-affinity, low-capacity pathway that predominates at MC concentrations present in occupational and environmental settings.

GSCH2Cl causes single-strand breaks in vivo and in vitro in DNA of mouse liver and lung. Formaldehyde–RNA adducts were found in human hepatocytes incubated with MC.

Chloroform

The primary use of chloroform is in the production of the refrigerant chlorodifluoromethane (Freon 22).

CHCl3 was among the first inhalation anesthetics, but it was replaced by safer compounds after about 1940.

CHCl3 is the most frequently found VOC in drinking water supplies in the US;

CHCl3 is a by-product of drinking water chlorination, levels are usually <25 ppb.

EPA classifies CHCl3 as a probable human carcinogen (group B2), meaning there is sufficient evidence for carcinogenicity in animals and inadequate or no evidence in humans.

Under certain conditions CHCl3 is hepatotoxic and nephrotoxic. These toxicities are potentiated by induction of P450s.

Metabolism of Chloroform

Both target organs metabolize CHCl3 to phosgene.

Phosgene, the electrophilic intermediate, is initially detoxified by covalently binding to cytosolic GSH.

Once GSH is depleted, phosgene can covalently bind hepatic and renal proteins and lipids.

Carbon Tetrachloride

CCl4 - previously widespread solvent used as cleaning agent, fire extinguisher, synthetic intermediate, grain fumigant, and human anthelmintic.

Its use has steadily declined since the 1970s, due to its hepatorenal toxicity, carcinogenicity, and contribution to atmospheric ozone depletion.

CCl4 appears to be ubiquitous in ambient air in the United States, and it is still found in groundwater from some wells and waste sites.

CCl4 is a classic hepatotoxin, but kidney injury is often more severe in humans.

Carbon Tetrachloride Metabolism

Cytochrome P450-dependent conversion of CCl4 to •CCl3 and then to CCl3OO• is bioactivation that initiates lipid peroxidation by abstracting a hydrogen atom from the polyunsaturated fatty acid of a phospholipid.

CCl4 -induced lipid peroxidation increases the permeability of the plasma membrane to calcium, leading to severe disturbances of the calcium homeostasis and necrotic cell death.

Benzene

• in the United States is commercially derived primarily from petroleum;

• has been utilized as a general purpose solvent, but it is now used principally in the synthesis of other chemicals;

• is present in gasoline at 1-2% by volume (antiknock properties).

Inhalation is the primary route of exposure. Gasoline vapor emission and auto exhaust are the key contributors to exposures of the general population.

Cigarette smoke is the major source of benzene in the home.

• Smokers exposure to benzene is about 6 -10 times greater than those of nonsmokers.

• Passive smoke can be a significant source of benzene exposure to nonsmokers.

Adverse Effects of Benzene

The most important adverse effect of benzene is hematopoietic toxicity.

Chronic exposure to benzene can lead to bone marrow damage, which affects blood cells formation.

High-level benzene exposures result in an increased risk of acute myelogenous leukemia (AML) in humans.

Metabolism of benzene occurs primarily in the liver, though metabolism in bone marrow is believed to play the key role in myelotoxicity.

Benzene Metabolism

The o- and p-benzoquinones are the ultimate toxic metabolites of benzene.

Toluene

• is present in paints, lacquers, thinners, cleaning agents, glues, and many other products.

• is used in the production of other chemicals.

• gasoline contains 5-7% toluene by weight; the largest source of atmospheric emissions and exposure of the general population.

Inhalation is the primary route of exposure, though skin contact occurs frequently.

Toluene is a favorite chemical of solvent abusers, who intentionally inhale high concentrations to achieve a euphoric effect.

Toluene Toxicity

The CNS is the primary target organ of toluene.

Toluene rapidly accumulates in and affects the brain, due to that organ’s high rate of blood perfusion and relatively high lipid content.

Manifestations of acute exposure range from slight dizziness and headache to unconsciousness, respiratory depression, and death.

Hepatic P450s catalyze metabolism of toluene primarily to benzyl alcohol and lesser amounts of cresols.

Benzyl alcohol is converted by ADH and aldehyde dehydrogenase (ALDH) to benzoic acid, which is primarily conjugated with glycine and eliminated in the urine as hippuric acid.

Solvent Abuse

• Inhalation of volatile substances to induce a psychoactive or mindaltering effect

• has become a major drug problem worldwide, particularly in disadvantaged populations and among adolescents

• participants repeatedly subject themselves to vapor concentrations high enough to produce effects that resemble alcohol intoxication.

Styrene

Styrene is primarily used in the manufacture of polystyrene items and in copolymers with acrylonitrile or 1,3-butadiene to produce synthetic rubber, latex, and reinforced plastics.

Exposures: the rubber industry; tobacco smoke, auto exhaust, and emissions from building materials.

Styrene is metabolized principally by P450 to styrene-7,8-oxide (SO). SO can bind covalently to proteins and nucleic acids. SO is detoxified by the actions of epoxide hydrolase and GST.

Automotive Gasoline

Automotive gasoline is a complex mixture of hundreds of hydrocarbons predominantly in the C4 to C12 range.

The number of people exposed in the manufacture, distribution, and use of gasoline make characterization of its acute and chronic toxicities important.

Generalizations regarding gasoline toxicity must be made with care, because its composition varies with the crude oil from which it is refined, the refining process, and the use of specific additives.

Concern about gasoline exposure is fueled in part by the toxicities of certain components, some of which are classified by EPA as known or probable human carcinogens (e.g., benzene and 1,3-butadiene).

Ethanol

Many humans experience greater exposure to ethanol (ethyl alcohol) than to any other solvent.

Ethyl alcohol used as an additive in gasoline, as a solvent in industry, in many household products, and in pharmaceuticals, it is also heavily consumed in alcoholic beverages.

Ethanol is distributed in body water and to some degree in adipose tissue.

Alcohol is eliminated by urinary excretion, exhalation, and metabolism at the rate of 16 mg/100 mL of blood per hour.

Ethanol Metabolism

Ethanol is metabolized to acetaldehyde by three enzymes:

1. The major pathway involves ADH-catalyzed oxidation to acetaldehyde.

2. A second enzyme, CYP2E1, is the principal isoform of the hepatic microsomal ethanol oxidizing system.

3. The third enzyme, catalase, utilizes H2O2. Little H2O2 available in hepatocytes to support the reaction, so catalase normally account for more than 10% of ethyl alcohol metabolism.

Differences in Responses to Ethanol

Gender differences in responses to ethanol are well recognized.

Women are more sensitive to alcohol, exhibit higher mortality than men, and display somewhat higher blood levels than men following ingestion of equivalent doses of ethanol. This phenomenon appears to be due in part to more extensive ADH-catalyzed metabolism of ethanol by the male gastric mucosa.

Fetal Alcohol Syndrome (FAS) is the most common, preventable cause of mental retardation.

Methanol

Methanol (wood alcohol) is primarily used as a starting material for the synthesis of chemicals such as formaldehyde, acetic acid, methacrylates, ethylene glycol, and methyl tertiary-butyl ether (MTBE).

It also functions as a denaturant for ethyl alcohol, rendering it unfit for consumption.

Exposure of the general population also occurs via the consumption of fruits, fruit juices, vegetables, and alcoholic beverages. Indirect exposure occurs via the hydrolysis of the artificial sweetener, aspartame.

Toxicity of Methanol

Serious CH3OH toxicity is most commonly associated with ingestion.

Acute methanol poisoning in humans is characterized by an asymptomatic latent period of 12–24 hours followed by acidosis, ocular toxicity, coma, and in extreme cases death.

Blindness and death have been reported with dosages as low as 0.1 mL/kg. Proposed mechanism of vision damage: formate inhibits mitochondrial enzyme, cytochrome c oxidase in electron transport chain, which is critical for the proper functioning of the retina, specifically the optic disk and optic nerve.

In cases of severe CH3OH poisoning, there is a direct correlation between the formic acid concentration and increased morbidity and mortality.

Treatment of Methanol Poisoning

Sodium bicarbonate is usually given i.v. to correct severe acidosis, and case reports suggest that it may enhance renal formate excretion.

Metabolic blockade is usually achieved with ethanol or 4-methylpyrazole (fomepizole), both acting as effective competitive inhibitors of ADH.

Folate or folinic acid (activated folate) therapy is also indicated to increase the efficiency of formate oxidation.

Hemodialysis is generally indicated when acidemia, high CH3OH concentrations, or visual symptoms are present, although there is conflicting data on whether it appreciably shortens the elimination half-life of formate.

Ethylene Glycol

Ethylene glycol (1,2-dihydroxyethane, EG) is a constituent of antifreeze, deicers, hydraulic fluids, drying agents, and inks, and is used to make plastics and polyester fibers.

Exposure: dermal, inhalation (spray), ingestion.

EG is quickly absorbed from the GI tract and is distributed throughout the total body water.

EG is metabolized by ADH to glycolaldehyde and on to glycolic acid (GA).

The rate-limiting step in the metabolism of EG is the conversion of GA to glyoxylic acid, which results in accumulation of GA in the blood.

Toxicity of Ethylene Glycol

The minimum acute lethal dose of EG in humans is estimated at ∼1.4 mL/kg, which equates to 100 mL for a 70-kg adult.

Acute poisoning entails three clinical stages after an asymptomatic period, during which EG is metabolized:

(1) a period of intoxication, the duration and degree depending on dose;

(2) the cardiopulmonary stage 12–24 hours after exposure, characterized by rapid pulse and rapid breathing;

(3) the renal toxicity stage 24–72 hours post-exposure. Metabolic acidosis can develop during stages 2 and 3.

Treatment for Ethylene Glycol Poisoning

In cases of severe EG poisoning, early diagnosis and aggressive therapeutic intervention are essential for a favorable clinical outcome.

Treatment of EG poisoning involves three primary goals:

(1) correction of the patient’s metabolic acidosis;

(2) inhibition of EG metabolism to its toxic metabolites;

(3) removal of EG and its toxic metabolites by hemodialysis.

Ethanol and 4-methylpyrazole (fomepizole) are frequently given as antidotes for EG poisoning and can prevent renal injury if given early in the course of intoxication.

Diethylene Glycol

Diethylene glycol (DEG) is similar in physicochemical properties to EG, but has a higher boiling point, viscosity, and specific gravity.

DEG serves as a chemical intermediate in the production of polyester resins and polyurethanes, and as a solvent for shellacs and printing ink.

It is hygroscopic, which leads to applications as a drying agent for natural and industrial gases, a humectant for cork and paper, and an additive in cosmetics.

The median lethal dose of DEG was estimated at 1.34 mL/kg.

DEG’s use as an excipient in a liquid sulfanilamide preparation resulted in 105 deaths in the United States in 1937.